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Cutaneous photosensitivity with a likely genetic cause v3.20 DNA2 Ida Ertmanska changed review comment from: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with early-onset poikiloderma being a consistent feature. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with cutaneous photosensitivity and bullae being consistent features. Hence, this gene can be promoted to Green at the next update.
Cutaneous photosensitivity with a likely genetic cause v3.20 DNA2 Ida Ertmanska Classified gene: DNA2 as Amber List (moderate evidence)
Cutaneous photosensitivity with a likely genetic cause v3.20 DNA2 Ida Ertmanska Added comment: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with early-onset poikiloderma being a consistent feature. Hence, this gene can be promoted to Green at the next update.
Cutaneous photosensitivity with a likely genetic cause v3.20 DNA2 Ida Ertmanska Gene: dna2 has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v5.15 DNA2 Ida Ertmanska Classified gene: DNA2 as Amber List (moderate evidence)
Pigmentary skin disorders v5.15 DNA2 Ida Ertmanska Added comment: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with early-onset poikiloderma being a consistent feature. Hence, this gene can be promoted to Green at the next update.
Pigmentary skin disorders v5.15 DNA2 Ida Ertmanska Gene: dna2 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v8.15 DNA2 Ida Ertmanska Classified gene: DNA2 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v8.15 DNA2 Ida Ertmanska Added comment: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with congenital bilateral cataracts being a consistent feature. Hence, this gene can be promoted to Green at the next update.
Bilateral congenital or childhood onset cataracts v8.15 DNA2 Ida Ertmanska Gene: dna2 has been classified as Amber List (Moderate Evidence).
Monogenic short stature v2.9 DNA2 Ida Ertmanska changed review comment from: Comment on list classification: As noted for Seckel syndrome, Rothmund-Thomson syndrome cases are not in the scope of this panel, because the short stature is syndromic.; to: Comment on list classification: As noted for Seckel syndrome, Rothmund-Thomson syndrome cases are not in the scope of this panel, because the short stature is syndromic and includes microcephaly.
Monogenic short stature v2.9 DNA2 Ida Ertmanska commented on gene: DNA2: Comment on list classification: As noted for Seckel syndrome, Rothmund-Thomson syndrome cases are not in the scope of this panel, because the short stature is syndromic.
Monogenic short stature v2.9 DNA2 Ida Ertmanska reviewed gene: DNA2: Rating: RED; Mode of pathogenicity: None; Publications: 37055165, 40693833; Phenotypes: Rothmund-Thomson syndrome, type 4, OMIM:620819, Seckel syndrome 8, OMIM:615807, Rothmund-Thomson syndrome type 4, MONDO:0970950, Seckel syndrome 8, MONDO:0014350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.19 DNA2 Ida Ertmanska gene: DNA2 was added
gene: DNA2 was added to Cutaneous photosensitivity with a likely genetic cause. Sources: Literature
Q3_26_promote_green tags were added to gene: DNA2.
Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNA2 were set to 37055165; 40693833
Phenotypes for gene: DNA2 were set to Rothmund-Thomson syndrome, type 4, OMIM:620819; Seckel syndrome 8, OMIM:615807; Rothmund-Thomson syndrome type 4, MONDO:0970950; Seckel syndrome 8, MONDO:0014350
Review for gene: DNA2 was set to GREEN
Added comment: ROTHMUND-THOMSON SYNDROME:
PMID: 37055165 Di Lazzaro Filho et al., 2023
OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.

6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients.
All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant.

PMID: 40693833 Ay et al., 2025
Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo.

This gene is associated with AR Rothmund-Thomson syndrome, type 4, OMIM:620819 in OMIM as of 11th Sept 2026.
Sources: Literature
Pigmentary skin disorders v5.14 DNA2 Ida Ertmanska gene: DNA2 was added
gene: DNA2 was added to Pigmentary skin disorders. Sources: Literature
Q3_26_promote_green tags were added to gene: DNA2.
Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNA2 were set to 37055165; 40693833
Phenotypes for gene: DNA2 were set to Rothmund-Thomson syndrome, type 4, OMIM:620819; Seckel syndrome 8, OMIM:615807; Rothmund-Thomson syndrome type 4, MONDO:0970950; Seckel syndrome 8, MONDO:0014350
Review for gene: DNA2 was set to GREEN
Added comment: ROTHMUND-THOMSON SYNDROME:
PMID: 37055165 Di Lazzaro Filho et al., 2023
OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.

6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients.
All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant.

PMID: 40693833 Ay et al., 2025
Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo.

This gene is associated with AR Rothmund-Thomson syndrome, type 4, OMIM:620819 in OMIM as of 11th Sept 2026.
Sources: Literature
Bilateral congenital or childhood onset cataracts v8.14 DNA2 Ida Ertmanska gene: DNA2 was added
gene: DNA2 was added to Bilateral congenital or childhood onset cataracts. Sources: Literature
Q3_26_promote_green tags were added to gene: DNA2.
Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNA2 were set to 37055165; 40693833
Phenotypes for gene: DNA2 were set to Rothmund-Thomson syndrome, type 4, OMIM:620819; Seckel syndrome 8, OMIM:615807; Rothmund-Thomson syndrome type 4, MONDO:0970950; Seckel syndrome 8, MONDO:0014350
Review for gene: DNA2 was set to GREEN
Added comment: ROTHMUND-THOMSON SYNDROME:
PMID: 37055165 Di Lazzaro Filho et al., 2023
OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.

6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients.
All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant.

PMID: 40693833 Ay et al., 2025
Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo.

This gene is associated with AR Rothmund-Thomson syndrome, type 4, OMIM:620819 in OMIM as of 11th Sept 2026.
Sources: Literature
Severe microcephaly v9.28 DNA2 Ida Ertmanska changed review comment from: ROTHMUND-THOMSON SYNDROME:
PMID: 37055165 Di Lazzaro Filho et al., 2023
OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.

6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients.
All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant.

PMID: 40693833 Ay et al., 2025
Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo.; to: ROTHMUND-THOMSON SYNDROME:
PMID: 37055165 Di Lazzaro Filho et al., 2023
OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.

6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients.
All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant.

PMID: 40693833 Ay et al., 2025
Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo.

This gene is associated with AR Rothmund-Thomson syndrome, type 4, OMIM:620819 in OMIM as of 11th Sept 2026.
Severe microcephaly v9.28 DNA2 Ida Ertmanska edited their review of gene: DNA2: Changed publications to: 37055165, 40693833
Severe microcephaly v9.28 DNA2 Ida Ertmanska changed review comment from: PMID: 37055165 Di Lazzaro Filho et al., 2023
Summary from OMIM 620819: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.; to: ROTHMUND-THOMSON SYNDROME:
PMID: 37055165 Di Lazzaro Filho et al., 2023
OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.

6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients.
All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant.

PMID: 40693833 Ay et al., 2025
Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo.
Severe microcephaly v9.28 DNA2 Ida Ertmanska changed review comment from: PMID: 37055165 Di Lazzaro Filho et al., 2023; to: PMID: 37055165 Di Lazzaro Filho et al., 2023
Summary from OMIM 620819: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.
Severe microcephaly v9.28 DNA2 Ida Ertmanska reviewed gene: DNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37055165; Phenotypes: Rothmund-Thomson syndrome, type 4, OMIM:620819, Seckel syndrome 8, OMIM:615807, Rothmund-Thomson syndrome type 4, MONDO:0970950, Seckel syndrome 8, MONDO:0014350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from three pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). This variant has been described across a number of CARASAL cohorts from varying backgrounds, though most patients described to-date are of European origin.

Hervé et al., 2012 (PMID 23175731): Identified a chromosome 20q13 region linked to a leukoencephalopathy phenotype in two French sisters. A later publication reported that this family was subsequently confirmed to carry the recurrent CTSA p.Arg325Cys variant (personal communication with the authors; 2026 report).

Bugiani et al., 2016 (PMID 27664989): First description of CARASAL in two Dutch kindreds. Haplotype analysis revealed a shared region of 1,145 kb on chromosome 20q13 suggesting a common ancestral origin, and the c.973C>T p.(Arg325Cys) variant (identified via exome sequencing) segregated with disease. The authors proposed that the introduced cysteine residue may alter protein folding, although SDS-PAGE experiments did not support this. Based on increased cathepsin A precursor protein, astrocytic endothelin-1 (ET-1) accumulation, increased premyelinating oligodendrocyte progenitors, and reduced myelin basic protein in patient white matter, they proposed that impaired ET-1 degradation contributes to vasculopathy and defective oligodendrocyte maturation. This mechanism is inferential and has not been experimentally validated.

Hwang et al., 2017 (PMID 28702507): Reported an additional British patient with CARASAL heterozygous for CTSA c.973C>T p(Arg325Cys). Analysis of the informative marker D20S838 suggested a common genetic ancestry with the previously reported Dutch families.

Budhdeo et al., 2022 (PMID 35904593): Described two further affected individuals, one of Chinese ancestry and one Brazilian individual of Italian origin, in who underwent exome sequencing and targeted Sanger sequencing, respectively. These cases expanded the ethnic distribution of CARASAL beyond the previously reported Dutch, British, and French families. Haplotype data were not available.

Cerfontaine et al., 2026 (PMID 41908989): Reported 21 affected individuals (including 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys), 4 affected obligate carriers) a from three Dutch pedigrees, including some overlap with the original 2016 Bugiani discovery cohort. The recurrent CTSA p.Arg325Cys variant was described as a Dutch founder variant and segregated with disease across multiple large pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI.

Yoon et al., 2023 (case report, accessed at:https://www.jns-journal.com/article/S0022-510X(23)01466-1/fulltext): Reported a Korean patient presenting with cognitive decline and leukodystrophy on brain imaging. Sequencing of a lysosomal disease panel identified heterozygous CTSA c.973C>T (p.Arg325Cys).

Population data:CTSA c.973C>T (p.Arg325Cys) is present in gnomAD v4 in one heterozygous individual (European non-Finnish ancestry), with no homozygotes observed (overall allele frequency 6.2 × 10^-7).
In silico data: AlphaMissense predicts the variant to be likely benign.

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Despite lacking functional evidence supporting variant pathogenicity and a yet-to-be determined disease mechanism, segregation and enrichment in relevant disease cohorts is convincing across multiple ethnic backgrounds. Thus a green rating is reiterated, with monoallelic inheritance.
Skeletal dysplasia v10.8 HPGD Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: HPGD.
Tag Q3_26_MOI tag was added to gene: HPGD.
Skeletal dysplasia v10.8 HPGD Ida Ertmanska changed review comment from: Comment on mode of inheritance: Out of more than 70 Primary hypertrophic osteoarthropathy (PHO) patients reported in literature, only 3 of them habroured monoallelic HPGD variants and were reported to have a mild phenotype. Some het carrier family members in recessive pedigrees presented with mild digital clubbing. Based on available evidence, the heterozygous cases are not in scope of the Skeletal dysplasia panel, and the mode of inheritance should be changed to BIALLELIC only.; to: Comment on mode of inheritance: Out of more than 70 Primary hypertrophic osteoarthropathy (PHO) patients reported in literature, only 3 of them habroured monoallelic HPGD variants and only direct HPGD/SLCO2A1 Sanger sequencing was used in these studies. Some het carrier family members in recessive pedigrees presented with mild digital clubbing - not in scope of this panel. Based on available literature, the evidence for a dominant association is limited and the mode of inheritance should be changed to BIALLELIC only. An expert_review tag was added to ensure GMS agreement regarding this change.
Skeletal dysplasia v10.8 HPGD Ida Ertmanska changed review comment from: PMID: 35813463 Lu et al., 2022
Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia).
Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants.

PMID: 26135126 Yuan et al., 2015
Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only.
Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing.
Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4.

PMID: 18500342 Uppal et al., 2008
Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. Only HPGD was sequenced, using PCR amplification.

HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.; to: PMID: 35813463 Lu et al., 2022
Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. All patients were negative for SLCO2A1 mutations.
The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia).
Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants.

PMID: 26135126 Yuan et al., 2015
Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only.
Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing. They were negative for SLCO2A1 mutations.
Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4.

PMID: 18500342 Uppal et al., 2008
Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. Only HPGD was sequenced, using PCR amplification.

HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.
Skeletal dysplasia v10.8 HPGD Ida Ertmanska changed review comment from: PMID: 35813463 Lu et al., 2022
Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia).
Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants.

PMID: 26135126 Yuan et al., 2015
Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only.
Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing.
Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4.

PMID: 18500342 Uppal et al., 2008
Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants.

HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.; to: PMID: 35813463 Lu et al., 2022
Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia).
Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants.

PMID: 26135126 Yuan et al., 2015
Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only.
Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing.
Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4.

PMID: 18500342 Uppal et al., 2008
Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. Only HPGD was sequenced, using PCR amplification.

HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.
Skeletal dysplasia v10.8 HPGD Ida Ertmanska changed review comment from: PMID: 35813463 Lu et al., 2022
Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia).
Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants.

PMID: 26135126 Yuan et al., 2015
Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H).
Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4.
Variant HPGD:c.488G>A, p.Arg163His has MAF = 0.00002673 (African population), no hmz.

PMID: 18500342 Uppal et al., 2008
Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants.

HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.; to: PMID: 35813463 Lu et al., 2022
Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia).
Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants.

PMID: 26135126 Yuan et al., 2015
Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only.
Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing.
Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4.

PMID: 18500342 Uppal et al., 2008
Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants.

HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.
Skeletal dysplasia v10.8 HPGD Ida Ertmanska commented on gene: HPGD: Comment on mode of inheritance: Out of more than 70 Primary hypertrophic osteoarthropathy (PHO) patients reported in literature, only 3 of them habroured monoallelic HPGD variants and were reported to have a mild phenotype. Some het carrier family members in recessive pedigrees presented with mild digital clubbing. Based on available evidence, the heterozygous cases are not in scope of the Skeletal dysplasia panel, and the mode of inheritance should be changed to BIALLELIC only.
Skeletal dysplasia v10.8 HPGD Ida Ertmanska changed review comment from: PMID: 35813463 Lu et al., 2022
Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia).
Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants.

PMID: 26135126 Yuan et al., 2015
Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H).
Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4.
Variant HPGD:c.488G>A, p.Arg163His has MAF = 0.00002673 (African population), no hmz.

PMID: 18500342 Uppal et al., 2008
Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants.

HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.; to: PMID: 35813463 Lu et al., 2022
Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia).
Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants.

PMID: 26135126 Yuan et al., 2015
Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H).
Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4.
Variant HPGD:c.488G>A, p.Arg163His has MAF = 0.00002673 (African population), no hmz.

PMID: 18500342 Uppal et al., 2008
Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants.

HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.
Skeletal dysplasia v10.8 HPGD Ida Ertmanska reviewed gene: HPGD: Rating: GREEN; Mode of pathogenicity: None; Publications: 18500342, 26135126, 35813463; Phenotypes: ?Digital clubbing, isolated congenital , OMIM:119900, Cranioosteoarthropathy, OMIM:259100, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, OMIM:259100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.81 SLC12A5 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: SLC12A5.
Tag Q3_26_MOI tag was added to gene: SLC12A5.
Early onset or syndromic epilepsy v9.81 SLC12A5 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. An expert_review rating was added to ensure agreement on this change.; to: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. An expert_review rating was added to ensure GMS agreement on this change.
Early onset or syndromic epilepsy v9.81 SLC12A5 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only.; to: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. An expert_review rating was added to ensure agreement on this change.
Early onset or syndromic epilepsy v9.81 SLC12A5 Ida Ertmanska commented on gene: SLC12A5: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only.
Early onset or syndromic epilepsy v9.81 SLC12A5 Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 24668262 Puskarjov et al., 2014
Study analyzed 378 (266 unrelated) patients with seizure disorders.
Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported).

PMID: 24928908 Kahle et al., 2014
Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article.
Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes.

PMID: 31104500 Till et al., 2019
Male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy. WES detected a het SLC12A5:c.1348G>A, p.Val450Ile variant. 15 hets reported in gnomAD v4. [Article mostly in Hungarian]

SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports:
PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5
PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H)
PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant); to: MONOALLELIC REPORTS:
PMID: 24668262 Puskarjov et al., 2014
Study analyzed 378 (266 unrelated) patients with seizure disorders.
Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported).

PMID: 24928908 Kahle et al., 2014
Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article.
Variant p.R1049C has 33 hets and MAF = 0.0001537 in gnomAD v4, no homozygotes.

PMID: 31104500 Till et al., 2019
Male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy. WES detected a het SLC12A5:c.1348G>A, p.Val450Ile variant. 15 hets reported in gnomAD v4. [Article mostly in Hungarian]

SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports:
PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5
PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H)
PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant)
Early onset or syndromic epilepsy v9.81 SLC12A5 Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 24668262 Puskarjov et al., 2014
Study analyzed 378 (266 unrelated) patients with seizure disorders.
Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported).

PMID: 24928908 Kahle et al., 2014
Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article.
Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes.

SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports:
PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5
PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H)
PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant); to: MONOALLELIC REPORTS:
PMID: 24668262 Puskarjov et al., 2014
Study analyzed 378 (266 unrelated) patients with seizure disorders.
Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported).

PMID: 24928908 Kahle et al., 2014
Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article.
Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes.

PMID: 31104500 Till et al., 2019
Male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy. WES detected a het SLC12A5:c.1348G>A, p.Val450Ile variant. 15 hets reported in gnomAD v4. [Article mostly in Hungarian]

SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports:
PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5
PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H)
PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant)
Early onset or syndromic epilepsy v9.81 SLC12A5 Ida Ertmanska edited their review of gene: SLC12A5: Changed publications to: 24668262, 24928908, 28477354, 38660387, 42033187
Early onset or syndromic epilepsy v9.81 SLC12A5 Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 24668262 Puskarjov et al., 2014
Study analyzed 378 (266 unrelated) patients with seizure disorders.
Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported).

PMID: 24928908 Kahle et al., 2014
Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article.
Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes.; to: MONOALLELIC REPORTS:
PMID: 24668262 Puskarjov et al., 2014
Study analyzed 378 (266 unrelated) patients with seizure disorders.
Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported).

PMID: 24928908 Kahle et al., 2014
Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article.
Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes.

SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports:
PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5
PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H)
PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant)
Retinal disorders v9.19 LRPAP1 Nicky Cronbach gene: LRPAP1 was added
gene: LRPAP1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: LRPAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRPAP1 were set to PMID: 23830514; 33951325; 31607522; 39444998
Phenotypes for gene: LRPAP1 were set to Non-syndromic high myopia; early-onset high myopia; pathological myopia
Penetrance for gene: LRPAP1 were set to Complete
Review for gene: LRPAP1 was set to GREEN
Added comment: Sources: Literature
Early onset or syndromic epilepsy v9.81 SLC12A5 Ida Ertmanska reviewed gene: SLC12A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24668262, 24928908; Phenotypes: {Epilepsy, idiopathic generalized, susceptibility to, 14}, OMIM:616685, Developmental and epileptic encephalopathy 34, OMIM:616645; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.81 SLC1A2 Ida Ertmanska Publications for gene: SLC1A2 were set to 27476654; 28777935; 23934111; 9180080; 28915517; 27445142
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska Tag Q3_26_expert_review was removed from gene: SLC1A2.
Tag Q3_26_MOI was removed from gene: SLC1A2.
Intellectual disability v11.29 SLC1A2 Ida Ertmanska commented on gene: SLC1A2: Comment on mode of inheritance: There are at least 16 individuals reported in literature with heterozygous missense varinats in SLC1A2 and a DEE. There are also 2 unrelated patients reported with biallelic SLC1A2 variants and syndromic early-onset epilepsy with normal intelligence / mild ID. Hence, the mode of inheritance should remain as MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown.
Intellectual disability v11.29 SLC1A2 Ida Ertmanska reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9180080, 28915517, 40174554; Phenotypes: Developmental and epileptic encephalopathy 41, OMIM:617105, developmental and epileptic encephalopathy, 41, MONDO:0014916; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous individuals reported in literature with heterozygous missense varinats in SLC1A2 and a DEE. There are also 2 unrelated patients reported with biallelic SLC1A2 variants and syndromic early-onset epilepsy with vision loss. A supportive mouse model showed that knockout slc1a2-/- mice develop severe epilepsy. Functional effects of the 2 recessive variants were assessed as LoF in HEK293T and COS-7 cell transfection experiments (PMID: 40174554). Hence, the mode of inheritance should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are at least 16 individuals reported in literature with heterozygous missense varinats in SLC1A2 and a DEE. There are also 2 unrelated patients reported with biallelic SLC1A2 variants and syndromic early-onset epilepsy with vision loss. A supportive mouse model showed that knockout slc1a2-/- mice develop severe epilepsy. Functional effects of the 2 recessive variants were assessed as LoF in HEK293T and COS-7 cell transfection experiments (PMID: 40174554). Hence, the mode of inheritance should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska commented on gene: SLC1A2: Comment on mode of inheritance: There are numerous individuals reported in literature with heterozygous missense varinats in SLC1A2 and a DEE. There are also 2 unrelated patients reported with biallelic SLC1A2 variants and syndromic early-onset epilepsy with vision loss. A supportive mouse model showed that knockout slc1a2-/- mice develop severe epilepsy. Functional effects of the 2 recessive variants were assessed as LoF in HEK293T and COS-7 cell transfection experiments (PMID: 40174554). Hence, the mode of inheritance should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska edited their review of gene: SLC1A2: Changed publications to: 9180080, 28915517, 40174554
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska changed review comment from: PMID: 40174554 Kovermann et al., 2025
Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517).
Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function.
1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants had neurodevelopmental impairment and epilepsy with seizure onset between 2 and 4 years of age, had normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. Both had severe vision loss, and one had bilateral hypoplasia of the optic nerves.

SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026.; to: PMID: 40174554 Kovermann et al., 2025
Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517).
Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function.
1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants had neurodevelopmental impairment and epilepsy with seizure onset between 2 and 4 years of age, had normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. Both had severe vision loss, and one had bilateral hypoplasia of the optic nerves.
In contrast, 2 individuals heterozygous for F249Sfs∗17 and A432D variants (also in the LoF category) had a more severe NDD phenotype without vision loss.

Functional: PMID: 9180080 Tanaka et al., 1997 - homozygous Slc1a2−/− mice have severe epilepsy with neurodegeneration resulting from reduced glial L-Glu uptake.

SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026.
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska changed review comment from: PMID: 40174554 Kovermann et al., 2025
Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517).
Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function.
1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants "either displayed normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. However, both had severe vision loss, and one had bilateral hypoplasia of the optic nerves."

SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026.; to: PMID: 40174554 Kovermann et al., 2025
Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517).
Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function.
1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants had neurodevelopmental impairment and epilepsy with seizure onset between 2 and 4 years of age, had normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. Both had severe vision loss, and one had bilateral hypoplasia of the optic nerves.

SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026.
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska changed review comment from: PMID: 40174554 Kovermann et al., 2025
Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517).
Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function.
1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants "either displayed normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. However, both had severe vision loss, and one had bilateral hypoplasia of the optic nerves."; to: PMID: 40174554 Kovermann et al., 2025
Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517).
Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function.
1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants "either displayed normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. However, both had severe vision loss, and one had bilateral hypoplasia of the optic nerves."

SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026.
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska changed review comment from: PMID: 40174554 Kovermann et al., 2025
Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517).
Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function.
1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study.; to: PMID: 40174554 Kovermann et al., 2025
Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517).
Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function.
1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants "either displayed normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. However, both had severe vision loss, and one had bilateral hypoplasia of the optic nerves."
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28915517, 40174554; Phenotypes: Developmental and epileptic encephalopathy 41, OMIM:617105, developmental and epileptic encephalopathy, 41, MONDO:0014916; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.80 SLC1A2 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: SLC1A2.
Tag Q3_26_MOI tag was added to gene: SLC1A2.
Early onset or syndromic epilepsy v9.80 CLCN3 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association.; to: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion.
Intellectual disability v11.29 CLCN3 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association.; to: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion.
Fetal anomalies v8.7 CLCN3 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association.; to: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion.
Early onset or syndromic epilepsy v9.80 CLCN3 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CLCN3.
Tag Q3_26_MOI tag was added to gene: CLCN3.
Intellectual disability v11.29 CLCN3 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CLCN3.
Tag Q3_26_MOI tag was added to gene: CLCN3.
Early onset or syndromic epilepsy v9.80 CLCN3 Ida Ertmanska reviewed gene: CLCN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34186028; Phenotypes: ?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517, Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v11.29 CLCN3 Ida Ertmanska reviewed gene: CLCN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34186028; Phenotypes: ?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517, Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v8.7 CLCN3 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CLCN3.
Tag Q3_26_MOI tag was added to gene: CLCN3.
Fetal anomalies v8.7 CLCN3 Ida Ertmanska reviewed gene: CLCN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34186028; Phenotypes: ?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517, Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.80 STXBP1 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: STXBP1.
Tag Q3_26_MOI tag was added to gene: STXBP1.
Intellectual disability v11.29 STXBP1 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: STXBP1.
Tag Q3_26_MOI tag was added to gene: STXBP1.
Early onset or syndromic epilepsy v9.80 STXBP1 Ida Ertmanska Phenotypes for gene: STXBP1 were changed from Developmental and epileptic encephalopathy 4, OMIM:612164 to Developmental and epileptic encephalopathy 4, OMIM:612164; developmental and epileptic encephalopathy, 4, MONDO:0012812
Intellectual disability v11.29 STXBP1 Ida Ertmanska reviewed gene: STXBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31855252; Phenotypes: Developmental and epileptic encephalopathy 4, OMIM:612164, developmental and epileptic encephalopathy, 4, MONDO:0012812; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.79 STXBP1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 reported pedigree where individuals with Lennox-Gastaut syndrome harboured biallelic STXBP1 variants. All other reported individuals have monoallelic variants. Hence, there is not enough evidence for a BIALLELIC association, and the MOI should be reverted to MONOALLELIC only.; to: Comment on mode of inheritance: To date, there is only 1 reported pedigree where individuals with Lennox-Gastaut syndrome harboured biallelic STXBP1 variants. All other reported individuals have monoallelic variants. Hence, there is not enough evidence for a BIALLELIC association, and the MOI should be reverted to MONOALLELIC only. An expert-review tag was added to ensure GMS agreement on this demotion.
Early onset or syndromic epilepsy v9.79 STXBP1 Ida Ertmanska reviewed gene: STXBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31855252; Phenotypes: Developmental and epileptic encephalopathy 4, OMIM:612164, developmental and epileptic encephalopathy, 4, MONDO:0012812; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v11.29 NUS1 Ida Ertmanska Tag Q3_26_demote_amber was removed from gene: NUS1.
Tag Q3_26_MOI tag was added to gene: NUS1.
Early onset or syndromic epilepsy v9.79 NUS1 Ida Ertmanska Tag Q3_26_demote_amber was removed from gene: NUS1.
Tag Q3_26_MOI tag was added to gene: NUS1.
Early onset or syndromic epilepsy v9.79 NUS1 Ida Ertmanska Phenotypes for gene: NUS1 were changed from Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082 to ?Congenital disorder of glycosylation, type 1aa, OMIM:617082; Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831
Intellectual disability v11.29 NUS1 Ida Ertmanska Phenotypes for gene: NUS1 were changed from Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082 to ?Congenital disorder of glycosylation, type 1aa, OMIM:617082; Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831
Intellectual disability v11.28 NUS1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC.; to: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC. As this is a proposed 'demotion', an expert-review tag was also added.
Early onset or syndromic epilepsy v9.78 NUS1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC.; to: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC. As this is a proposed 'demotion', an expert-review tag was also added.
Intellectual disability v11.28 NUS1 Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: NUS1.
Tag Q3_26_expert_review tag was added to gene: NUS1.
Early onset or syndromic epilepsy v9.78 NUS1 Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: NUS1.
Tag Q3_26_expert_review tag was added to gene: NUS1.
Early onset or syndromic epilepsy v9.78 NUS1 Ida Ertmanska reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25066056; Phenotypes: ?Congenital disorder of glycosylation, type 1aa, OMIM:617082, Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v11.28 NUS1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous NUS1 variant, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC.; to: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC.
Intellectual disability v11.28 NUS1 Ida Ertmanska reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25066056; Phenotypes: ?Congenital disorder of glycosylation, type 1aa, OMIM:617082, Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in IFIH1. Heterozygous gain-of-function variants are thought to result in Aicardi-Goutieres syndrome (autoimmune disorder), while putative LoF variants have been reported in patients with inborn errors of immunity and early-onset IBD. Many cases harbour relatively common hypomorphic variants, which slightly impair MDA5 activity and increase susceptibility to infections with incomplete penetrance. True recessive cases are relatively rare, with only 6 individuals reported with biallelic rare variants in IFIH1 (PMIDs: 29018476; 34185153). Nonetheless, MOI should remain BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.; to: Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in IFIH1. Heterozygous gain-of-function variants are thought to result in Aicardi-Goutieres syndrome (autoimmune disorder), while putative LoF variants have been reported in patients with inborn errors of immunity and early-onset IBD. Many cases harbour relatively common hypomorphic variants, which slightly impair MDA5 activity and increase susceptibility to infections with incomplete penetrance. True recessive cases are relatively rare, with only 6 individuals reported with biallelic rare variants in IFIH1 (PMIDs: 29018476; 34185153). Based on available evidence, MOI should remain BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska commented on gene: IFIH1: Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in IFIH1. Heterozygous gain-of-function variants are thought to result in Aicardi-Goutieres syndrome (autoimmune disorder), while putative LoF variants have been reported in patients with inborn errors of immunity and early-onset IBD. Many cases harbour relatively common hypomorphic variants, which slightly impair MDA5 activity and increase susceptibility to infections with incomplete penetrance. True recessive cases are relatively rare, with only 6 individuals reported with biallelic rare variants in IFIH1 (PMIDs: 29018476; 34185153). Nonetheless, MOI should remain BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska edited their review of gene: IFIH1: Changed phenotypes to: Immunodeficiency 95, OMIM:619773, immunodeficiency 95, MONDO:0030692, Aicardi-Goutieres syndrome 7, OMIM:615846, Aicardi-Goutieres syndrome 7, MONDO:0014367
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska edited their review of gene: IFIH1: Changed publications to: 28606988, 28716935, 29018476, 34185153, 34726731, 38757311
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska changed review comment from: PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34185153 Cananzi et al., 2021
Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported.
Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis.

Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 29018476 Zaki et al. 2017
Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.

IFIH1 is associated with AD Aicardi-Goutieres syndrome 7, OMIM:615846, AD Singleton-Merten syndrome 1, OMIM:182250, and AR Immunodeficiency 95, OMIM:619773 (Accessed 9th Sept 2026).; to: PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34185153 Cananzi et al., 2021
Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported.
Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis.

Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 29018476 Zaki et al. 2017
Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.

IFIH1 is associated with AD Aicardi-Goutieres syndrome 7, OMIM:615846, AD Singleton-Merten syndrome 1, OMIM:182250, and AR Immunodeficiency 95, OMIM:619773 (Accessed 9th Sept 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska changed review comment from: PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34185153 Cananzi et al., 2021
Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported.
Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis.

Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 29018476 Zaki et al. 2017
Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.; to: PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34185153 Cananzi et al., 2021
Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported.
Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis.

Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 29018476 Zaki et al. 2017
Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.

IFIH1 is associated with AD Aicardi-Goutieres syndrome 7, OMIM:615846, AD Singleton-Merten syndrome 1, OMIM:182250, and AR Immunodeficiency 95, OMIM:619773 (Accessed 9th Sept 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska changed review comment from: PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34185153 Cananzi et al., 2021
Cohort of 42 Very Early Onset IBD probands. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported.
Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 29018476 Zaki et al. 2017
Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.; to: PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34185153 Cananzi et al., 2021
Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported.
Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis.

Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 29018476 Zaki et al. 2017
Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska edited their review of gene: IFIH1: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska edited their review of gene: IFIH1: Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska changed review comment from: PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.; to: PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34185153 Cananzi et al., 2021
Cohort of 42 Very Early Onset IBD probands. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported.
Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 29018476 Zaki et al. 2017
Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska changed review comment from: PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.; to: PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska edited their review of gene: IFIH1: Changed rating: RED; Changed publications to: 34726731, 28716935, 28606988; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 IFIH1 Ida Ertmanska reviewed gene: IFIH1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 95, OMIM:619773, immunodeficiency 95, MONDO:0030692; Mode of inheritance: None
Likely inborn error of metabolism v9.33 LBR Ida Ertmanska Phenotypes for gene: LBR were changed from ?Reynolds syndrome 613471; Greenberg skeletal dysplasia 215140; Pelger-Huet anomaly 169400; Pelger-Huet anomaly with mild skeletal anomalies 618019 to Pelger-Huet anomaly, OMIM:169400; Greenberg skeletal dysplasia, OMIM:215140; Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, OMIM:618019; ?Reynolds syndrome, OMIM:613471
Likely inborn error of metabolism v9.32 LBR Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: LBR.
Tag Q3_26_MOI tag was added to gene: LBR.
Likely inborn error of metabolism v9.32 LBR Ida Ertmanska changed review comment from: Comment on mode of inheritance: Pelger-Huet anomaly, seen in carriers of heterozygous LBR variants, does not usually cause any symptoms and thus it is considered a benign condition. Hence, the mode of inheritance should be changed to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. An expert_review tag has been added to ensure GMS agreement with this demotion.; to: Comment on mode of inheritance: Pelger-Huet anomaly, seen in numerous carriers of heterozygous LBR variants, does not usually cause any symptoms and thus it is considered a benign condition. There is also one patient reported with a het LBR variant and Reynolds syndrome. However, the variant is present in homozygous state in gnomAD, and its significance is hard to determine. Hence, the mode of inheritance should be changed to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. An expert_review tag has been added to ensure GMS agreement with this demotion.
Likely inborn error of metabolism v9.32 LBR Ida Ertmanska edited their review of gene: LBR: Changed publications to: 12118250, 19468205, 20522425
Likely inborn error of metabolism v9.32 LBR Ida Ertmanska changed review comment from: MONOALLELIC CASES
Reynolds syndrome:
PMID: 20522425 Gaudy-Marqueste et al., 2010
76-year-old Caucasian woman with Reynolds syndrome (primary biliary cholangitis and limited cutaneous systemic sclerosis). She was het for LBR c.1114C>T; p.Arg372Cys - AF in gnomAD is 0.0002441, with 2 homozygotes reported.

Pelger-Huet anomaly (PHA) is considered to be a benign disorder in most instances, as individuals with PHA are typically healthy. It is an inherited blood condition in which the nuclei of several types of white blood cells (neutrophils and eosinophils) have unusual shape and structure. See PMID: 12118250 Hoffmann et al., 2002.

LBR is associated with AR regressive spondylometaphyseal dysplasia (Moderate, 2023) and AR Greenberg dysplasia (Moderate, 2023) in ClinGen. LBR is linked to AR Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, AR Greenberg skeletal dysplasia, AD Pelger-Huet anomaly, and putatively linked to AD ?Reynolds syndrome in OMIM (accessed 9th Sept 2026).; to: MONOALLELIC CASES
Reynolds syndrome:
PMID: 20522425 Gaudy-Marqueste et al., 2010
76-year-old Caucasian woman with Reynolds syndrome (primary biliary cholangitis and limited cutaneous systemic sclerosis). She was het for LBR c.1114C>T; p.Arg372Cys - AF in gnomAD is 0.0002441, with 2 homozygotes reported.

Pelger-Huet anomaly (PHA) is considered to be a benign disorder in most instances, as individuals with PHA are typically healthy. It is an inherited blood condition in which the nuclei of several types of white blood cells (neutrophils and eosinophils) have unusual shape and structure. See PMID: 12118250 Hoffmann et al., 2002 and PMID: 19468205 Speeckaert et al., 2009.

LBR is associated with AR regressive spondylometaphyseal dysplasia (Moderate, 2023) and AR Greenberg dysplasia (Moderate, 2023) in ClinGen. LBR is linked to AR Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, AR Greenberg skeletal dysplasia, AD Pelger-Huet anomaly, and putatively linked to AD ?Reynolds syndrome in OMIM (accessed 9th Sept 2026).
Likely inborn error of metabolism v9.32 LBR Ida Ertmanska changed review comment from: MONOALLELIC CASES
Reynolds syndrome:
PMID: 20522425 Gaudy-Marqueste et al., 2010
76-year-old Caucasian woman with Reynolds syndrome (primary biliary cholangitis and limited cutaneous systemic sclerosis). She was het for LBR c.1114C>T; p.Arg372Cys - AF in gnomAD is 0.0002441, with 2 homozygotes reported.

Pelger-Huet anomaly (PHA) is considered to be a benign disorder in most instances, as individuals with PHA are typically healthy.
It is an inherited blood condition in which the nuclei of several types of white blood cells (neutrophils and eosinophils) have unusual shape and structure. PMID: 12118250 Hoffmann et al., 2002.

LBR is associated with AR regressive spondylometaphyseal dysplasia (Moderate, 2023) and AR Greenberg dysplasia (Moderate, 2023) in ClinGen. LBR is linked to AR Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, AR Greenberg skeletal dysplasia, AD Pelger-Huet anomaly, and putatively linked to AD ?Reynolds syndrome in OMIM (accessed 9th Sept 2026).; to: MONOALLELIC CASES
Reynolds syndrome:
PMID: 20522425 Gaudy-Marqueste et al., 2010
76-year-old Caucasian woman with Reynolds syndrome (primary biliary cholangitis and limited cutaneous systemic sclerosis). She was het for LBR c.1114C>T; p.Arg372Cys - AF in gnomAD is 0.0002441, with 2 homozygotes reported.

Pelger-Huet anomaly (PHA) is considered to be a benign disorder in most instances, as individuals with PHA are typically healthy. It is an inherited blood condition in which the nuclei of several types of white blood cells (neutrophils and eosinophils) have unusual shape and structure. See PMID: 12118250 Hoffmann et al., 2002.

LBR is associated with AR regressive spondylometaphyseal dysplasia (Moderate, 2023) and AR Greenberg dysplasia (Moderate, 2023) in ClinGen. LBR is linked to AR Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, AR Greenberg skeletal dysplasia, AD Pelger-Huet anomaly, and putatively linked to AD ?Reynolds syndrome in OMIM (accessed 9th Sept 2026).
Likely inborn error of metabolism v9.32 LBR Ida Ertmanska commented on gene: LBR: Comment on mode of inheritance: Pelger-Huet anomaly, seen in carriers of heterozygous LBR variants, does not usually cause any symptoms and thus it is considered a benign condition. Hence, the mode of inheritance should be changed to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. An expert_review tag has been added to ensure GMS agreement with this demotion.
Likely inborn error of metabolism v9.32 LBR Ida Ertmanska edited their review of gene: LBR: Changed publications to: 12118250, 20522425
Likely inborn error of metabolism v9.32 LBR Ida Ertmanska reviewed gene: LBR: Rating: GREEN; Mode of pathogenicity: None; Publications: 20522425; Phenotypes: Pelger-Huet anomaly, OMIM:169400, Greenberg skeletal dysplasia, OMIM:215140, Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, OMIM:618019, ?Reynolds syndrome, OMIM:613471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from two pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from three pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers, from two pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from two pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers, from two pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.
Ehlers Danlos syndrome with a likely monogenic cause v4.20 ATP6V1E1 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ATP6V1E1.
Ehlers Danlos syndrome with a likely monogenic cause v4.20 ATP6V1E1 Ida Ertmanska Tag Q3_26_promote_green was removed from gene: ATP6V1E1.
Ehlers Danlos syndrome with a likely monogenic cause v4.20 ATP6V1E1 Ida Ertmanska Classified gene: ATP6V1E1 as Amber List (moderate evidence)
Ehlers Danlos syndrome with a likely monogenic cause v4.20 ATP6V1E1 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated individuals reported in literature with biallelic ATP6V1E1 variants and syndromic cutis laxa, with variable features including congenital heart defects, hypotonia, aortic dilation, contractures, and more. Hence, this gene can be promoted to Green on Ehlers Danlos syndrome with a likely monogenic cause.
Ehlers Danlos syndrome with a likely monogenic cause v4.20 ATP6V1E1 Ida Ertmanska Gene: atp6v1e1 has been classified as Amber List (Moderate Evidence).
Ehlers Danlos syndrome with a likely monogenic cause v4.19 ATP6V1E1 Ida Ertmanska gene: ATP6V1E1 was added
gene: ATP6V1E1 was added to Ehlers Danlos syndrome with a likely monogenic cause. Sources: Literature
Q3_26_promote_green tags were added to gene: ATP6V1E1.
Mode of inheritance for gene: ATP6V1E1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP6V1E1 were set to 27023906; 28065471
Phenotypes for gene: ATP6V1E1 were set to Cutis laxa, autosomal recessive, type IIC, OMIM:617402; autosomal recessive cutis laxa type 2C, MONDO:0027462
Review for gene: ATP6V1E1 was set to GREEN
Added comment: PMID: 27023906 Alazami et al., 2016
Study of a cohort of 40 families with inherited connective tissue disorders.
Family 5 - Saudi brothers homozygous for ATP6V1E1:c.634C>T, p.Arg212Trp (2 alleles reported in gnomAD v4.1.1., no hom). Seq method: WES followed by WGS (ATP6V1E1 variant missed by WES due to poor coverage).
The sibs presented with cutis laxa, dysmorphic facial features, strabismus, congenital heart defects, nephrocalcinosis, midline cleft palate. Pregnancy was complicated by oligohydramnios and hydronephrosis. Parents are first cousins, unaffected.

PMID: 28065471 Van Damme et al., 2018
Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan).
Both families with ATP6V1E1 variants were consanguineous, and the probands were homozygous for a ATP6V1E1 variant each: c.383T>C, p.Leu128Pro in PI & c.634C>T, p.Arg212Trp in PII.
Variant p.Leu128Pro not found in gnomAD v4.1.1.
Patient phenotypes: cutis laxa 2/2, severe hypotonia 1 (1 not determined), cardiac abnormalities 2/2, aortic dilation 1/2, contractures 1/2; seizures and MRI abnormalities were not determined.
All parents reported to be unaffected.

This gene is associated with Cutis laxa, autosomal recessive, type IIC, OMIM:617402 in OMIM, and ATP6V1E1-related cutis laxa (biallelic_autosomal) in G2P with a Strong confidence level (resources accessed 9th Sept 2026).
Sources: Literature
Ehlers Danlos syndrome with a likely monogenic cause v4.18 ATP6V1A Ida Ertmanska Phenotypes for gene: ATP6V1A were changed from Cutis laxa, autosomal recessive, type IID, OMIM:617403 to Cutis laxa, autosomal recessive, type IID, OMIM:617403; autosomal recessive cutis laxa type 2D, MONDO:0027451
Early onset or syndromic epilepsy v9.78 ATP6V1A Ida Ertmanska commented on gene: ATP6V1A: Comment on mode of inheritance: There are more than 30 individuals reported in literature with heterozygous de novo missense variants in ATP6V1A and a Developmental and epileptic encephalopathy (including early onset seizures in at least 28 cases). There are also 6 probands reported with biallelic ATP6V1A variants, of which only 2 presented with seizures. Hence, the mode of inheritance should be changed to
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. As this is a demotion of the BIALLELIC MOI, an expert_review tag was also added.
Early onset or syndromic epilepsy v9.78 ATP6V1A Ida Ertmanska Phenotypes for gene: ATP6V1A were changed from Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403 to Developmental and epileptic encephalopathy 93, OMIM:618012; developmental and epileptic encephalopathy 93, MONDO:0020632
Early onset or syndromic epilepsy v9.77 ATP6V1A Ida Ertmanska edited their review of gene: ATP6V1A: Changed phenotypes to: Developmental and epileptic encephalopathy 93, OMIM:618012, developmental and epileptic encephalopathy 93, MONDO:0020632
Early onset or syndromic epilepsy v9.77 ATP6V1A Ida Ertmanska Publications for gene: ATP6V1A were set to 29668857; 28065471
Early onset or syndromic epilepsy v9.76 ATP6V1A Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: ATP6V1A.
Tag Q3_26_expert_review tag was added to gene: ATP6V1A.
Ehlers Danlos syndrome with a likely monogenic cause v4.17 ATP6V1A Ida Ertmanska edited their review of gene: ATP6V1A: Changed publications to: 28065471, 33320377, 40225911
Ehlers Danlos syndrome with a likely monogenic cause v4.17 ATP6V1A Ida Ertmanska changed review comment from: PMID: 33320377 Vogt et al., 2021
Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES.

Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*)

Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).; to: BIALLELIC CASES:
PMID: 33320377 Vogt et al., 2021
Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family.

Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*)

Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).

PMID: 28065471 Van Damme et al., 2017
Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys.
Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum).
All parents reported to be unaffected.

MONOALLELIC CASES:
PMID: 40225911 Ma et al., 2024
Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu).
Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient.

ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026).
Early onset or syndromic epilepsy v9.76 ATP6V1A Ida Ertmanska changed review comment from: BIALLELIC CASES:
PMID: 33320377 Vogt et al., 2021
Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family.

Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*)

Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).

PMID: 28065471 Van Damme et al., 2017
Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys.
Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum).

MONOALLELIC CASES:
PMID: 40225911 Ma et al., 2024
Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu).
Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient.

ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026).; to: BIALLELIC CASES:
PMID: 33320377 Vogt et al., 2021
Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family.

Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*)

Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).

PMID: 28065471 Van Damme et al., 2017
Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys.
Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum).
All parents reported to be unaffected.

MONOALLELIC CASES:
PMID: 40225911 Ma et al., 2024
Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu).
Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient.

ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026).
Early onset or syndromic epilepsy v9.76 ATP6V1A Ida Ertmanska edited their review of gene: ATP6V1A: Changed publications to: 28065471, 33320377, 40225911
Early onset or syndromic epilepsy v9.76 ATP6V1A Ida Ertmanska changed review comment from: PMID: 33320377 Vogt et al., 2021
Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family.

Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*)

Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).; to: BIALLELIC CASES:
PMID: 33320377 Vogt et al., 2021
Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family.

Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*)

Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).

PMID: 28065471 Van Damme et al., 2017
Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys.
Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum).

MONOALLELIC CASES:
PMID: 40225911 Ma et al., 2024
Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu).
Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient.

ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026).
Early onset or syndromic epilepsy v9.76 ATP6V1A Ida Ertmanska reviewed gene: ATP6V1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33320377; Phenotypes: Cutis laxa, autosomal recessive, type IID, OMIM:617403, autosomal recessive cutis laxa type 2D, MONDO:0027451; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ehlers Danlos syndrome with a likely monogenic cause v4.17 ATP6V1A Ida Ertmanska changed review comment from: PMID: 33320377 Vogt et al., 2021
Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES.

Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*)

Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).; to: PMID: 33320377 Vogt et al., 2021
Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES.

Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*)

Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).
Ehlers Danlos syndrome with a likely monogenic cause v4.17 ATP6V1A Ida Ertmanska reviewed gene: ATP6V1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33320377; Phenotypes: Cutis laxa, autosomal recessive, type IID, OMIM:617403, autosomal recessive cutis laxa type 2D, MONDO:0027451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593).

Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989)

In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.
Leukodystrophy, adult onset v7.9 CTSA Luke Stuart reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35904593, 41908989, 27664989; Phenotypes: Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394), cathepsin a-related arteriopathy-strokes-leukoencephalopathy (MONDO:0035551); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Proteinuric renal disease v6.18 APOE Ida Ertmanska commented on gene: APOE: Comment on mode of inheritance: There are numerous patients with proteinuria and glomerulopathy linked to APOE variants. However, most of these patients harbour monoallelic rare variants, together with a homozygous APOE2 risk allele. There seems to be only 1 case reported with biallelic rare APOE missense variants, inherited from unaffected parents (PMID: 35119017). Hence, the mode of inheritance should stay MONOALLELIC, until more evidence emerges.
Proteinuric renal disease v6.18 APOE Ida Ertmanska changed review comment from: PMID: 24570682 Kawanishi et al., 2013
Report of 3 likely Japanese cases of APOE homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 patients were homozygous for APOE p.Arg158Cys variant - NM_000041.4: c.526C>T, p.Arg176Cys - common variant, B/LB in ClinVar. Risk factor.
Case 1 - 66yo male, diagnosed with diabetes at 50 yrs, untreated; testing showed urinary abnormality of protein 3+ (urinary protein 2.07g/day) and occult blood 1+, serum creatinine level of 0.96 mg/dl; on renal biopsy, 1/11 glomeruli showed global sclerosis, and the other glomeruli showed massive foam cell infiltration in the glomerular capillaries and mildly expanded mesangium.
Case 2 - 58yo male with nephrotic syndrome; urinary protein 7.38 g/day, hypoalbuminemia (1.9 g/dl); he was treated for diabetes since the age of 50 years; renal biopsy revealed 5 of 22 glomeruli with global sclerosis; residual glomeruli showed massive foam cell infiltration in the glomerular capillaries and severely widened mesangium - foam cells stained positive for CD68.
Case 3 - 78yo male with nephrotic syndrome; medical history includes hypertension, hypothyroidism, and diabetes mellitus; urinary protein 2.5 g/day, red blood cells in urine (1–4/hpf). A kidney biopsy revealed 21 glomeruli, of which 2 were globally sclerotic. The glomeruli showed increased mesangial matrices and mild GBM thickening. Massive foam cells had infiltrated into the glomerular capillaries and mesangial region.

PMID: 29692990 Fukunaga et al., 2018
Report of a Japanese 20yo female with proteinuria (3+) and hematuria (3+); on renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change; diagnosed with membranous nephropathy. She was homozygous for APOE2 allele and heterozygous for APOE p.Ser197Cys rare variant - NM_000041.4: c.644C>G, p.Ser215Cys (not in gnomAD 4.1.1).

PMID: 31874799 Saito et al., 2020; to: PMID: 24570682 Kawanishi et al., 2013
Report of 3 likely Japanese cases of APOE homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 patients were homozygous for APOE p.Arg158Cys variant - NM_000041.4: c.526C>T, p.Arg176Cys - common variant, B/LB in ClinVar. Risk factor.
Case 1 - 66yo male, diagnosed with diabetes at 50 yrs, untreated; testing showed urinary abnormality of protein 3+ (urinary protein 2.07g/day) and occult blood 1+, serum creatinine level of 0.96 mg/dl; on renal biopsy, 1/11 glomeruli showed global sclerosis, and the other glomeruli showed massive foam cell infiltration in the glomerular capillaries and mildly expanded mesangium.

Case 2 - 58yo male with nephrotic syndrome; urinary protein 7.38 g/day, hypoalbuminemia (1.9 g/dl); he was treated for diabetes since the age of 50 years; renal biopsy revealed 5 of 22 glomeruli with global sclerosis; residual glomeruli showed massive foam cell infiltration in the glomerular capillaries and severely widened mesangium - foam cells stained positive for CD68.

Case 3 - 78yo male with nephrotic syndrome; medical history includes hypertension, hypothyroidism, and diabetes mellitus; urinary protein 2.5 g/day, red blood cells in urine (1–4/hpf). A kidney biopsy revealed 21 glomeruli, of which 2 were globally sclerotic. The glomeruli showed increased mesangial matrices and mild GBM thickening. Massive foam cells had infiltrated into the glomerular capillaries and mesangial region.

PMID: 29692990 Fukunaga et al., 2018
Report of a Japanese 20yo female with proteinuria (3+) and hematuria (3+); on renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change; diagnosed with membranous nephropathy. She was homozygous for APOE2 allele and heterozygous for APOE p.Ser197Cys rare variant - NM_000041.4: c.644C>G, p.Ser215Cys (not in gnomAD 4.1.1).

PMID: 35119017 Li et al., 2021
Report of a 28-year-old man who presented with severe proteinuria (4+), hyperlipidemia (serum total cholesterol, 7.09 mmol/L, low-density lipoprotein cholesterol [LDL-C], 6.39 mmol/L), edema of both legs, and normal serum albumin level; he was diagnosed with lipoprotein glomerulopathy. Renal biopsy revealed lipoprotein thrombi in the glomeruli. Immunofluorescence staining revealed APOE-positive deposits, particularly within the glomeruli. He was comp het for APOE variants: c.127C > T (p.Arg43Cys) & c.149G > A (p.Arg50His) - in trans, inherited from unaffected het parents. Both variants are rare in gnomAD, with no homozygotes reported.

PMID: 35950048 Koshino et al., 2022
Case report: 28-year-old Japanese man with mild proteinuria (+1) and hematuria, harbouring het APOE variant p.(Ser197Cys) and homozygous apoE2/2 risk allele. Kidney biopsy revealed mesangial proliferation, mesangial matrix expansion, and segmental spike lesion; EM showed massive deposits with various electron densities, the glomerular basement membrane (GBM) structure was partly degenerated by these deposits.
Proteinuric renal disease v6.18 APOE Ida Ertmanska changed review comment from: PMID: 24570682 Kawanishi et al., 2013
Report of 3 likely Japanese cases of APOE homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 patients were homozygous for APOE p.Arg158Cys variant - NM_000041.4: c.526C>T, p.Arg176Cys - common variant, B/LB in ClinVar. Risk factor.
Case 1 - 66yo male, diagnosed with diabetes at 50 yrs, untreated; testing showed urinary abnormality of protein 3+ (urinary protein 2.07g/day) and occult blood 1+, serum creatinine level of 0.96 mg/dl; on renal biopsy, 1/11 glomeruli showed global sclerosis, and the other glomeruli showed massive foam cell infiltration in the glomerular capillaries and mildly expanded mesangium.
Case 2 - 58yo male with nephrotic syndrome; urinary protein 7.38 g/day, hypoalbuminemia (1.9 g/dl); he was treated for diabetes since the age of 50 years; renal biopsy revealed 5 of 22 glomeruli with global sclerosis; residual glomeruli showed massive foam cell infiltration in the glomerular capillaries and severely widened mesangium - foam cells stained positive for CD68.
Case 3 - 78yo male with nephrotic syndrome; medical history includes hypertension, hypothyroidism, and diabetes mellitus; urinary protein 2.5 g/day, red blood cells in urine (1–4/hpf). A kidney biopsy revealed 21 glomeruli, of which 2 were globally sclerotic. The glomeruli showed increased mesangial matrices and mild GBM thickening. Massive foam cells had infiltrated into the glomerular capillaries and mesangial region.

PMID: 29692990 Fukunaga et al., 2018
Report of a Japanese 20yo female with proteinuria (3+) and hematuria (3+); on renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change; diagnosed with membranous nephropathy. She was heterozygous for APOE p.Ser197Cys variant - NM_000041.4: c.644C>G, p.Ser215Cys (not in gnomAD 4.1.1).

PMID: 31874799 Saito et al., 2020; to: PMID: 24570682 Kawanishi et al., 2013
Report of 3 likely Japanese cases of APOE homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 patients were homozygous for APOE p.Arg158Cys variant - NM_000041.4: c.526C>T, p.Arg176Cys - common variant, B/LB in ClinVar. Risk factor.
Case 1 - 66yo male, diagnosed with diabetes at 50 yrs, untreated; testing showed urinary abnormality of protein 3+ (urinary protein 2.07g/day) and occult blood 1+, serum creatinine level of 0.96 mg/dl; on renal biopsy, 1/11 glomeruli showed global sclerosis, and the other glomeruli showed massive foam cell infiltration in the glomerular capillaries and mildly expanded mesangium.
Case 2 - 58yo male with nephrotic syndrome; urinary protein 7.38 g/day, hypoalbuminemia (1.9 g/dl); he was treated for diabetes since the age of 50 years; renal biopsy revealed 5 of 22 glomeruli with global sclerosis; residual glomeruli showed massive foam cell infiltration in the glomerular capillaries and severely widened mesangium - foam cells stained positive for CD68.
Case 3 - 78yo male with nephrotic syndrome; medical history includes hypertension, hypothyroidism, and diabetes mellitus; urinary protein 2.5 g/day, red blood cells in urine (1–4/hpf). A kidney biopsy revealed 21 glomeruli, of which 2 were globally sclerotic. The glomeruli showed increased mesangial matrices and mild GBM thickening. Massive foam cells had infiltrated into the glomerular capillaries and mesangial region.

PMID: 29692990 Fukunaga et al., 2018
Report of a Japanese 20yo female with proteinuria (3+) and hematuria (3+); on renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change; diagnosed with membranous nephropathy. She was homozygous for APOE2 allele and heterozygous for APOE p.Ser197Cys rare variant - NM_000041.4: c.644C>G, p.Ser215Cys (not in gnomAD 4.1.1).

PMID: 31874799 Saito et al., 2020
Proteinuric renal disease v6.18 APOE Ida Ertmanska reviewed gene: APOE: Rating: GREEN; Mode of pathogenicity: None; Publications: 24570682, 29692990; Phenotypes: Lipoprotein glomerulopathy, OMIM:611771, lipoprotein glomerulopathy, MONDO:0012725; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v8.7 TBX6 Luke Stuart reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25564734, 33058178, 23335591, 12620991; Phenotypes: Spondylocostal dysostosis 5 (OMIM #122600), spondylocostal dysostosis 5 (MONDO:0007389); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v10.8 TBX6 Luke Stuart reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PIMD: 25564734, 33058178, 23335591; Phenotypes: Spondylocostal dysostosis 5 (OMIM #122600), spondylocostal dysostosis 5 (MONDO:0007389); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v8.35 OGDH Achchuthan Shanmugasundram Classified gene: OGDH as Red List (low evidence)
Hereditary neuropathy or pain disorder v8.35 OGDH Achchuthan Shanmugasundram Gene: ogdh has been classified as Red List (Low Evidence).
Hereditary neuropathy or pain disorder v8.34 OGDH Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated amber with current evidence.; to: Comment on list classification: There is one patient reported with neuropathy. Although there is functional evidence available for the reported variant from Drosophila model, only locomotion defects was reported as the phenotype in the publication, which support association with ataxia. This gene should be rated red with current evidence on the neuropathy panel.
Hereditary neuropathy or pain disorder v8.34 OGDH Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: RED
Optic neuropathy v6.51 OGDH Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated red with current evidence.; to: Comment on list classification: There is one patient and functional evidence from Drosophila models available. But, the evidence from drosophila model only supports locomotion defects and not any eye phenotypes. Hence, this gene should be rated red with current evidence.
Hereditary neuropathy or pain disorder v8.34 OGDH Achchuthan Shanmugasundram Classified gene: OGDH as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v8.34 OGDH Achchuthan Shanmugasundram Gene: ogdh has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v8.33 OGDH Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated red with current evidence.; to: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated amber with current evidence.
Hereditary neuropathy or pain disorder v8.33 OGDH Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: AMBER
Possible mitochondrial disorder, nuclear genes v5.25 VPS13C Eleanor Williams commented on gene: VPS13C
Neurodegenerative disorders, adult onset v9.15 VPS13C Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype Parkinson disease 23, early onset, OMIM:616840 accessed on 7th Sept 2026
Neurodegenerative disorders, adult onset v9.15 VPS13C Eleanor Williams Phenotypes for gene: VPS13C were changed from Parkinson disease 23, early onset, OMIM:616840; autosomal recessive early-onset Parkinson disease 23, MONDO:0014796 to Parkinson disease 23, early onset, OMIM:616840; autosomal recessive early-onset Parkinson disease 23, MONDO:0014796
Neurodegenerative disorders, adult onset v9.14 VPS13C Eleanor Williams Phenotypes for gene: VPS13C were changed from Parkinson disease 23, autosomal recessive, early onset, OMIM:616840 to Parkinson disease 23, early onset, OMIM:616840; autosomal recessive early-onset Parkinson disease 23, MONDO:0014796
Neurodegenerative disorders, adult onset v9.13 VPS13C Eleanor Williams Publications for gene: VPS13C were set to 26942284; 28137300; 28862745
Hereditary neuropathy or pain disorder v8.33 MRPS34 Alexander Rossor gene: MRPS34 was added
gene: MRPS34 was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene: MRPS34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS34 were set to 41506652
Phenotypes for gene: MRPS34 were set to Cerebellar ataxia, distal motor neuropathy; pyramidal syndrome; leukoencephalopathy on brain MRI; Treatment with oral folinic acid
Review for gene: MRPS34 was set to AMBER
Added comment: One case associated with neuropathy. A likely cause of neuropathy as multiple other cerebral folate gene variants also causing neuropathy as part of extended phenotype. Certainly not green at this stage but no good evidence it isn't pathogenic so should not be downgraded to red
Sources: Other
Hereditary neuropathy or pain disorder v8.33 MRPS23 Alexander Rossor gene: MRPS23 was added
gene: MRPS23 was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene: MRPS23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS23 were set to 41506652
Phenotypes for gene: MRPS23 were set to Cerebellar ataxia, distal motor neuropathy; pyramidal syndrome; leukoencephalopathy on brain MRI; Treatment with oral folinic acid
Review for gene: MRPS23 was set to AMBER
Added comment: One case associated with neuropathy. A likely cause of neuropathy as multiple other cerebral folate gene variants also causing neuropathy as part of extended phenotype. Certainly not green at this stage but no good evidence it isn't pathogenic so should not be downgraded to red
Sources: Other
Hereditary neuropathy or pain disorder v8.33 MRPS22 Alexander Rossor gene: MRPS22 was added
gene: MRPS22 was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene: MRPS22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS22 were set to 41506652
Phenotypes for gene: MRPS22 were set to Cerebellar ataxia, distal motor neuropathy; pyramidal syndrome; leukoencephalopathy on brain MRI; Treatment with oral folinic acid
Review for gene: MRPS22 was set to AMBER
Added comment: Once case associated with neuropathy. A likely cause of neuropathy as multiple other cerebral folate gene variants also causing neuropathy as part of extended phenotype. Certainly not green at this stage but no good evidence it isn't pathogenic so should not be downgraded to red
Sources: Other
Hereditary neuropathy or pain disorder v8.33 FOLR1 Alexander Rossor gene: FOLR1 was added
gene: FOLR1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOLR1 were set to 27743887
Phenotypes for gene: FOLR1 were set to Developmental regression; epilepsy; leukodystrophy; cerebellar atrophy; axonal neuropathy
Review for gene: FOLR1 was set to AMBER
Added comment: Once case associated with neuropathy. A likely cause of neuropathy as multiple other cerebral folate gene variants also causing neuropathy as part of extended phenotype. Certainly not green at this stage but no good evidence it isn't pathogenic so should not be downgraded to red
Sources: Expert list
Paediatric or syndromic cardiomyopathy v8.14 DSG2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least three unrelated cases reported with childhood/ juvenile onset cardiomyopathy. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal ' in the next GMS update.
Paediatric or syndromic cardiomyopathy v8.14 DSG2 Achchuthan Shanmugasundram Mode of inheritance for gene: DSG2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v8.13 DSG2 Achchuthan Shanmugasundram Phenotypes for gene: DSG2 were changed from Cardiomyopathy, dilated, 1BB,; Arrhythmogenic right ventricular dysplasia 10 to Arrhythmogenic right ventricular dysplasia 10, OMIM:610193; arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Cardiomyopathy, dilated, 1BB, OMIM:612877; dilated cardiomyopathy 1BB, MONDO:0013030
Paediatric or syndromic cardiomyopathy v8.12 DSG2 Achchuthan Shanmugasundram Publications for gene: DSG2 were set to
Paediatric or syndromic cardiomyopathy v8.11 DSG2 Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: DSG2.
Paediatric or syndromic cardiomyopathy v8.11 DSG2 Achchuthan Shanmugasundram reviewed gene: DSG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31645976, 33949662, 37288269, 39706847; Phenotypes: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434, Cardiomyopathy, dilated, 1BB, OMIM:612877, dilated cardiomyopathy 1BB, MONDO:0013030; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v4.11 DSG2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in DSG2 gene with arrhythmogenic right ventricular cardiomyopathy. There are also two biallelic cases reported with dilated cardiomyopathy.

The GMS Cardiology Specialist Group decided that all green genes that are present on the Arrhythmogenic right ventricular cardiomyopathy panel should also be green on this panel due to possible phenotypic overlap.

Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Dilated and arrhythmogenic cardiomyopathy v4.11 DSG2 Achchuthan Shanmugasundram Mode of inheritance for gene: DSG2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v4.10 DSG2 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: DSG2.
Tag Q3_26_MOI tag was added to gene: DSG2.
Arrhythmogenic right ventricular cardiomyopathy v3.21 DSG2 Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: DSG2.
Dilated and arrhythmogenic cardiomyopathy v4.10 DSG2 Achchuthan Shanmugasundram Publications for gene: DSG2 were set to 23500315; 27532257
Dilated and arrhythmogenic cardiomyopathy v4.9 DSG2 Achchuthan Shanmugasundram Phenotypes for gene: DSG2 were changed from Arrhythmogenic right ventricular dysplasia 10; Arrhythmogenic right ventricular dysplasia 10 (610193); Cardiomyopathy, dilated, 1BB (612877) to Arrhythmogenic right ventricular dysplasia 10, OMIM:610193; arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Cardiomyopathy, dilated, 1BB, OMIM:612877; dilated cardiomyopathy 1BB, MONDO:0013030
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram edited their review of gene: DSG2: Changed publications to: 16773573, 18678517, 28818065, 30454721, 31645976, 33949662, 37288269, 39706847
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but associated with dilated cardiomyopathy in OMIM (MIM #612877).

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain.

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but associated with dilated cardiomyopathy in OMIM (MIM #612877).

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain.

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.

Below are reported cases with biallelic variants and dilated cardiomyopathy:

PMID:18678517 (2008) reported a single index case with dilated cardiomyopathy and carried a homozygous DSG2 p.Val55Met/ p.Val56Met variant, with an affected father and an asymptomatic mother both identified as heterozygous carriers. A broader cohort screen of 538 idiopathic DCM patients found 13 additional heterozygous carriers versus 3 in 617 controls.

PMID:33949662 (2021) reported the identification of a homozygous p.Arg119Ter variant in a patient with juvenile-onset severe biventricular heart failure, for which iPSC-cardiomyocyte modeling showed disrupted desmosome deposition and abnormal intercalated discs.
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen.

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain.

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but associated with dilated cardiomyopathy in OMIM (MIM #612877).

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain.

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram edited their review of gene: DSG2: Changed phenotypes to: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434, Cardiomyopathy, dilated, 1BB, OMIM:612877, dilated cardiomyopathy 1BB, MONDO:0013030
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram reviewed gene: DSG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16773573, 28818065, 30454721, 31645976, 37288269, 39706847; Phenotypes: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v11.28 AIMP2 Ida Ertmanska changed review comment from: Additional cases:
PMID: 38374194 Abolhassani et al., 2024
Patient 925, 3yo Iranian female, with NM_006303.4(AIMP2):c.34_35delinsC (p.Gly12ProfsTer?). She presented with: Preterm birth; Low birth weight; Microcephaly; Mild learning difficulty; Developmental delay, speech & motor; Epilepsy; Hypertonia; Limb atrophy & spasticity; Muscle weakness; Strabismus; Ophthalmoplegia; Visual impairment; Anemia. Also homozygous for a VUS SBF1 variant p.Met524Arg (SBF1 is associated with recessive CMT).

PMID: 35140751 Mazaheri et al., 2022
Iranian proband - 7-month-old infant with a progressive neurological disorder characterized by lack of development, weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy. WES revealed a homozygous AIMP2 c.670A>T (p.Lys224Ter) variant, confirmed het in each parent. No mention of seizures. Variant predicted to escape NMD.

PMID: 35568357 Masih et al., 2022
Patient F32.1 - 5yo Indian male - homozygous for NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys). Clinical presentation: severe DD/ID, generalised tonic-clonic seizures, dysmorphic features, short stature, feeding difficulties, spastic quadriparesis, thin corpus callosum on MRI. Diagnosed with Leukodystrophy, hypomyelinating, 17.

PMID: 26795593 Helbig et al., 2016
Proband with Epileptic encephalopathy. Compound het for AIMP2 c.575-2A>G and c.72_73del (p.Met24IlefsTer25). Patient also has alteration in LRFN2 (not associated with disease in OMIM).

This gene is associated with AR Leukodystrophy, hypomyelinating, 17, MIM:618006 (OMIM accessed 19th Jan 2025). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025).; to: Additional cases:
PMID: 38374194 Abolhassani et al., 2024
Patient 925, 3yo Iranian female, with NM_006303.4(AIMP2):c.34_35delinsC (p.Gly12ProfsTer?). She presented with: Preterm birth; Low birth weight; Microcephaly; Mild learning difficulty; Developmental delay, speech & motor; Epilepsy; Hypertonia; Limb atrophy & spasticity; Muscle weakness; Strabismus; Ophthalmoplegia; Visual impairment; Anemia. Also homozygous for a VUS SBF1 variant p.Met524Arg (SBF1 is associated with recessive CMT).

PMID: 35140751 Mazaheri et al., 2022
Iranian proband - 7-month-old infant with a progressive neurological disorder characterized by lack of development, weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy. WES revealed a homozygous AIMP2 c.670A>T (p.Lys224Ter) variant, confirmed het in each parent. No mention of seizures. Variant predicted to escape NMD.

PMID: 35568357 Masih et al., 2022
Patient F32.1 - 5yo Indian male - homozygous for NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys). Clinical presentation: severe DD/ID, generalised tonic-clonic seizures, dysmorphic features, short stature, feeding difficulties, spastic quadriparesis, thin corpus callosum on MRI. Diagnosed with Leukodystrophy, hypomyelinating, 17.

PMID: 26795593 Helbig et al., 2016
Proband with Epileptic encephalopathy. Compound het for AIMP2 c.575-2A>G and c.72_73del (p.Met24IlefsTer25). Patient also has alteration in LRFN2 (not associated with disease in OMIM).

This gene is associated with AR Leukodystrophy, hypomyelinating, 17, MIM:618006 (OMIM accessed 19th Jan 2026). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025).
Arrhythmogenic right ventricular cardiomyopathy v3.21 DSG2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in DSG2 gene with arrhythmogenic right ventricular cardiomyopathy. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Arrhythmogenic right ventricular cardiomyopathy v3.21 DSG2 Achchuthan Shanmugasundram Mode of inheritance for gene: DSG2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arrhythmogenic right ventricular cardiomyopathy v3.20 DSG2 Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen.

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain.

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen.

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain.

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.
Arrhythmogenic right ventricular cardiomyopathy v3.20 DSG2 Achchuthan Shanmugasundram Phenotypes for gene: DSG2 were changed from Cardiomyopathy, dilated, 1BB (612877); Arrhythmogenic right ventricular dysplasia 10 ; Arrhythmogenic right ventricular dysplasia 10 (610193) to Arrhythmogenic right ventricular dysplasia 10, OMIM:610193; arrhythmogenic right ventricular dysplasia 10, MONDO:0012434
Arrhythmogenic right ventricular cardiomyopathy v3.19 DSG2 Achchuthan Shanmugasundram Publications for gene: DSG2 were set to 27532257; 23500315; 29567486
Arrhythmogenic right ventricular cardiomyopathy v3.18 DSG2 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: DSG2.
Arrhythmogenic right ventricular cardiomyopathy v3.18 DSG2 Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen.

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen.

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain.

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.
Arrhythmogenic right ventricular cardiomyopathy v3.18 DSG2 Achchuthan Shanmugasundram edited their review of gene: DSG2: Changed publications to: 16773573, 28818065, 30454721, 31645976, 37288269, 39706847
Arrhythmogenic right ventricular cardiomyopathy v3.18 DSG2 Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen.


Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen.

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.
Arrhythmogenic right ventricular cardiomyopathy v3.18 DSG2 Achchuthan Shanmugasundram reviewed gene: DSG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16773573, 28818065, 31645976, 37288269, 39706847; Phenotypes: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v4.8 CRYAB Achchuthan Shanmugasundram Classified gene: CRYAB as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v4.8 CRYAB Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with isolated dilated cardiomyopathy (DCM). However, the variant was not specified for one of the cases. Hence, the gene should be rated amber with 'watchlist' tagged added for future review with new evidence.
Dilated and arrhythmogenic cardiomyopathy v4.8 CRYAB Achchuthan Shanmugasundram Gene: cryab has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v4.7 CRYAB Achchuthan Shanmugasundram Phenotypes for gene: CRYAB were changed from Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810 to Cardiomyopathy, dilated, 1II, OMIM:615184; dilated cardiomyopathy 1II, MONDO:0014073
Dilated and arrhythmogenic cardiomyopathy v4.6 CRYAB Achchuthan Shanmugasundram Publications for gene: CRYAB were set to
Dilated and arrhythmogenic cardiomyopathy v4.5 CRYAB Achchuthan Shanmugasundram Mode of inheritance for gene: CRYAB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v4.4 CRYAB Achchuthan Shanmugasundram Tag watchlist tag was added to gene: CRYAB.
Dilated and arrhythmogenic cardiomyopathy v4.4 CRYAB Achchuthan Shanmugasundram reviewed gene: CRYAB: Rating: AMBER; Mode of pathogenicity: None; Publications: 40046506, 41153379, 42170542; Phenotypes: Cardiomyopathy, dilated, 1II, OMIM:615184, dilated cardiomyopathy 1II, MONDO:0014073; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v8.11 CRYAB Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are at least five unrelated families reported with syndromic or early onset crdiomyopathy, particulrly dilated cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are at least five unrelated families reported with syndromic or early onset crdiomyopathy, particularly dilated cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v8.11 CRYAB Achchuthan Shanmugasundram Classified gene: CRYAB as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v8.11 CRYAB Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least five unrelated families reported with syndromic or early onset crdiomyopathy, particulrly dilated cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v8.11 CRYAB Achchuthan Shanmugasundram Gene: cryab has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v8.10 CRYAB Achchuthan Shanmugasundram Phenotypes for gene: CRYAB were changed from Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810 to Cardiomyopathy, dilated, 1II, OMIM:615184; dilated cardiomyopathy 1II, MONDO:0014073; Myopathy, myofibrillar, 2A, adult-onset, OMIM:608810; myofibrillar myopathy 2, MONDO:0012130
Paediatric or syndromic cardiomyopathy v8.9 CRYAB Achchuthan Shanmugasundram Publications for gene: CRYAB were set to
Paediatric or syndromic cardiomyopathy v8.8 CRYAB Achchuthan Shanmugasundram Mode of inheritance for gene: CRYAB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v8.7 CRYAB Achchuthan Shanmugasundram Tag Q3_26_demote_amber tag was added to gene: CRYAB.
Paediatric or syndromic cardiomyopathy v8.7 CRYAB Achchuthan Shanmugasundram reviewed gene: CRYAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27904835, 28493373, 32420686, 38212463, 42170542; Phenotypes: Cardiomyopathy, dilated, 1II, OMIM:615184, dilated cardiomyopathy 1II, MONDO:0014073, Myopathy, myofibrillar, 2A, adult-onset, OMIM:608810, myofibrillar myopathy 2, MONDO:0012130; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v10.8 PAX3 Ida Ertmanska reviewed gene: PAX3: Rating: RED; Mode of pathogenicity: None; Publications: 7726174, 12949970, 26443304, 35607853, 41141997, 41159045; Phenotypes: Waardenburg syndrome, type 1, OMIM:193500, Waardenburg syndrome type 1, MONDO:0008670, Waardenburg syndrome, type 3, OMIM:148820, Waardenburg syndrome type 3, MONDO:0007862, Klein-Waardenburg syndrome; Mode of inheritance: None
White matter disorders and cerebral calcification - childhood onset v8.13 CNP Achchuthan Shanmugasundram Classified gene: CNP as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v8.13 CNP Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated families and functional evidence including mouse model in support of the association of CNP with leukodystrophy. Hence, this gene can be promoted to green rating in the next GMS update.
White matter disorders and cerebral calcification - childhood onset v8.13 CNP Achchuthan Shanmugasundram Gene: cnp has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v8.12 CNP Achchuthan Shanmugasundram Tag watchlist was removed from gene: CNP.
Tag Q3_26_promote_green tag was added to gene: CNP.
White matter disorders and cerebral calcification - childhood onset v8.12 CNP Achchuthan Shanmugasundram Phenotypes for gene: CNP were changed from ?Leukodystrophy, hypomyelinating, 20, OMIM:619071 to ?Leukodystrophy, hypomyelinating, 20, OMIM:619071; leukodystrophy, hypomyelinating, 20, MONDO:0033657
White matter disorders and cerebral calcification - childhood onset v8.11 CNP Achchuthan Shanmugasundram Publications for gene: CNP were set to 32128616; 12590258
White matter disorders and cerebral calcification - childhood onset v8.10 CNP Achchuthan Shanmugasundram changed review comment from: PMID:32128616 (2020) reported a consanguineous Omani family with three affected siblings displaying a remarkably consistent phenotype of neuroregression with profound brain white matter loss. They were identified with a homozygous missense variant c.245C>T (p.Ser82Leu) in CNP gene, suggested to function as a null allele (immunoblot + F-actin defects in fibroblasts).

PMID:40396300 (2025) reported a novel case of a child presenting with hypomyelinating leukodystrophy type 20, and identified with homozygous nonsense variant c.295G>T (p.Glu99Ter), supported by RT-qPCR showing reduced CNP mRNA.

PMID:12590258 (2003) reported that deficiency of CNP in mice led to axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death.

This gene has been tentatively associated with hypomyelinating leukodystrophy in OMIM (MIM #619071), but not in Gene2Phenotype or ClinGen.; to: PMID:32128616 (2020) reported a consanguineous Omani family with three affected siblings displaying a remarkably consistent phenotype of neuroregression with profound brain white matter loss. They were identified with a homozygous missense variant c.245C>T (p.Ser82Leu) in CNP gene, suggested to function as a null allele (immunoblot + F-actin defects in fibroblasts).

PMID:40396300 (2025) reported a novel case of a child presenting with hypomyelinating leukodystrophy type 20, and identified with homozygous nonsense variant c.295G>T (p.Glu99Ter), supported by RT-qPCR showing reduced CNP mRNA.

PMID:12590258 (2003) reported that deficiency of CNP in mice led to axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death.

This gene has been tentatively associated with hypomyelinating leukodystrophy in OMIM (MIM #619071 - last accessed 03 September 2026), but not in Gene2Phenotype or ClinGen.
White matter disorders and cerebral calcification - childhood onset v8.10 CNP Achchuthan Shanmugasundram reviewed gene: CNP: Rating: GREEN; Mode of pathogenicity: None; Publications: 12590258, 32128616, 40396300; Phenotypes: ?Leukodystrophy, hypomyelinating, 20, OMIM:619071, leukodystrophy, hypomyelinating, 20, MONDO:0033657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: POLR3K.
Ataxia and cerebellar anomalies - childhood onset v9.35 POLR3K Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: POLR3K.
Hereditary spastic paraplegia, childhood onset v9.13 POLR3K Achchuthan Shanmugasundram Phenotypes for gene: POLR3K were changed from Leukodystrophy, hypomyelinating, 21, OMIM:619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310; leukodystrophy, hypomyelinating, 21, MONDO:0030263
Hereditary spastic paraplegia, childhood onset v9.12 POLR3K Achchuthan Shanmugasundram Publications for gene: POLR3K were set to 30584594; 33659930
Hereditary spastic paraplegia, childhood onset v9.11 POLR3K Achchuthan Shanmugasundram reviewed gene: POLR3K: Rating: AMBER; Mode of pathogenicity: None; Publications: 30584594, 40225923; Phenotypes: Leukodystrophy, hypomyelinating, 21, OMIM:619310, leukodystrophy, hypomyelinating, 21, MONDO:0030263; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v9.35 POLR3K Achchuthan Shanmugasundram Classified gene: POLR3K as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v9.35 POLR3K Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases (counting the two cases with potential founder variant as one) reported with three different variants in POLR3K (two cases homozygous for the suggested founder missense variant and one case compound heterozygous for a different missense variant and a ~17.8 kb deletion). All patients had cerebellar atrophy and two of them had ataxia. There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - childhood onset v9.35 POLR3K Achchuthan Shanmugasundram Gene: polr3k has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v9.34 POLR3K Achchuthan Shanmugasundram Tag watchlist was removed from gene: POLR3K.
Ataxia and cerebellar anomalies - childhood onset v9.34 POLR3K Achchuthan Shanmugasundram Publications for gene: POLR3K were set to 30584594; 33659930
Ataxia and cerebellar anomalies - childhood onset v9.33 POLR3K Achchuthan Shanmugasundram Phenotypes for gene: POLR3K were changed from Leukodystrophy, hypomyelinating, 21, OMIM:619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310; leukodystrophy, hypomyelinating, 21, MONDO:0030263
Ataxia and cerebellar anomalies - childhood onset v9.32 POLR3K Achchuthan Shanmugasundram reviewed gene: POLR3K: Rating: GREEN; Mode of pathogenicity: None; Publications: 30584594, 40225923; Phenotypes: Leukodystrophy, hypomyelinating, 21, OMIM:619310, leukodystrophy, hypomyelinating, 21, MONDO:0030263; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram changed review comment from: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype (onset was in late childhood/ adolescence). This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram changed review comment from: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp), with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Tag watchlist was removed from gene: POLR3K.
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Classified gene: POLR3K as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases (counting the two cases with potential founder variant as one) reported with three different variants in POLR3K (two cases homozygous for the suggested founder missense variant and one case compound heterozygous for a different missense variant and a ~17.8 kb deletion). There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Gene: polr3k has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v8.9 POLR3K Achchuthan Shanmugasundram Phenotypes for gene: POLR3K were changed from Leukodystrophy, hypomyelinating, 21, OMIM:619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310; leukodystrophy, hypomyelinating, 21, MONDO:0030263
White matter disorders and cerebral calcification - childhood onset v8.8 POLR3K Achchuthan Shanmugasundram Publications for gene: POLR3K were set to 30584594; 33659930
White matter disorders and cerebral calcification - childhood onset v8.7 POLR3K Achchuthan Shanmugasundram changed review comment from: PMID:40225923 (2024) reported a single female patient compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp), with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).
White matter disorders and cerebral calcification - childhood onset v8.7 POLR3K Achchuthan Shanmugasundram edited their review of gene: POLR3K: Changed publications to: 30584594, 40225923
White matter disorders and cerebral calcification - childhood onset v8.7 POLR3K Achchuthan Shanmugasundram reviewed gene: POLR3K: Rating: GREEN; Mode of pathogenicity: None; Publications: 40225923; Phenotypes: Leukodystrophy, hypomyelinating, 21, OMIM:619310, leukodystrophy, hypomyelinating, 21, MONDO:0030263; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v8.7 NSMCE2 Ida Ertmanska Classified gene: NSMCE2 as Amber List (moderate evidence)
Fetal anomalies v8.7 NSMCE2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including IUGR and oligohydramnios noted on prenatal scans. Taken together, there is enough evidence in literature to promote this gene to Green at the next update.
Fetal anomalies v8.7 NSMCE2 Ida Ertmanska Gene: nsmce2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v8.6 NSMCE2 Ida Ertmanska gene: NSMCE2 was added
gene: NSMCE2 was added to Fetal anomalies. Sources: Literature
Q3_26_promote_green tags were added to gene: NSMCE2.
Mode of inheritance for gene: NSMCE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSMCE2 were set to 25105364; https://doi.org/10.1002/ajmg.a.70286
Phenotypes for gene: NSMCE2 were set to Seckel syndrome 10, OMIM:617253; Seckel syndrome, MONDO:0014991
Review for gene: NSMCE2 was set to GREEN
Added comment: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before print
Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans.
His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD).

PMID: 39184883 Tatiya, Kesri, and Ukey, 2024
14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made.

PMID: 25105364 Payne et al., 2014
Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene. Both families are of European ancestry, and while not immediately related, they had shared common ancestral haplotypes.
Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by re-expression of WT, but not SUMO-ligase–deficient NSMCE.

Additional evidence (Decipher case):
Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25​del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks.

The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).
Sources: Literature
Severe microcephaly v9.28 NSMCE2 Ida Ertmanska Phenotypes for gene: NSMCE2 were changed from Seckel syndrome 10, 617253; SCKL10 to Seckel syndrome 10, OMIM:617253; Seckel syndrome, MONDO:0014991
Severe microcephaly v9.27 NSMCE2 Ida Ertmanska Classified gene: NSMCE2 as Amber List (moderate evidence)
Severe microcephaly v9.27 NSMCE2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update.
Severe microcephaly v9.27 NSMCE2 Ida Ertmanska Gene: nsmce2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v9.26 NSMCE2 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: NSMCE2.
Severe microcephaly v9.26 NSMCE2 Ida Ertmanska changed review comment from: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before publication
Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans.
His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD).

PMID: 39184883 Tatiya, Kesri, and Ukey, 2024
14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made.

PMID: 25105364 Payne et al., 2014
Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene.
Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE.

Additional evidence (Decipher case):
Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25​del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks.

The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).; to: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before print
Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans.
His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD).

PMID: 39184883 Tatiya, Kesri, and Ukey, 2024
14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made.

PMID: 25105364 Payne et al., 2014
Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene.
Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE.

Additional evidence (Decipher case):
Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25​del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks.

The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).
Severe microcephaly v9.26 NSMCE2 Ida Ertmanska changed review comment from: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before publication
Study described an 11-year-old male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency.

The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).; to: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before publication
Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans.
His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD).

PMID: 39184883 Tatiya, Kesri, and Ukey, 2024
14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made.

PMID: 25105364 Payne et al., 2014
Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene.
Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE.

Additional evidence (Decipher case):
Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25​del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks.

The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).
Severe microcephaly v9.26 NSMCE2 Ida Ertmanska changed review comment from: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026
Study described an 11-year-old male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency.

The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).; to: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before publication
Study described an 11-year-old male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency.

The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).
Severe microcephaly v9.26 NSMCE2 Ida Ertmanska reviewed gene: NSMCE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25105364, https://doi.org/10.1002/ajmg.a.70286; Phenotypes: Seckel syndrome 10, OMIM:617253, Seckel syndrome, MONDO:0014991; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Short QT syndrome v3.25 CACNA1C Ida Ertmanska commented on gene: CACNA1C: Comment on list classification: There are several individuals reported in literature with monoallelic CACNA1C variants and Short QT Syndrome (SQTS), or Brugada syndrome with SQTS. However, this association has been classified as Disputed in ClinGen. Some allele frequencies are too high in population databases, there is little functional evidence supporting the variant pathogenicity, and most variants are ranked as VUS according to ACMG criteria. There is no robust evidence linking SQTS to CACNA1C variants. Hence this gene should be demoted at the next GMS update. An expert-review tag was added as this is a proposed demotion of a Green gene.
Short QT syndrome v3.25 CACNA1C Ida Ertmanska edited their review of gene: CACNA1C: Changed phenotypes to: Brugada syndrome 3, OMIM:611875, Timothy syndrome, OMIM:601005, Long QT syndrome 8, OMIM:618447
Short QT syndrome v3.25 CACNA1C Ida Ertmanska Publications for gene: CACNA1C were set to 24291113; 16301704; 30027834; 30279520; 17224476; 28427417; 28490369; 29759541; 29697308
Short QT syndrome v3.24 CACNA1C Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CACNA1C.
Short QT syndrome v3.24 CACNA1C Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: CACNA1C.
Short QT syndrome v3.24 CACNA1C Ida Ertmanska edited their review of gene: CACNA1C: Changed rating: AMBER
Short QT syndrome v3.24 CACNA1C Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. B/LB in ClinGen.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."; to: The association between CACNA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

CACNA1C association with AD Brugada syndrome is also Disputed in ClinGen as of 2025: "Many reported variants in CACNA1C are too common in population databases, and functional studies have shown that both common and rare variants can produce similar effects [PMID: 17224476, 20817017]."

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. B/LB in ClinGen.

PMID: 34999275 Novelli et al., 2022
563 BrS probands underwent CACNA1C sequencing - identified 11 different rare variants in 9 patients. Most of these were classified as VUS according to ACMG criteria.
"CACNA1C is an infrequent but definitive cause of BrS typically associated with short QT."

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."
Short QT syndrome v3.24 CACNA1C Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."; to: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. B/LB in ClinGen.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."
Short QT syndrome v3.24 CACNA1C Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."; to: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."
Short QT syndrome v3.24 CACNA1C Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype; to: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."
Short QT syndrome v3.24 CACNA1C Ida Ertmanska reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: None; Publications: 17224476, 20817017, 24291113, 28427417; Phenotypes: Brugada syndrome 3, OMIM:611875, Timothy syndrome, OMIM:601005, Long QT syndrome 8, OMIM:618447, Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, OMIM:620029; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v8.14 RYR3 Ida Ertmanska gene: RYR3 was added
gene: RYR3 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: RYR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RYR3 were set to 39762984; 41022857
Phenotypes for gene: RYR3 were set to congenital heart disease, MONDO:0005453
Review for gene: RYR3 was set to RED
Added comment: PMID: 39762984 Kim et al., 2025
Trio WGS study of 18 probands with congenital anomalies.
P4 = het de novo c.12295G > T (p.Glu4099Ter) variant in RYR3; patient features: duodenal atresia, cardiovascular abnormalities, and vesicoureteral reflux. Variant not in gnomAD v4.1.1.
Zebrafish ryr3 knockout showed enlarged atria and ventricle compared to controls at 3dpf.

PMID: 41022857 Jeong & Bulyk, 2025
Study investigated congenital heart defect (CHD) and orofacial cleft (OFC) parent-offspring trio cohorts (n = 3835 and 1844, respectively).
4 de novo missense (L110I, S2130L, Y2743C, F2957L) variants identified in a CHD cohort. Y2743C has a homozygote & MAF=0.0002760 in gnomAD (higher than expected for AD disease).
Sources: Literature
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska commented on gene: RYR3: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3: 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, 3 with syndromic contractures, and some studies report an association with congenital heart disease. There are at least 15 individuals, primarily of Chinese origin, with RYR3 variants and a developmental and epileptic encephalopathy. 4 individuals harboured heterozygous de novo variants, while 11/15 harboured biallelic RYR3 variants (primarily missense and splice). Additional variable features included developmental delay, hypotonia, dystonia, motor dyspraxia. Based on the confounding literature, a ClinGen Limited classification, limited functional evidence, and common variants being reported as causal, this gene should remain Amber, until more evidence emerges.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452).

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
RYR3 is only associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2024
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. Normal muscle strength and tone in all extremities, normal head MRI.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452).

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
RYR3 is only associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).
Congenital myopathy v7.81 RYR3 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a proposed demotion of a Green gene, an expert-review tag was added.; to: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, sometimes with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a proposed demotion of a Green gene, an expert-review tag was added.
Congenital myopathy v7.81 RYR3 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a demotion of a Green gene, an expert-review tag was added.; to: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a proposed demotion of a Green gene, an expert-review tag was added.
Congenital myopathy v7.81 RYR3 Ida Ertmanska Publications for gene: RYR3 were set to 29498452
Congenital myopathy v7.80 RYR3 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: RYR3.
Tag Q3_26_demote_red tag was added to gene: RYR3.
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges.; to: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a demotion of a Green gene, an expert-review tag was added.
Congenital myopathy v7.80 RYR3 Ida Ertmanska commented on gene: RYR3: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges.
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018
Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy.
WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Partial phenotype overlap: some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).; to: PMID 29498452 Nilipour et al., 2018
Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy.
WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) - 6mo female with arthrogryposis multiplex congenita, hypotonia, facial dysmorphism. Comp het variants in MYO18B also detected.
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A - female with bilateral clubfoot, finger contractures, GDD, enteropathy. She had repeated episodes resembling seizures around age 2 yrs - these resolved without treatment. No signs of muscle disease. CGH array detected a 144kb microdeletion in 6q22.31 of unknown significance.
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) - 15yo female with high arched palate, contractures, ulnar deviation, scoliosis. Parents are consanguineous.

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Partial phenotype overlap: some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018
Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy.
WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).; to: PMID 29498452 Nilipour et al., 2018
Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy.
WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Partial phenotype overlap: some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).; to: PMID 29498452 Nilipour et al., 2018
Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy.
WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452).

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452).

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
RYR3 is only associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452).

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
Neurodegenerative disorders, adult onset v9.12 VPS13C Achchuthan Shanmugasundram Classified gene: VPS13C as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v9.12 VPS13C Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least 10 unrelated patients available in support of the association of this gene with early-onset Parkinson's disease. Hence, this gene can be promoted to green rating in the next GMS update.
Neurodegenerative disorders, adult onset v9.12 VPS13C Achchuthan Shanmugasundram Gene: vps13c has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v9.11 VPS13C Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: VPS13C.
Neurodegenerative disorders, adult onset v9.11 VPS13C Achchuthan Shanmugasundram reviewed gene: VPS13C: Rating: GREEN; Mode of pathogenicity: None; Publications: 26942284, 28862745, 30452786, 33579389, 34875562; Phenotypes: Parkinson disease 23, early onset, OMIM:616840, autosomal recessive early-onset Parkinson disease 23, MONDO:0014796; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., https://doi.org/10.1016/j.gendis.2026.102341).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., https://doi.org/10.1016/j.gendis.2026.102341).

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., https://doi.org/10.1016/j.gendis.2026.102341).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).
Malformations of cortical development v8.11 TMEM161B Alexandra Njegic reviewed gene: TMEM161B: Rating: AMBER; Mode of pathogenicity: None; Publications: 36669111, 38593811, 37486637; Phenotypes: Polymicrogyria; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341).

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., https://doi.org/10.1016/j.gendis.2026.102341).

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651;29667327;39220738;39840699, and https://doi.org/10.1016/j.gendis.2026.102341).

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341).

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).
Congenital myopathy v7.80 RYR3 Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018
Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His)
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu)

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651;29667327;39220738;39840699, and https://doi.org/10.1016/j.gendis.2026.102341).

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed publications to: 25262651, 29667327, 39220738, 39840699, https://doi.org/10.1016/j.gendis.2026.102341
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES.
FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed publications to: 25262651, 39220738, 39840699, https://doi.org/10.1016/j.gendis.2026.102341
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES.
FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
Malformations of cortical development v8.11 TMEM161B Alexandra Njegic gene: TMEM161B was added
gene: TMEM161B was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: TMEM161B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM161B were set to 36669111; 38593811; 37486637
Phenotypes for gene: TMEM161B were set to pol
Penetrance for gene: TMEM161B were set to unknown
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed publications to: 25262651, 39220738, 39840699
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2025
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska reviewed gene: RYR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 39220738, 39840699; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myopathy v7.80 RYR3 Ida Ertmanska reviewed gene: RYR3: Rating: RED; Mode of pathogenicity: None; Publications: 29498452, 31230720; Phenotypes: Congenital myopathy 20, OMIM:620310, congenital myopathy 20, MONDO:0957215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v8.33 EGR2 Achchuthan Shanmugasundram Phenotypes for gene: EGR2 were changed from Charcot-Marie-Tooth disease, type 1D, MIM:607678; Dejerine-Sottas disease, MIM:145900; Hypomyelinating neuropathy, congenital, 1, MIM:605253 to Charcot-Marie-Tooth disease, type 1D, OMIM:607678; Dejerine-Sottas disease, OMIM:145900; Hypomyelinating neuropathy, congenital, 1, OMIM:605253
Short QT syndrome v3.24 CACNA1C Ida Ertmanska Tag disputed tag was added to gene: CACNA1C.
Likely inborn error of metabolism v9.32 HSPA9 Ida Ertmanska Phenotypes for gene: HSPA9 were changed from Even-plus syndrome, OMIM:616854 to Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194; Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801
Possible mitochondrial disorder, nuclear genes v5.25 HSPA9 Ida Ertmanska Phenotypes for gene: HSPA9 were changed from Even-plus syndrome, OMIM:616854; Anemia, sideroblastic, 4, OMIM:182170 to Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194; Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801
Likely inborn error of metabolism v9.31 HSPA9 Ida Ertmanska Publications for gene: HSPA9 were set to 26598328; 32869452; 35779070; 36052765
Possible mitochondrial disorder, nuclear genes v5.24 HSPA9 Ida Ertmanska Publications for gene: HSPA9 were set to 26491070; 26598328; 32869452; 35779070; 36052765
Possible mitochondrial disorder, nuclear genes v5.23 HSPA9 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: HSPA9.
Likely inborn error of metabolism v9.30 HSPA9 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: HSPA9.
Possible mitochondrial disorder, nuclear genes v5.23 HSPA9 Ida Ertmanska commented on gene: HSPA9: Comment on mode of inheritance: As reviewed previously, there are more than 3 unrelated cases are reported with biallelic HSPA9 variants and EVEN-PLUS syndrome. There are also several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants and CSA (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Both EVEN-PLUS syndrome and Sideroblastic anemia stem from mitochondrial dysfunction. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
Likely inborn error of metabolism v9.30 HSPA9 Ida Ertmanska commented on gene: HSPA9: Comment on mode of inheritance: As reviewed previously, there are more than 3 unrelated cases are reported with biallelic HSPA9 variants and EVEN-PLUS syndrome. There are also several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants and CSA (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Both EVEN-PLUS syndrome and Sideroblastic anemia stem from mitochondrial dysfunction. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
Likely inborn error of metabolism v9.30 HSPA9 Ida Ertmanska reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212; Phenotypes: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194, Even-plus syndrome, OMIM:616854, even-plus syndrome, MONDO:0014801; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v5.23 HSPA9 Ida Ertmanska reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212; Phenotypes: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194, Even-plus syndrome, OMIM:616854, even-plus syndrome, MONDO:0014801; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v10.25 HSPA9 Ida Ertmanska Phenotypes for gene: HSPA9 were changed from Even-plus syndrome, OMIM:616854; Anemia, sideroblastic, 4, OMIM:182170 to Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194; Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801
Mitochondrial disorders v10.24 HSPA9 Ida Ertmanska Publications for gene: HSPA9 were set to 26491070; 26598328; 32869452; 35779070; 36052765
Mitochondrial disorders v10.23 HSPA9 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: HSPA9.
Mitochondrial disorders v10.23 HSPA9 Ida Ertmanska commented on gene: HSPA9: Comment on mode of inheritance: As reviewed previously, there are more than 3 unrelated cases are reported with biallelic HSPA9 variants and EVEN-PLUS syndrome. There are also several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants and CSA (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Both EVEN-PLUS syndrome and Sideroblastic anemia stem from mitochondrial dysfunction. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
Rare anaemia v4.10 HSPA9 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
Mitochondrial disorders v10.23 HSPA9 Ida Ertmanska edited their review of gene: HSPA9: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare anaemia v4.10 HSPA9 Ida Ertmanska edited their review of gene: HSPA9: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare anaemia v4.10 HSPA9 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
Rare anaemia v4.10 HSPA9 Ida Ertmanska edited their review of gene: HSPA9: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mitochondrial disorders v10.23 HSPA9 Ida Ertmanska edited their review of gene: HSPA9: Added comment: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (pC487Sfs*3 & p.E577K in Family K; p.V296* & ?p.203_204ins3 in family L).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population.
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 30401706 Ducamp & Fleming, 2018 review
"a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant"

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; Changed publications to: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212; Changed phenotypes to: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194, Even-plus syndrome, OMIM:616854, even-plus syndrome, MONDO:0014801; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Rare anaemia v4.10 HSPA9 Ida Ertmanska Phenotypes for gene: HSPA9 were changed from sideroblastic anaemia; 182170 Sideroblastic anaemia 4; 182170 sideroblastic anaemia type 4; Sideroblastic anaemia type 4, 182170 to Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194
Rare anaemia v4.9 HSPA9 Ida Ertmanska Publications for gene: HSPA9 were set to 26491070
Rare anaemia v4.8 HSPA9 Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212
Rare anaemia v4.8 HSPA9 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: HSPA9.
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. ; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a homozygous rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype.
Rare anaemia v4.8 HSPA9 Ida Ertmanska commented on gene: HSPA9: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a homozygous rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population.
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 30401706 Ducamp & Fleming, 2018 review
"a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant"

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (pC487Sfs*3 & p.E577K in Family K; p.V296* & ?p.203_204ins3 in family L).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population.
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 30401706 Ducamp & Fleming, 2018 review
"a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant"

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 30401706 Ducamp & Fleming, 2018 review
"a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant"

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population.
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 30401706 Ducamp & Fleming, 2018 review
"a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant"

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 30401706 Ducamp & Fleming, 2018 review
"a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant"

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.
FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR).

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.
Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa.
Patient VA-39 - 9yo female, presented with pallor, weakness, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
P2 - harboured V355A and a polymorphism in trans in HSPA9.
Pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.

Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants:
Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans.
Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
Described as pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
Skeletal dysplasia v10.8 HSPA9 Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 26598328, DOI:10.4172/1747-0862.1000350, 32869452, 35779070, 36094340, 36052765
Skeletal dysplasia v10.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26598328 Royer-Bertrand et al., 2015
Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome.
Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients.
P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees.
P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae.

DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018
Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. She was comp het for HSPA9 variants c.446A>T, p.Asn149Ile and c.1687A>T, p.Lys563Ter.

PMID: 32869452 Younger et al., 2020
WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia.

PMID: 35779070 Pacio-Miguez et al., 2022
Reported two families.
F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification.
F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents).

PMID: 36052765 Li et al., 2022
Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora.
Sources: Literature; to: PMID: 26598328 Royer-Bertrand et al., 2015
Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome.
Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients.
P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees.
P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae.

DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018
Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. She was comp het for HSPA9 variants c.446A>T, p.Asn149Ile and c.1687A>T, p.Lys563Ter.

PMID: 32869452 Younger et al., 2020
WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia.

PMID: 35779070 Pacio-Miguez et al., 2022
Reported two families.
F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification.
F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents).

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 36052765 Li et al., 2022
Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora.
Sources: Literature
Rare anaemia v4.8 HSPA9 Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 26491070, 33398880, 36094340, 38360212
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.
Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa.
Patient VA-39 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls.
P2 - harboured V355A and a polymorphism in trans in HSPA9.
Pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.
Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa.
Patient VA-39 - 9yo female, presented with pallor, weakness, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. HSPA9 mRNA expression was noted to be 1000-fold lower than controls.
P2 - harboured V355A and a polymorphism in trans in HSPA9.
Pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
Skeletal dysplasia v10.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26598328 Royer-Bertrand et al., 2015
Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome.
Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients.
P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees.
P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae.

DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018
Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG.

PMID: 32869452 Younger et al., 2020
WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia.

PMID: 35779070 Pacio-Miguez et al., 2022
Reported two families.
F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification
F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents).

PMID: 36052765 Li et al., 2022
Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora.
Sources: Literature; to: PMID: 26598328 Royer-Bertrand et al., 2015
Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome.
Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients.
P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees.
P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae.

DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018
Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. She was comp het for HSPA9 variants c.446A>T, p.Asn149Ile and c.1687A>T, p.Lys563Ter.

PMID: 32869452 Younger et al., 2020
WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia.

PMID: 35779070 Pacio-Miguez et al., 2022
Reported two families.
F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification.
F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents).

PMID: 36052765 Li et al., 2022
Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora.
Sources: Literature
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.
Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa.
P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls.
P2 - harboured V355A and a polymorphism in trans in HSPA9.
Pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.
Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa.
Patient VA-39 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls.
P2 - harboured V355A and a polymorphism in trans in HSPA9.
Pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
Rare anaemia v4.8 HSPA9 Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 26491070, 33398880, 38360212
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.
Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals.
The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa.
P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls.
P2 - harboured V355A and a polymorphism in trans in HSPA9.
Pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.
Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant).
In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype".
The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa.
P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls.
P2 - harboured V355A and a polymorphism in trans in HSPA9.
Pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
Rare anaemia v4.8 HSPA9 Ida Ertmanska changed review comment from: PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa.
P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls.
P2 - harboured V355A and a polymorphism in HSPA9.; to: PMID: 26491070 Schmitz-Abe et al., 2015
Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected.
Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals.
Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals.
The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign).
2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance.

PMID: 33398880 Li et al., 2021
Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T.

PMID: 38360212 Sharma et al., 2024
290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa.
P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls.
P2 - harboured V355A and a polymorphism in trans in HSPA9.
Pseudodominant inheritance.

Functional: PMID: 25550197 Krysiak et al., 2016
Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
Rare anaemia v4.8 HSPA9 Ida Ertmanska reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 33398880, 38360212; Phenotypes: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v10.8 HSPA9 Ida Ertmanska Classified gene: HSPA9 as Amber List (moderate evidence)
Skeletal dysplasia v10.8 HSPA9 Ida Ertmanska Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v10.7 HSPA9 Ida Ertmanska Classified gene: HSPA9 as Red List (low evidence)
Skeletal dysplasia v10.7 HSPA9 Ida Ertmanska Added comment: Comment on list classification: Skeletal dysplasia is a major feature of EVEN-PLUS syndrome, caused by biallelic variants in HSPA9. There are at least 7 unrelated EVEN-PLUS families reported in literature, with characteristic skeletal features: hypoplastic nasal bones, dysplastic femoral heads, bifid distal femurs, dysplastic epiphyses, delayed ossification, and short stature. Hence, this gene should be promoted to Green at the next update.
Skeletal dysplasia v10.7 HSPA9 Ida Ertmanska Gene: hspa9 has been classified as Red List (Low Evidence).
Skeletal dysplasia v10.6 HSPA9 Ida Ertmanska changed review comment from: PMID: 26598328 Royer-Bertrand et al., 2015
Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome.

DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018
Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG.

PMID: 32869452 Younger et al., 2020
WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia.

PMID: 35779070 Pacio-Miguez et al., 2022
Reported two families.
F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification
F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents).

PMID: 36052765 Li et al., 2022
Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora.
Sources: Literature; to: PMID: 26598328 Royer-Bertrand et al., 2015
Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome.
Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients.
P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees.
P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae.

DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018
Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG.

PMID: 32869452 Younger et al., 2020
WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia.

PMID: 35779070 Pacio-Miguez et al., 2022
Reported two families.
F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification
F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents).

PMID: 36052765 Li et al., 2022
Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora.
Sources: Literature
Malformations of cortical development v8.11 ATP1A2 Eleanor Williams Phenotypes for gene: ATP1A2 were changed from Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, http://purl.obolibrary.org/obo/MONDO_0859204 to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MONDO:0859204
Malformations of cortical development v8.10 ATP1A2 Eleanor Williams Phenotypes for gene: ATP1A2 were changed from Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602 to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, http://purl.obolibrary.org/obo/MONDO_0859204
Malformations of cortical development v8.9 ATP1A2 Eleanor Williams Publications for gene: ATP1A2 were set to 30690204; 31608932
DDG2P v8.2 FRYL Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is only evidence available from a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated amber.

However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of moderate and abiove should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P.; to: Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is evidence available from only a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated green.

However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of 'moderate' and above should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P.
DDG2P v8.2 FRYL Achchuthan Shanmugasundram Classified gene: FRYL as Green List (high evidence)
DDG2P v8.2 FRYL Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is only evidence available from a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated amber.

However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of moderate and abiove should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P.
DDG2P v8.2 FRYL Achchuthan Shanmugasundram Gene: fryl has been classified as Green List (High Evidence).
DDG2P v8.1 FRYL Achchuthan Shanmugasundram changed review comment from: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution.

Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support.

Key concerns limiting confidence:
(1) Half of the reported variants (7) are present in gnomAD v4.1.1.
(2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism.
(3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar.
(4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease
(5) No familial segregation data exist (all cases simplex).
(6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution.

This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp.
Overall, this represents a single-publication gene-disease claim with substantive unresolved population genetics and functional modelling concerns — further independent case series and reconciliation with gnomAD v4 constraint data are needed before upgrading to green.; to: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution.

Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support.

Key concerns limiting confidence:
(1) Half of the reported variants (7) are present in gnomAD v4.1.1.
(2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism.
(3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar.
(4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease
(5) No familial segregation data exist (all cases simplex).
(6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution.

This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp.
DDG2P v8.1 FRYL Achchuthan Shanmugasundram edited their review of gene: FRYL: Changed rating: AMBER
DDG2P v8.1 FRYL Achchuthan Shanmugasundram edited their review of gene: FRYL: Added comment: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution.

Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support.

Key concerns limiting confidence:
(1) Half of the reported variants (7) are present in gnomAD v4.1.1.
(2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism.
(3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar.
(4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease
(5) No familial segregation data exist (all cases simplex).
(6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution.

This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp.
Overall, this represents a single-publication gene-disease claim with substantive unresolved population genetics and functional modelling concerns — further independent case series and reconciliation with gnomAD v4 constraint data are needed before upgrading to green.; Changed phenotypes to: Pan-Chung-Bellen syndrome, OMIM:621049, Pan-Chung-Bellen syndrome, MONDO:0975953, FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities
Skeletal dysplasia v10.6 HSPA9 Ida Ertmanska gene: HSPA9 was added
gene: HSPA9 was added to Skeletal dysplasia. Sources: Literature
Q3_26_promote_green tags were added to gene: HSPA9.
Mode of inheritance for gene: HSPA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSPA9 were set to 26598328; DOI:10.4172/1747-0862.1000350; 32869452; 35779070; 36052765
Phenotypes for gene: HSPA9 were set to Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801; epiphysial-vertebral-ear dysplasia-nose-plus associated findings syndrome
Review for gene: HSPA9 was set to GREEN
Added comment: PMID: 26598328 Royer-Bertrand et al., 2015
Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome.

DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018
Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG.

PMID: 32869452 Younger et al., 2020
WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia.

PMID: 35779070 Pacio-Miguez et al., 2022
Reported two families.
F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification
F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents).

PMID: 36052765 Li et al., 2022
Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora.
Sources: Literature
Malformations of cortical development v8.8 ATP1A2 Ida Ertmanska edited their review of gene: ATP1A2: Changed publications to: 33880529, 37870493, 38549198, 39046620
Malformations of cortical development v8.8 ATP1A2 Ida Ertmanska edited their review of gene: ATP1A2: Changed publications to: 33880529, 37870493
Malformations of cortical development v8.8 ATP1A2 Ida Ertmanska commented on gene: ATP1A2: Comment on mode of inheritance: While polymicrogyria is a consistent feature in patients with biallelic ATP1A2 variants, there is only 1 individual reported with polymicrogyria and a monoallelic ATP1A2 variant. Hence, the MOI should remain BIALLELIC, autosomal or pseudoautosomal.
Malformations of cortical development v8.8 ATP1A2 Ida Ertmanska changed review comment from: Monoallelic cases:
PMID: 33880529 Vetro et al., 2021
Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations).

Additional biallelic cases:
PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.

PMID: 39046620 Hassani & Malekzadeh, 2024
Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns.

PMID: 38549198 Burrill et al., 2024
Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal.; to: Monoallelic cases:
PMID: 33880529 Vetro et al., 2021
Report of 6 patients who harboured 5 distinct heterozygous missense variants in ATP1A2. 3/6 patients had severe ID/DD, 2 - moderate, and 1 individual had no DD/ID. 2/6 patients had postnatal microcephaly. Polymicrogyria was present in just 1/6 individuals reported (P6) - more common in patients with ATP1A3 variants. Alternating hemiplegia was not present in any of the probands.

Additional biallelic cases:
PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.

PMID: 39046620 Hassani & Malekzadeh, 2024
Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns.

PMID: 38549198 Burrill et al., 2024
Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal.
Early onset or syndromic epilepsy v9.76 ATP1A2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 2nd Sept 2026.
Early onset or syndromic epilepsy v9.76 ATP1A2 Ida Ertmanska Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MONDO:0859204; Developmental and epileptic encephalopathy 98, OMIM:619605; developmental and epileptic encephalopathy 98, MONDO:0030472
Early onset or syndromic epilepsy v9.75 ATP1A2 Ida Ertmanska Publications for gene: ATP1A2 were set to 15159495; 29610157; 28058944; 18028407; 12953268
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska Tag Q3_26_promote_green was removed from gene: ATP1A2.
Tag Q3_26_MOI tag was added to gene: ATP1A2.
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ATP1A2.
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are now at least 7 unrelated families reported in literature with biallelic ATP1A2 variants and; to: Comment on mode of inheritance: There are now at least 7 unrelated families reported in literature with biallelic ATP1A2 variants and the 'Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies' syndrome. 2 unrelated individuals presented with epilepsy shortly after birth, and 2 further cases were reported with in-utero seizures. Hence, the mode of inheriatance should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska commented on gene: ATP1A2: Comment on mode of inheritance: There are now at least 7 unrelated families reported in literature with biallelic ATP1A2 variants and
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska edited their review of gene: ATP1A2: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Malformations of cortical development v8.8 ATP1A2 Ida Ertmanska changed review comment from: Monoallelic cases:
PMID: 33880529 Vetro et al., 2021

Additional biallelic cases:
PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.

PMID: 39046620 Hassani & Malekzadeh, 2024
Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns.

PMID: 38549198 Burrill et al., 2024
Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal.; to: Monoallelic cases:
PMID: 33880529 Vetro et al., 2021
Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations).

Additional biallelic cases:
PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.

PMID: 39046620 Hassani & Malekzadeh, 2024
Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns.

PMID: 38549198 Burrill et al., 2024
Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal.
Malformations of cortical development v8.8 ATP1A2 Ida Ertmanska changed review comment from: PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.; to: Monoallelic cases:
PMID: 33880529 Vetro et al., 2021

Additional biallelic cases:
PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.

PMID: 39046620 Hassani & Malekzadeh, 2024
Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns.

PMID: 38549198 Burrill et al., 2024
Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal.
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska edited their review of gene: ATP1A2: Changed publications to: 28811059, 31608932, 30690204, 37870493, 38549198, 39046620
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska changed review comment from: BIALLELIC CASES:
PMID: 28811059 Wilbur et al., 2017
Report of a boy who presented at age three months with epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. WES identified ATP1A2 comp het variants (p.Arg548Cys) & (p.Arg1008Trp).

PMID: 31608932 Chatron et al., 2019
Report of four cases from 2 independent families with recessive lethal syndromic polymicrogyria. Examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. Probands from both families were homozygous for unique nonsense variants in ATP1A2.

PMID: 30690204 Monteiro et al., 2020
Report of three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LoF variants in ATP1A2 were found on WES.
P1 & P2 - affected sibs, male and female, Brazilian. Seizures developed soon after birth in P1, and in-utero seizures suspected by the mother in P2. P2 was homozygous for NM_000702: c.2104_2105delTG, p.(Cys702Serfs*12). P1 confirmed to be homozygous for the same variant with Sanger seq, unaffected parents were het.
P3 - Hispanic female neonate. Abnormal fetal movements noted, consistent with seizure activity. WES identified a homozygous ATP1A2 c.835del, p.(Arg279Glyfs*4) variant.

PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.; to: BIALLELIC CASES:
PMID: 28811059 Wilbur et al., 2017
Report of a boy who presented at age three months with epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. WES identified ATP1A2 comp het variants (p.Arg548Cys) & (p.Arg1008Trp).

PMID: 31608932 Chatron et al., 2019
Report of four cases from 2 independent families with recessive lethal syndromic polymicrogyria. Examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. Probands from both families were homozygous for unique nonsense variants in ATP1A2.

PMID: 30690204 Monteiro et al., 2020
Report of three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LoF variants in ATP1A2 were found on WES.
P1 & P2 - affected sibs, male and female, Brazilian. Seizures developed soon after birth in P1, and in-utero seizures suspected by the mother in P2. P2 was homozygous for NM_000702: c.2104_2105delTG, p.(Cys702Serfs*12). P1 confirmed to be homozygous for the same variant with Sanger seq, unaffected parents were het.
P3 - Hispanic female neonate. Abnormal fetal movements noted, consistent with seizure activity. WES identified a homozygous ATP1A2 c.835del, p.(Arg279Glyfs*4) variant.

PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.

PMID: 39046620 Hassani & Malekzadeh, 2024
Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns.

PMID: 38549198 Burrill et al., 2024
Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal.
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska edited their review of gene: ATP1A2: Changed publications to: 28811059, 31608932, 30690204, 37870493
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska changed review comment from: BIALLELIC CASES:
PMID: 28811059 Wilbur et al., 2017
Report of a boy who presented at age three months with epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. WES identified ATP1A2 comp het variants (p.Arg548Cys) & (p.Arg1008Trp).

PMID: 31608932 Chatron et al., 2019
Report of four cases from 2independent families with recessive lethal syndromic polymicrogyria. Examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts.

PMID: 30690204 Monteiro et al., 2020
Report of three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LoF variants in ATP1A2 were found on WES.
P2 was homozygous for NM_000702: c.2104_2105delTG, p.(Cys702Serfs*12).; to: BIALLELIC CASES:
PMID: 28811059 Wilbur et al., 2017
Report of a boy who presented at age three months with epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. WES identified ATP1A2 comp het variants (p.Arg548Cys) & (p.Arg1008Trp).

PMID: 31608932 Chatron et al., 2019
Report of four cases from 2 independent families with recessive lethal syndromic polymicrogyria. Examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. Probands from both families were homozygous for unique nonsense variants in ATP1A2.

PMID: 30690204 Monteiro et al., 2020
Report of three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LoF variants in ATP1A2 were found on WES.
P1 & P2 - affected sibs, male and female, Brazilian. Seizures developed soon after birth in P1, and in-utero seizures suspected by the mother in P2. P2 was homozygous for NM_000702: c.2104_2105delTG, p.(Cys702Serfs*12). P1 confirmed to be homozygous for the same variant with Sanger seq, unaffected parents were het.
P3 - Hispanic female neonate. Abnormal fetal movements noted, consistent with seizure activity. WES identified a homozygous ATP1A2 c.835del, p.(Arg279Glyfs*4) variant.

PMID: 37870493 Furukawa et al., 2023
Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.
Early onset or syndromic epilepsy v9.74 ATP1A2 Ida Ertmanska reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28811059, 31608932, 30690204; Phenotypes: Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602, fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MONDO:0859204; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v11.28 DEPDC5 Ida Ertmanska Tag Q3_26_demote_red was removed from gene: DEPDC5.
Tag Q3_26_MOI tag was added to gene: DEPDC5.
Intellectual disability v11.28 DEPDC5 Ida Ertmanska changed review comment from: Comment on list classification: Based on large literature reviews, intellectual disability is present in only 12-28% of individuals with DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants. Hence, this gene should be downgraded to Red on this panel; DEPDC5 is already Green on Early onset or syndromic epilepsy. As this is a demotion, an 'expert-review' tag is added to ensure NHSE agreement.; to: Comment on mode of inheritance: Based on large literature reviews, intellectual disability is present in only 12-28% of individuals with monoallelic DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants, and this gene is already Green on Early onset or syndromic epilepsy.
In patients with biallelic DEPDC5 variants, developmental delay is more severe, and was the presenting feature in several cases (PMID:36067010). Hence, the MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. As this is a demotion for monoallelic cases, an 'expert-review' tag is added to ensure NHSE agreement.
Intellectual disability v11.28 DEPDC5 Ida Ertmanska edited their review of gene: DEPDC5: Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v11.28 DEPDC5 Ida Ertmanska Added comment: Comment on phenotypes: Phenotypes updated on 1st Sept 2026.
Intellectual disability v11.28 DEPDC5 Ida Ertmanska Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1, OMIM:604364 to Epilepsy, familial focal, with variable foci 1, OMIM:604364; epilepsy, familial focal, with variable foci 1, MONDO:0024556; Developmental and epileptic encephalopathy 111, OMIM:620504; developmental and epileptic encephalopathy 111, MONDO:0957780
Intellectual disability v11.27 DEPDC5 Ida Ertmanska Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701
Intellectual disability v11.26 DEPDC5 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: DEPDC5.
Tag Q3_26_demote_red tag was added to gene: DEPDC5.
Intellectual disability v11.26 DEPDC5 Ida Ertmanska changed review comment from: Comment on list classification: Based on large literature review, intellectual disability is present in only 12-28% of individuals with DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants. Hence, this gene should be downgraded to Red on this panel; DEPDC5 is already Green on Early onset or syndromic epilepsy. As this is a demotion, an 'expert-review' tag is added to ensure NHSE agreement.; to: Comment on list classification: Based on large literature reviews, intellectual disability is present in only 12-28% of individuals with DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants. Hence, this gene should be downgraded to Red on this panel; DEPDC5 is already Green on Early onset or syndromic epilepsy. As this is a demotion, an 'expert-review' tag is added to ensure NHSE agreement.
Intellectual disability v11.26 DEPDC5 Ida Ertmanska commented on gene: DEPDC5: Comment on list classification: Based on large literature review, intellectual disability is present in only 12-28% of individuals with DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants. Hence, this gene should be downgraded to Red on this panel; DEPDC5 is already Green on Early onset or syndromic epilepsy. As this is a demotion, an 'expert-review' tag is added to ensure NHSE agreement.
Intellectual disability v11.26 DEPDC5 Ida Ertmanska edited their review of gene: DEPDC5: Changed rating: RED
Intellectual disability v11.26 DEPDC5 Ida Ertmanska edited their review of gene: DEPDC5: Added comment: https://www.ncbi.nlm.nih.gov/books/NBK385626/ - DEPDC5-Related Epilepsy entry on GeneReviews (Baulac & Baldassari, updated in 2023) states that 100% of individuals with DEPDC5-related disease present with epilepsy (most commonly frontal lobe seizures / sleep-related hypermotor epilepsy). Meanwhile, neurodevelopment and behaviour is normal in most reported cases. Intellectual disability was present in only 12% of individuals, and likely secondary to brain malfromations and infantile spasms.

PMID: 41118617 Ochoa-Urrea et al., 2025
Review of 170 families with DEPDC5-Related Epilepsy. 76.1% of variant carriers developed epilepsy by age 10 years. Cortical malformations were present in 28% of those with available MRI.
Early seizure onset strongly correlated with drug resistance (p = 2.4e-08), intellectual disability (p = 2.1e-08), and lesional MRI (p = 2.2e-08).
Intellectual disability, usually mild, was identified in 27% of affected individuals, and psychiatric comorbidities—such as attention deficits, oppositional behaviours, mood disorders, and autism—affected 46% of the studied cohort. ID was reported exclusively in individuals with existing epilepsy.; Changed publications to: 32848577, 36067010, 41118617
Intellectual disability v11.26 DEPDC5 Ida Ertmanska changed review comment from: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel:

The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype.

PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy.

PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway.

DEPDC5 is now associated with AR Developmental and epileptic encephalopathy 111, OMIM:620504, as well as AD Epilepsy, familial focal, with variable foci 1, OMIM:604364 (OMIM accessed 1st Sept 2026).; to: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel:

The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype.

PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy.

PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway.

DEPDC5 is now associated with AR Developmental and epileptic encephalopathy 111, OMIM:620504, as well as AD Epilepsy, familial focal, with variable foci 1, OMIM:604364 (OMIM accessed 1st Sept 2026).
Intellectual disability v11.26 DEPDC5 Ida Ertmanska changed review comment from: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel:

The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype.

PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy.

PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway.; to: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel:

The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype.

PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy.

PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway.

DEPDC5 is now associated with AR Developmental and epileptic encephalopathy 111, OMIM:620504, as well as AD Epilepsy, familial focal, with variable foci 1, OMIM:604364 (OMIM accessed 1st Sept 2026).
Intellectual disability v11.26 DEPDC5 Ida Ertmanska changed review comment from: Literature review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel:

The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype.

PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy.

PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway.; to: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel:

The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype.

PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy.

PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway.
Intellectual disability v11.26 DEPDC5 Ida Ertmanska reviewed gene: DEPDC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 32848577, 36067010; Phenotypes: Epilepsy, familial focal, with variable foci 1, OMIM:604364, epilepsy, familial focal, with variable foci 1, MONDO:0024556, Developmental and epileptic encephalopathy 111, OMIM:620504, developmental and epileptic encephalopathy 111, MONDO:0957780; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.74 DEPDC5 Ida Ertmanska Added comment: Comment on phenotypes: Recessive phenotype terms updated 1st Sept 2026.
Early onset or syndromic epilepsy v9.74 DEPDC5 Ida Ertmanska Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1, OMIM:604364 to Epilepsy, familial focal, with variable foci 1, OMIM:604364; epilepsy, familial focal, with variable foci 1, MONDO:0024556; Developmental and epileptic encephalopathy 111, OMIM:620504; developmental and epileptic encephalopathy 111, MONDO:0957780
Malformations of cortical development v8.8 DEPDC5 Ida Ertmanska Added comment: Comment on phenotypes: Recessive phenotype terms updated 1st Sept 2026.
Malformations of cortical development v8.8 DEPDC5 Ida Ertmanska Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1, OMIM:604364; Focal cortical dysplasia to Epilepsy, familial focal, with variable foci 1, OMIM:604364; epilepsy, familial focal, with variable foci 1, MONDO:0024556; Developmental and epileptic encephalopathy 111, OMIM:620504; developmental and epileptic encephalopathy 111, MONDO:0957780
Pneumothorax - familial v3.8 ABL1 Matthew Edwards gene: ABL1 was added
gene: ABL1 was added to Pneumothorax - familial. Sources: NHS GMS
Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ABL1 were set to PMID: 32643838; PMID: 41416177; PMID: 23826103; PMID: 33223528
Phenotypes for gene: ABL1 were set to CONGENITAL HEART DEFECTS AND SKELETAL MALFORMATIONS SYNDROME; CHDSKM
Penetrance for gene: ABL1 were set to unknown
Review for gene: ABL1 was set to GREEN
Added comment: This gene is green on R125 FTAA panel, and several papers have pneumothorax as a presenting feature of CHDSKM (see PMIDs above). Our lab has also had a case with a pathogenic variant and pneumothorax as the primary presenting feature. Appropriate therefore for gene to be represnted on this panel.
Sources: NHS GMS
Arthrogryposis v10.23 SMARCAD1 Ida Ertmanska Classified gene: SMARCAD1 as Amber List (moderate evidence)
Arthrogryposis v10.23 SMARCAD1 Ida Ertmanska Added comment: Comment on list classification: There are now multiple individuals reported in literature with monoallelic SMARCAD1 variants and Basan syndrome or Huriez syndrome, both of which may include contractures. However, contractures are usually mild, e.g., only little finger affected. It is also a less prominent feature than the cutaneous symptoms. Hence, this gene should be rated Amber based on available evidence.
Arthrogryposis v10.23 SMARCAD1 Ida Ertmanska Gene: smarcad1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v10.22 SMARCAD1 Ida Ertmanska Phenotypes for gene: SMARCAD1 were changed from Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600 to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600; isolated congenital adermatoglyphia, MONDO:0007619; absence of fingerprints-congenital milia syndrome, MONDO:0007507; palmoplantar keratoderma-sclerodactyly syndrome, MONDO:0008416
Palmoplantar keratodermas v4.20 SMARCAD1 Ida Ertmanska Phenotypes for gene: SMARCAD1 were changed from Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600 to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600; isolated congenital adermatoglyphia, MONDO:0007619; absence of fingerprints-congenital milia syndrome, MONDO:0007507; palmoplantar keratoderma-sclerodactyly syndrome, MONDO:0008416
Ichthyosis and erythrokeratoderma v4.21 SMARCAD1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes updated 28th Aug 2026.
Ichthyosis and erythrokeratoderma v4.21 SMARCAD1 Ida Ertmanska Phenotypes for gene: SMARCAD1 were changed from Basan syndrome, OMIM:129200; palmoplantar keratoderma to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600; isolated congenital adermatoglyphia, MONDO:0007619; absence of fingerprints-congenital milia syndrome, MONDO:0007507; palmoplantar keratoderma-sclerodactyly syndrome, MONDO:0008416
Ichthyosis and erythrokeratoderma v4.20 SMARCAD1 Ida Ertmanska Publications for gene: SMARCAD1 were set to 24909267; 26932190; 24664640
Ichthyosis and erythrokeratoderma v4.19 SMARCAD1 Ida Ertmanska Mode of inheritance for gene: SMARCAD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ichthyosis and erythrokeratoderma v4.18 SMARCAD1 Ida Ertmanska Classified gene: SMARCAD1 as Red List (low evidence)
Ichthyosis and erythrokeratoderma v4.18 SMARCAD1 Ida Ertmanska Gene: smarcad1 has been classified as Red List (Low Evidence).
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska Tag watchlist was removed from gene: SMARCAD1.
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska edited their review of gene: SMARCAD1: Changed rating: RED
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska commented on gene: SMARCAD1: Comment on list classification: While there are numerous patients reported with variants in SMARCAD1, none of them presented with ichthyosis or erythrokeratoderma. Hence, this gene should be rated Red - 'watchlist' tag removed. Instead, this gene is proposed for promotion to Green on the Palmoplantar keratodermas panel.
Palmoplantar keratodermas v4.19 SMARCAD1 Ida Ertmanska Classified gene: SMARCAD1 as Amber List (moderate evidence)
Palmoplantar keratodermas v4.19 SMARCAD1 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 families reported in literature with monoallelic variants in SMARCAD1 and Huriez syndrome, which includes scleroatrophy of hands and feet, as well as palmoplantar hyperkeratosis. Some individuals with Basan syndrome also presented with palmoplantar keratoderma. Both syndromes are caused by monoallelic variants (deletions and splice variants) that affect the same splice site in the short skin-specific isoform of SMARCAD1. Based on available evidence, this gene can be promoted to Green at the next update.
Palmoplantar keratodermas v4.19 SMARCAD1 Ida Ertmanska Gene: smarcad1 has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v4.18 SMARCAD1 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: SMARCAD1.
Palmoplantar keratodermas v4.18 SMARCAD1 Ida Ertmanska edited their review of gene: SMARCAD1: Changed rating: GREEN
Arthrogryposis v10.21 SMARCAD1 Ida Ertmanska gene: SMARCAD1 was added
gene: SMARCAD1 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: SMARCAD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCAD1 were set to 21820097; 24909267; 26932190; 29409814; 30289605; 33400266; 34909722; 35212137
Phenotypes for gene: SMARCAD1 were set to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600
Review for gene: SMARCAD1 was set to AMBER
Added comment: HURIEZ SYNDROME
PMID: 35212137 Loh et al., 2022
Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age.
Family 1 - proband had mild hyperkeratosis of soles, thin palmar skin, and weak, pointed nails. Sanger seq revealed a heterozygous 11-bp deletion in SMARCAD1: g.94253671_94253682del.
Family 2 - male proband presented with scleroatrophy of hands, contracture of the little finger, sclerodactyly of distal extremities, hypoplastic nails, hypohidrosis. Proband and his affected mother were both het for a deletion affecting the SMARCAD1 donor splice site: g.94253673del
Family 3 - case previously described in PMID: 8731679 Hamm, 1996 and PMID: 29409814 Günther et al., 2018

PMID: 33400266 Loh et al., 2021
Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1
Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2).

PMID: 29409814 Günther et al., 2018
Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C.

BASAN SYNDROME:
PMID: 34909722 Elhaji et al., 2021
Report of 2 families (Canadian and Dutch) with Basan syndrome:
Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform.

Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients.
Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210).

PMID: 30289605 Valentin et al., 2018
Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform.

PMID: 26932190 Li et al., 2016
Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01.

NON-SYNDROMIC ADERMATOGLYPHIA:
PMID: 32769257 Alruwaili & Hai, 2019
Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform.

PMID: 24909267 Nousbeck et al., 2014
3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A)

PMID: 21820097 Nousbeck et al., 2011
Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T.

N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED

SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).
Sources: Literature
Palmoplantar keratodermas v4.18 SMARCAD1 Ida Ertmanska gene: SMARCAD1 was added
gene: SMARCAD1 was added to Palmoplantar keratodermas. Sources: Literature
Mode of inheritance for gene: SMARCAD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCAD1 were set to 21820097; 24909267; 26932190; 29409814; 30289605; 33400266; 34909722; 35212137
Phenotypes for gene: SMARCAD1 were set to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600
Review for gene: SMARCAD1 was set to AMBER
Added comment: HURIEZ SYNDROME
PMID: 35212137 Loh et al., 2022
Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age.
Family 1 - proband had mild hyperkeratosis of soles, thin palmar skin, and weak, pointed nails. Sanger seq revealed a heterozygous 11-bp deletion in SMARCAD1: g.94253671_94253682del.
Family 2 - male proband presented with scleroatrophy of hands, contracture of the little finger, sclerodactyly of distal extremities, hypoplastic nails, hypohidrosis. Proband and his affected mother were both het for a deletion affecting the SMARCAD1 donor splice site: g.94253673del
Family 3 - case previously described in PMID: 8731679 Hamm, 1996 and PMID: 29409814 Günther et al., 2018

PMID: 33400266 Loh et al., 2021
Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1
Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2).

PMID: 29409814 Günther et al., 2018
Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C.

BASAN SYNDROME:
PMID: 34909722 Elhaji et al., 2021
Report of 2 families (Canadian and Dutch) with Basan syndrome:
Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform.

Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients.
Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210).

PMID: 30289605 Valentin et al., 2018
Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform.

PMID: 26932190 Li et al., 2016
Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01.

NON-SYNDROMIC ADERMATOGLYPHIA:
PMID: 32769257 Alruwaili & Hai, 2019
Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform.

PMID: 24909267 Nousbeck et al., 2014
3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A)

PMID: 21820097 Nousbeck et al., 2011
Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T.

N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED

SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).
Sources: Literature
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska changed review comment from: HURIEZ SYNDROME
PMID: 35212137 Loh et al., 2022
Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age.

PMID: 33400266 Loh et al., 2021
Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1
Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2).

PMID: 29409814 Günther et al., 2018
Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C.

BASAN SYNDROME:
PMID: 34909722 Elhaji et al., 2021
Report of 2 families (Canadian and Dutch) with Basan syndrome:
Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform.

Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients.
Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210).

PMID: 30289605 Valentin et al., 2018
Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform.

PMID: 26932190 Li et al., 2016
Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01.

NON-SYNDROMIC ADERMATOGLYPHIA:
PMID: 32769257 Alruwaili & Hai, 2019
Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform.

PMID: 24909267 Nousbeck et al., 2014
3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A)

PMID: 21820097 Nousbeck et al., 2011
Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T.

N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED

SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).; to: HURIEZ SYNDROME
PMID: 35212137 Loh et al., 2022
Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age.
Family 1 - proband had mild hyperkeratosis of soles, thin palmar skin, and weak, pointed nails. Sanger seq revealed a heterozygous 11-bp deletion in SMARCAD1: g.94253671_94253682del.
Family 2 - male proband presented with scleroatrophy of hands, contracture of the little finger, sclerodactyly of distal extremities, hypoplastic nails, hypohidrosis. Proband and his affected mother were both het for a deletion affecting the SMARCAD1 donor splice site: g.94253673del
Family 3 - case previously described in PMID: 8731679 Hamm, 1996 and PMID: 29409814 Günther et al., 2018

PMID: 33400266 Loh et al., 2021
Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1
Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2).

PMID: 29409814 Günther et al., 2018
Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C.

BASAN SYNDROME:
PMID: 34909722 Elhaji et al., 2021
Report of 2 families (Canadian and Dutch) with Basan syndrome:
Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform.

Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients.
Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210).

PMID: 30289605 Valentin et al., 2018
Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform.

PMID: 26932190 Li et al., 2016
Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01.

NON-SYNDROMIC ADERMATOGLYPHIA:
PMID: 32769257 Alruwaili & Hai, 2019
Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform.

PMID: 24909267 Nousbeck et al., 2014
3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A)

PMID: 21820097 Nousbeck et al., 2011
Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T.

N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED

SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska edited their review of gene: SMARCAD1: Changed rating: AMBER; Changed publications to: 21820097, 24909267, 26932190, 29409814, 30289605, 33400266, 34909722, 35212137
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska changed review comment from: HURIEZ SYNDROME
PMID: 33400266 Loh et al., 2021
Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1
Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2).

PMID: 29409814 Günther et al., 2018
Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C.

BASAN SYNDROME:
PMID: 34909722 Elhaji et al., 2021
Report of 2 families (Canadian and Dutch) with Basan syndrome:
Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform.

Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients.
Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210).

PMID: 30289605 Valentin et al., 2018
Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform.

PMID: 26932190 Li et al., 2016
Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01.

NON-SYNDROMIC ADERMATOGLYPHIA:
PMID: 24909267 Nousbeck et al., 2014
3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A)

PMID: 21820097 Nousbeck et al., 2011
Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T.

N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED

SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).; to: HURIEZ SYNDROME
PMID: 35212137 Loh et al., 2022
Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age.

PMID: 33400266 Loh et al., 2021
Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1
Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2).

PMID: 29409814 Günther et al., 2018
Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C.

BASAN SYNDROME:
PMID: 34909722 Elhaji et al., 2021
Report of 2 families (Canadian and Dutch) with Basan syndrome:
Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform.

Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients.
Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210).

PMID: 30289605 Valentin et al., 2018
Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform.

PMID: 26932190 Li et al., 2016
Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01.

NON-SYNDROMIC ADERMATOGLYPHIA:
PMID: 32769257 Alruwaili & Hai, 2019
Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform.

PMID: 24909267 Nousbeck et al., 2014
3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A)

PMID: 21820097 Nousbeck et al., 2011
Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T.

N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED

SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska edited their review of gene: SMARCAD1: Changed publications to: 21820097, 24909267, 26932190, 29409814, 30289605, 33400266, 34909722
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska changed review comment from: HURIEZ SYNDROME
PMID: 33400266 Loh et al., 2021
Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1
Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2).

PMID: 29409814 Günther et al., 2018
Report of 2 families with Huriez syndrome. SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C.

BASAN SYNDROME:
PMID: 26932190 Li et al., 2016
Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1. Variant co-segregated with disease, maximal LOD score was 3.01.

N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED

SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).; to: HURIEZ SYNDROME
PMID: 33400266 Loh et al., 2021
Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1
Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2).

PMID: 29409814 Günther et al., 2018
Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C.

BASAN SYNDROME:
PMID: 34909722 Elhaji et al., 2021
Report of 2 families (Canadian and Dutch) with Basan syndrome:
Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform.

Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients.
Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210).

PMID: 30289605 Valentin et al., 2018
Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform.

PMID: 26932190 Li et al., 2016
Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01.

NON-SYNDROMIC ADERMATOGLYPHIA:
PMID: 24909267 Nousbeck et al., 2014
3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A)

PMID: 21820097 Nousbeck et al., 2011
Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T.

N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED

SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska edited their review of gene: SMARCAD1: Changed publications to: 26932190, 29409814, 33400266
Ichthyosis and erythrokeratoderma v4.17 SMARCAD1 Ida Ertmanska reviewed gene: SMARCAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26932190, 33400266; Phenotypes: Adermatoglyphia, OMIM:136000, Basan syndrome, OMIM:129200, Huriez syndrome, OMIM:181600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v8.1 FRYL Julie Evans reviewed gene: FRYL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Clefting v7.10 PAX3 Ida Ertmanska changed review comment from: PMID: 34918979 Liang et al., 2021
Report of a Chinese pedigree with nonsyndromic cleft lip with or without palate. PAX3 missense variant detected: c.92C>G, p.(Thr31Ser).

PMID: 27081571 Yoshida et al., 2016
Report of a 10 mo Japanese boy with pigmentation abnormalities of the right iris, ocular hypertelorism (W index: 2.00), right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. Family history of iris pigmentation abnormality and hearing loss on mother's side. Proband was het for PAX3: c.1107C>G, p.(Ser369Arg), parents not tested. Variant not in gnomAD v4.1.1.

PMID: 18483623 Wu et al., 2008 - mouse model
Persistent expression of Pax3 in cranial neural crest cells resulted in cleft palate, ocular defects, malformation of the sphenoid bone, and perinatal lethality in mice.; to: PMID: 34918979 Liang et al., 2021
Report of a Chinese pedigree with nonsyndromic cleft lip with or without palate. Son (proband, 11yo male) and his father affected. Both affected individuals were het for a PAX3 missense variant: c.92C>G, p.(Thr31Ser). Method: Trio WES. Variant was absent in the healthy mother, as well as 113 unrelated healthy controls.

PMID: 27081571 Yoshida et al., 2016
Report of a 10 mo Japanese boy with pigmentation abnormalities of the right iris, ocular hypertelorism (W index: 2.00), right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. Family history of iris pigmentation abnormality and hearing loss on mother's side. Proband was het for PAX3: c.1107C>G, p.(Ser369Arg), parents not tested. Variant not in gnomAD v4.1.1.

PMID: 18483623 Wu et al., 2008 - mouse model
Persistent expression of Pax3 in cranial neural crest cells resulted in cleft palate, ocular defects, malformation of the sphenoid bone, and perinatal lethality in mice.
Clefting v7.10 PAX3 Ida Ertmanska reviewed gene: PAX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18483623, 27081571, 34918979; Phenotypes: orofacial cleft, MONDO:0000358, Waardenburg syndrome, type 1, OMIM:193500, Waardenburg syndrome type 1, MONDO:0008670; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v9.32 ATP6V0C Ida Ertmanska changed review comment from: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients.; to: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. Ataxia has also been reported in the epilepsy/developmental cases associated with SNVs in this gene.
Ataxia and cerebellar anomalies - childhood onset v9.32 ATP6V0C Ida Ertmanska changed review comment from: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber.; to: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients.
Acute rhabdomyolysis v3.1 CAV3 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CAV3.
Tag Q3_26_MOI tag was added to gene: CAV3.
Rhabdomyolysis and metabolic muscle disorders v6.9 CAV3 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance (1), limb girdle muscular dystrophy (1), and mild proximal muscle weakness (2). One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change.; to: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance (1), limb girdle muscular dystrophy (1), and mild proximal muscle weakness (2). One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should remain MONOALLELIC, due to conflicting evidence for a BIALLELIC association. A 'watchlist-moi' tag was added in anticipation of stronger evidence for the recessive assocation.
Rhabdomyolysis and metabolic muscle disorders v6.9 CAV3 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change.; to: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance (1), limb girdle muscular dystrophy (1), and mild proximal muscle weakness (2). One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change.
Rhabdomyolysis and metabolic muscle disorders v6.9 CAV3 Ida Ertmanska commented on gene: CAV3: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change.
Rhabdomyolysis and metabolic muscle disorders v6.9 CAV3 Ida Ertmanska Deleted their comment
Rhabdomyolysis and metabolic muscle disorders v6.9 CAV3 Ida Ertmanska edited their review of gene: CAV3: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rhabdomyolysis and metabolic muscle disorders v6.9 CAV3 Ida Ertmanska Tag Q3_26_MOI was removed from gene: CAV3.
Tag watchlist_moi tag was added to gene: CAV3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 CAV3 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should remain as MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. A 'watchlist-moi' tag was added in anticipation of stronger evidence for the recessive assocation.; to: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy (1 individual), and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should remain as MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. A 'watchlist-moi' tag was added in anticipation of stronger evidence for the recessive assocation.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 CAV3 Ida Ertmanska commented on gene: CAV3: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should remain as MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. A 'watchlist-moi' tag was added in anticipation of stronger evidence for the recessive assocation.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 CAV3 Ida Ertmanska reviewed gene: CAV3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9536092, 12666119, 15668980, 16730439, 18253147, 37166430; Phenotypes: caveolinopathy MONDO:0016146, Myopathy, distal, Tateyama type, OMIM:614321, Rippling muscle disease 2, OMIM:606072, rippling muscle disease 2, MONDO:0019947, distal myopathy, Tateyama type, MONDO:0013686; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 CAV3 Ida Ertmanska Deleted their review
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 CAV3 Ida Ertmanska Tag Q3_26_MOI was removed from gene: CAV3.
Tag watchlist_moi tag was added to gene: CAV3.
Acute rhabdomyolysis v3.1 CAV3 Ida Ertmanska edited their review of gene: CAV3: Added comment: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Acute rhabdomyolysis v3.1 CAV3 Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.; to: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including 8 homozygotes - VUS leaning Benign.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 DCLRE1B Ida Ertmanska Classified gene: DCLRE1B as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 DCLRE1B Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic DCLRE1B variants and bone marrow failure, with pancytopenia or severe lymphopenia, which required transfusions early on. Additional variable features included microcephaly, IBD, and delayed speech. Only P2 had mucocutaneous features of dyskeratosis congenita, including sparse hair, leukoplakia, nail dystrophy, and skin hyperpigmentation. Based on available evidence, this gene can be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 DCLRE1B Ida Ertmanska Gene: dclre1b has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.104 DCLRE1B Ida Ertmanska Phenotypes for gene: DCLRE1B were changed from Dyskeratosis congenita, autosomal recessive 8, OMIM:620133 to Dyskeratosis congenita, autosomal recessive 8, OMIM:620133; dyskeratosis congenita, autosomal recessive 8, MONDO:0859319
Primary immunodeficiency or monogenic inflammatory bowel disease v9.103 DCLRE1B Ida Ertmanska Publications for gene: DCLRE1B were set to 20479256
Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 DCLRE1B Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: DCLRE1B.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 DCLRE1B Ida Ertmanska reviewed gene: DCLRE1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 35007328; Phenotypes: Dyskeratosis congenita, autosomal recessive 8, OMIM:620133, dyskeratosis congenita, autosomal recessive 8, MONDO:0859319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v9.11 ATXN1_CAG Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 case from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O8 (43 year old) symptomatic for SCA1 and O20 (20 years old) is pre-symptomatic . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals. 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 case from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.
Hereditary ataxia, adult onset v9.11 ATXN1_CAG Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 case from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.
Hereditary spastic paraplegia, adult onset v6.14 ATXN1_CAG Eleanor Williams reviewed STR: ATXN1_CAG: Rating: ; Mode of pathogenicity: None; Publications: 39289638, 25344417, 36618024, 8619528; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia, adult onset v9.11 ATXN1_CAG Eleanor Williams Publications for STR: ATXN1_CAG were set to
Hereditary ataxia, adult onset v9.10 ATXN1_CAG Eleanor Williams reviewed STR: ATXN1_CAG: Rating: ; Mode of pathogenicity: None; Publications: 39289638, 25344417, 36618024, 8619528; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy or pain disorder v8.32 ATXN1_CAG Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years awith a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic   (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) 
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).   
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) 

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic   (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) 
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).   
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) 

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.
Dystonia, chorea or related movement disorder, adult onset v6.9 ATXN1_CAG Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years awith a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years, and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.
Dystonia, chorea or related movement disorder, adult onset v6.9 ATXN1_CAG Eleanor Williams Publications for STR: ATXN1_CAG were set to
Dystonia, chorea or related movement disorder, adult onset v6.8 ATXN1_CAG Eleanor Williams edited their review of STR: ATXN1_CAG: Added comment: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years awith a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; Changed publications to: 39289638, 25344417, 36618024, 8619528
Hereditary neuropathy or pain disorder v8.32 ATXN1_CAG Eleanor Williams Publications for STR: ATXN1_CAG were set to
Hereditary neuropathy or pain disorder v8.31 ATXN1_CAG Eleanor Williams reviewed STR: ATXN1_CAG: Rating: ; Mode of pathogenicity: None; Publications: 39289638, 25344417, 36618024, 8619528; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v9.32 ATP6V0C Ida Ertmanska Tag Q3_26_NHS_review tag was added to gene: ATP6V0C.
Ataxia and cerebellar anomalies - childhood onset v9.32 ATP6V0C Ida Ertmanska edited their review of gene: ATP6V0C: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v9.32 ATP6V0C Ida Ertmanska Phenotypes for gene: ATP6V0C were changed from progressive ataxia and cognitive decline to Ataxia, HP:0001251
Ataxia and cerebellar anomalies - childhood onset v9.31 ATP6V0C Ida Ertmanska Mode of inheritance for gene: ATP6V0C was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v9.30 ATP6V0C Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ATP6V0C.
Ataxia and cerebellar anomalies - childhood onset v9.30 ATP6V0C Ida Ertmanska Tag currently-ngs-unreportable was removed from gene: ATP6V0C.
Ataxia and cerebellar anomalies - childhood onset v9.30 ATP6V0C Ida Ertmanska changed review comment from: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber.; to: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber.
Ataxia and cerebellar anomalies - childhood onset v9.30 ATP6V0C Ida Ertmanska edited their review of gene: ATP6V0C: Added comment: Comment on list classification: As reviewed by Lucy Jackson, the ATP6V0C triplications can now be detected by the WGS CNV pipeline. Hence, this gene should be promoted to Green at the next update.; Changed rating: GREEN; Changed phenotypes to: Ataxia, HP:0001251
Neurodegenerative disorders, adult onset v9.11 ARPP21 Achchuthan Shanmugasundram Classified gene: ARPP21 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v9.11 ARPP21 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two independent large-scale genetic studies (PMIDs: 38960585 & 41917433) linked ARRP21 to ALS with consistent variants (p.Pro529Leu/ p.Pro563Leu & p.Pro747Leu) and clinical severity, but no functional validation of any disease variant exists, analysis suggested variant embedded in founder-type haplotype and replication failed in Asian/Australian cohorts. ClinGen GCEP has still rated it with 'Limited' evidence, with it's last review on 14 January 2025. Hence, this gene should be rated amber with this evidence.

The 'watchlist' tag has been added to re-review once functional data or a formal GCEP upgrade emerge.
Neurodegenerative disorders, adult onset v9.11 ARPP21 Achchuthan Shanmugasundram Gene: arpp21 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v8.5 PAX3 Ida Ertmanska reviewed gene: PAX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26443304, 35607853; Phenotypes: Waardenburg syndrome, type 1, OMIM:193500, Waardenburg syndrome type 1, MONDO:0008670, Waardenburg syndrome, type 3, OMIM:148820, Waardenburg syndrome type 3, MONDO:0007862, Klein-Waardenburg syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v9.10 ARPP21 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: ARPP21.
Neurodegenerative disorders, adult onset v9.10 ARPP21 Achchuthan Shanmugasundram Publications for gene: ARPP21 were set to 8120638; 29581509; 30811981; 31653410; 3358193; 38960585; 41917433
Neurodegenerative disorders, adult onset v9.9 ARPP21 Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1.

PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21.

PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes.

PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations.

PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1.

There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons .

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen.
Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1.

PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21.

PMID:33581934 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes.

PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations.

PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1.

There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons .

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen.
Sources: Literature
Neurodegenerative disorders, adult onset v9.9 ARPP21 Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 8120638, 29581509, 30811981, 31653410, 33581934, 38960585, 41917433
Neurodegenerative disorders, adult onset v9.9 ARPP21 Achchuthan Shanmugasundram Publications for gene: ARPP21 were set to 30811981; 38960585; 41917433
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1.

PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21.

PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes.

PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations.

PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1.


Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1.

PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21.

PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes.

PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations.

PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1.

There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons .

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen.
Sources: Literature
Limb disorders v9.4 PAX3 Ida Ertmanska Phenotypes for gene: PAX3 were changed from Waardenburg syndrome, type 3, 148820 to Waardenburg syndrome, type 1, OMIM:193500; Waardenburg syndrome type 1, MONDO:0008670; Waardenburg syndrome, type 3, OMIM:148820; Waardenburg syndrome type 3, MONDO:0007862; Klein-Waardenburg syndrome
Limb disorders v9.3 PAX3 Ida Ertmanska Publications for gene: PAX3 were set to 6340503; 12949970; 7726174; 26443304; 8447316; 11683776; 30173992; 35607853
Limb disorders v9.2 PAX3 Ida Ertmanska edited their review of gene: PAX3: Changed publications to: 7726174, 12949970, 26443304, 35607853, 41141997, 41159045
Limb disorders v9.2 PAX3 Ida Ertmanska Publications for gene: PAX3 were set to 6340503; 12949970; 7726174; 26443304; 8447316; 11683776; 30173992
Limb disorders v9.1 PAX3 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with biallelic PAX3 variants and Waardenburg syndrome type 3 / Klein syndrome. This syndrome includes limb deformities not present in patients with monoallelic PAX3 variants. Hence, the MOI should remain as BIALLELIC, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with biallelic PAX3 variants and Waardenburg syndrome type 3 / Klein syndrome. This syndrome includes limb deformities not present in patients with monoallelic PAX3 variants. Hence, the MOI should remain as BIALLELIC, autosomal or pseudoautosomal.
Limb disorders v9.1 PAX3 Ida Ertmanska changed review comment from: ADDITIONAL CASES SINCE 2019:

PMID: 35607853 Salah et al., 2022 - biallelic case
Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins.
Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome.

PMID: 41141997 Chen et al., 2025
Report of a proband with a deletion affecting PAX3. A detailed ultrasound examination at 14 weeks of gestation revealed no fetal anomalies. She presented with telecanthus but no pigmentary skin anomalies at birth. She developed jaundice and neonatal infection - not consistent with WS diagnosis. Isolated congenital spina bifida was noted in a previous pregnancy, terminated at 20 weeks. CMA analysis showed a 543-kb deletion in the 2q36.1 region [arr(GRCh38) 2q36.1(222,250,171_222,792,701) × 1], encompassing PAX3, FARSB, MOGAT1, and SGPP2 genes - PAX3 gene determined to explain this family's phenotypes. Deletion was confirmed to be paternally inherited.
The father (I:1) displayed characteristic WS facial features (DC, synophrys, a white forelock, and a broad nasal root) but had normal hearing, intellectual ability, and growth.

PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).; to: ADDITIONAL CASES SINCE 2019:

PMID: 35607853 Salah et al., 2022 - biallelic case
Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins.
Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome.

PMID: 41141997 Chen et al., 2025 - het deletion
Report of a proband with a deletion affecting PAX3. A detailed ultrasound examination at 14 weeks of gestation revealed no fetal anomalies. She presented with telecanthus but no pigmentary skin anomalies at birth. She developed jaundice and neonatal infection - not consistent with WS diagnosis. Isolated congenital spina bifida was noted in a previous pregnancy, terminated at 20 weeks. CMA analysis showed a 543-kb deletion in the 2q36.1 region [arr(GRCh38) 2q36.1(222,250,171_222,792,701) × 1], encompassing PAX3, FARSB, MOGAT1, and SGPP2 genes - PAX3 gene determined to explain this family's phenotypes. Deletion was confirmed to be paternally inherited.
The father (I:1) displayed characteristic WS facial features (DC, synophrys, a white forelock, and a broad nasal root) but had normal hearing, intellectual ability, and growth.

PMID: 41159045 Zafiri et al., 2025 - het missense variant
Report of a 33yo male patient with WS type 1: white forelock, skin depigmentation (white patches on the abdoment), severe neurosensory hearing loss. A c.209G>A (p.Cys70Tyr) variant was detected in the PAX3 gene in heterozygosity. Father and brother were het for the same change, but had normal hearing, with only a white forelock noted in the brother.

PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).
Limb disorders v9.1 PAX3 Ida Ertmanska changed review comment from: PMID: 7726174 Zlotogora et al. 1995
Report of a large kindred with Waardenburg syndrome type 1 and a heterozygous mutation S84F in PAX3 gene. 1 child, born of consanguineous parents, had a severe phenotype consistent with WS type 3. This child was homozygous for the S84F mutation. The child presented with dystopia canthorum, partial albinism, and very severe upper limb defects. Severe changes were present in the upper limbs, with rigidity of the larger joints -including shoulders, elbows, and wrists-as well as of the smaller joints of the fingers. Muscle wasting was severe in the pectoral region, the shoulders, and upper limbs. Axillary webs were present on both sides. There was a slight degree of contracture of the knees, and there was calcaneovalgus deformation of the feet.

PMID: 12949970 Wollnik et al., 2003
Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het).

PMID: 26443304 Mousty et al., 2015
Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted.

PMID: 35607853 Salah et al., 2022
Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins.
Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome.

PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).; to: ADDITIONAL CASES SINCE 2019:

PMID: 35607853 Salah et al., 2022 - biallelic case
Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins.
Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome.

PMID: 41141997 Chen et al., 2025
Report of a proband with a deletion affecting PAX3. A detailed ultrasound examination at 14 weeks of gestation revealed no fetal anomalies. She presented with telecanthus but no pigmentary skin anomalies at birth. She developed jaundice and neonatal infection - not consistent with WS diagnosis. Isolated congenital spina bifida was noted in a previous pregnancy, terminated at 20 weeks. CMA analysis showed a 543-kb deletion in the 2q36.1 region [arr(GRCh38) 2q36.1(222,250,171_222,792,701) × 1], encompassing PAX3, FARSB, MOGAT1, and SGPP2 genes - PAX3 gene determined to explain this family's phenotypes. Deletion was confirmed to be paternally inherited.
The father (I:1) displayed characteristic WS facial features (DC, synophrys, a white forelock, and a broad nasal root) but had normal hearing, intellectual ability, and growth.

PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 8120638, 29581509, 30811981, 31653410, 3358193, 38960585, 41917433
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene.

PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21.
Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1.

PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21.

PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes.

PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations.

PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1.


Sources: Literature
Limb disorders v9.1 PAX3 Ida Ertmanska edited their review of gene: PAX3: Changed publications to: 7726174, 12949970, 26443304, 35607853
Limb disorders v9.1 PAX3 Ida Ertmanska changed review comment from: PMID: 12949970 Wollnik et al., 2003
Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het).

PMID: 26443304 Mousty et al., 2015
Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted.

PMID: 35607853 Salah et al., 2022
Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins.
Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome.

PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).; to: PMID: 7726174 Zlotogora et al. 1995
Report of a large kindred with Waardenburg syndrome type 1 and a heterozygous mutation S84F in PAX3 gene. 1 child, born of consanguineous parents, had a severe phenotype consistent with WS type 3. This child was homozygous for the S84F mutation. The child presented with dystopia canthorum, partial albinism, and very severe upper limb defects. Severe changes were present in the upper limbs, with rigidity of the larger joints -including shoulders, elbows, and wrists-as well as of the smaller joints of the fingers. Muscle wasting was severe in the pectoral region, the shoulders, and upper limbs. Axillary webs were present on both sides. There was a slight degree of contracture of the knees, and there was calcaneovalgus deformation of the feet.

PMID: 12949970 Wollnik et al., 2003
Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het).

PMID: 26443304 Mousty et al., 2015
Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted.

PMID: 35607853 Salah et al., 2022
Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins.
Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome.

PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).
Limb disorders v9.1 PAX3 Ida Ertmanska commented on gene: PAX3: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with biallelic PAX3 variants and Waardenburg syndrome type 3 / Klein syndrome. This syndrome includes limb deformities not present in patients with monoallelic PAX3 variants. Hence, the MOI should remain as BIALLELIC, autosomal or pseudoautosomal.
Limb disorders v9.1 PAX3 Ida Ertmanska edited their review of gene: PAX3: Changed rating: GREEN; Changed publications to: 12949970 26443304, 35607853; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v9.1 PAX3 Ida Ertmanska changed review comment from: PMID: 12949970 Wollnik et al., 2003
Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for p.Y90H

PMID: 26443304 Mousty et al., 2015
Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted.

PMID: 35607853 Salah et al., 2022
Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins.
Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome.

PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).; to: PMID: 12949970 Wollnik et al., 2003
Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het).

PMID: 26443304 Mousty et al., 2015
Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted.

PMID: 35607853 Salah et al., 2022
Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins.
Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome.

PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).
Limb disorders v9.1 PAX3 Ida Ertmanska reviewed gene: PAX3: Rating: ; Mode of pathogenicity: None; Publications: 26443304, 35607853; Phenotypes: Waardenburg syndrome, type 1, OMIM:193500, Waardenburg syndrome type 1, MONDO:0008670, Waardenburg syndrome, type 3, OMIM:148820, Waardenburg syndrome type 3, MONDO:0007862, Klein-Waardenburg syndrome; Mode of inheritance: None
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 30811981, 31653410, 3358193, 38960585, 41917433
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene.
Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene.

PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21.
Sources: Literature
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 30811981, 31653410, 38960585, 41917433
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram gene: ARPP21 was added
gene: ARPP21 was added to Neurodegenerative disorders, adult onset. Sources: Literature
Mode of inheritance for gene: ARPP21 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARPP21 were set to 30811981; 38960585; 41917433
Phenotypes for gene: ARPP21 were set to amyotrophic lateral sclerosis, MONDO:0004976
Review for gene: ARPP21 was set to AMBER
Added comment: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene.
Sources: Literature
Hereditary neuropathy or pain disorder v8.31 COL6A3 Luke Stuart reviewed gene: COL6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 42520849; Phenotypes: Motor peripheral neuropathy, MONDO:0002316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v11.26 RIC1 Ida Ertmanska Publications for gene: RIC1 were set to 31932796; 27878435
Intellectual disability v11.25 RIC1 Ida Ertmanska commented on gene: RIC1
Bilateral congenital or childhood onset cataracts v8.13 RIC1 Ida Ertmanska changed review comment from: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family with a founder variant, plus a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.; to: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family with a founder variant, plus a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BIALLELIC, autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.
Bilateral congenital or childhood onset cataracts v8.13 RIC1 Ida Ertmanska Publications for gene: RIC1 were set to 27878435; 31932796
Bilateral congenital or childhood onset cataracts v8.12 RIC1 Ida Ertmanska Phenotypes for gene: RIC1 were changed from CATIFA syndrome 618761 to CATIFA syndrome, OMIM:618761; Catifa syndrome, MONDO:0032901
Bilateral congenital or childhood onset cataracts v8.11 RIC1 Ida Ertmanska commented on gene: RIC1
Possible mitochondrial disorder, nuclear genes v5.23 UQCC1 Ida Ertmanska Mode of inheritance for gene: UQCC1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v10.23 UQCC1 Ida Ertmanska Tag watchlist tag was added to gene: UQCC1.
Mitochondrial disorders v10.23 UQCC1 Ida Ertmanska Classified gene: UQCC1 as Amber List (moderate evidence)
Mitochondrial disorders v10.23 UQCC1 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases. MOI set to BOTH for the moment, as it is not clear what mode is correct here.
Mitochondrial disorders v10.23 UQCC1 Ida Ertmanska Gene: uqcc1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v10.22 UQCC1 Ida Ertmanska commented on gene: UQCC1: PMID: 39504961 AlAbdi et al., 2025
Study of a large exome/genome dataset - Arab population, 17,592 local exomes and 768 local genomes. A founder variant in UQCC1 (NM_018244.5:c.656T>A;p.(Ile219Asn)) was identified in two Arab families with lactic acidosis and borderline microcephaly. Diagnosed with 'UQCC1-related mitochondrial energy disorder'. 1 individual was homozygous, and 3 heterozygous for the variant (presuming all 4 are affected?). No segregation or functional evidence provided.
Mitochondrial disorders v10.22 UQCC1 Ida Ertmanska Mode of inheritance for gene: UQCC1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v10.21 UQCC1 Ida Ertmanska Publications for gene: UQCC1 were set to
Mitochondrial disorders v10.20 UQCC1 Ida Ertmanska Added comment: Comment on phenotypes: No OMIM phenotype associated as of 20th Aug 2026.
Mitochondrial disorders v10.20 UQCC1 Ida Ertmanska Phenotypes for gene: UQCC1 were changed from No OMIM phenotype to mitochondrial respiratory chain complex deficiency, MONDO:0000066
Possible mitochondrial disorder, nuclear genes v5.22 UQCC1 Ida Ertmanska Added comment: Comment on phenotypes: No OMIM phenotype associated as of 20th Aug 2026.
Possible mitochondrial disorder, nuclear genes v5.22 UQCC1 Ida Ertmanska Phenotypes for gene: UQCC1 were changed from mitochondrial respiratory chain complex deficiency, MONDO:0000066 to mitochondrial respiratory chain complex deficiency, MONDO:0000066
Possible mitochondrial disorder, nuclear genes v5.21 UQCC1 Ida Ertmanska Phenotypes for gene: UQCC1 were changed from No OMIM phenotype to mitochondrial respiratory chain complex deficiency, MONDO:0000066
Possible mitochondrial disorder, nuclear genes v5.20 UQCC1 Ida Ertmanska Publications for gene: UQCC1 were set to
Possible mitochondrial disorder, nuclear genes v5.19 UQCC1 Ida Ertmanska Classified gene: UQCC1 as Amber List (moderate evidence)
Possible mitochondrial disorder, nuclear genes v5.19 UQCC1 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases. MOI set to BOTH for the moment, as it is not clear what mode is correct here.
Possible mitochondrial disorder, nuclear genes v5.19 UQCC1 Ida Ertmanska Gene: uqcc1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder, nuclear genes v5.18 UQCC1 Ida Ertmanska Tag watchlist tag was added to gene: UQCC1.
Possible mitochondrial disorder, nuclear genes v5.18 UQCC1 Ida Ertmanska reviewed gene: UQCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24385928, 39504961; Phenotypes: mitochondrial respiratory chain complex deficiency, MONDO:0000066; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorder with complex III deficiency v2.14 UQCC1 Ida Ertmanska Tag watchlist tag was added to gene: UQCC1.
Mitochondrial disorder with complex III deficiency v2.14 UQCC1 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases.; to: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases. MOI set to BOTH for the moment, as it is not clear what mode is correct here.
Mitochondrial disorder with complex III deficiency v2.14 UQCC1 Ida Ertmanska Classified gene: UQCC1 as Amber List (moderate evidence)
Mitochondrial disorder with complex III deficiency v2.14 UQCC1 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases.
Mitochondrial disorder with complex III deficiency v2.14 UQCC1 Ida Ertmanska Gene: uqcc1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex III deficiency v2.13 UQCC1 Ida Ertmanska Mode of inheritance for gene: UQCC1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorder with complex III deficiency v2.12 UQCC1 Ida Ertmanska Added comment: Comment on phenotypes: No OMIM phenotype associated as of 20th Aug 2026.
Mitochondrial disorder with complex III deficiency v2.12 UQCC1 Ida Ertmanska Phenotypes for gene: UQCC1 were changed from mitochondrial respiratory chain complex deficiency, MONDO:0000066 to mitochondrial respiratory chain complex deficiency, MONDO:0000066
Mitochondrial disorder with complex III deficiency v2.11 UQCC1 Ida Ertmanska Phenotypes for gene: UQCC1 were changed from No OMIM phenotype to mitochondrial respiratory chain complex deficiency, MONDO:0000066
Mitochondrial disorder with complex III deficiency v2.10 UQCC1 Ida Ertmanska Publications for gene: UQCC1 were set to
Mitochondrial disorder with complex III deficiency v2.9 UQCC1 Ida Ertmanska changed review comment from: PMID: 39504961 AlAbdi et al., 2025
Study of a large exome/genome dataset - Arab population, 17,592 local exomes and 768 local genomes. A founder variant in UQCC1 (NM_018244.5:c.656T>A;p.(Ile219Asn)) was identified in two Arab families with lactic acidosis and borderline microcephaly. Diagnosed with 'UQCC1-related mitochondrial energy disorder'. 1 individual was homozygous, and 3 heterozygous for the variant (presuming all 4 are affected?). No segregation or functional evidence provided.; to: PMID: 39504961 AlAbdi et al., 2025
Study of a large exome/genome dataset - Arab population, 17,592 local exomes and 768 local genomes. A founder variant in UQCC1 (NM_018244.5:c.656T>A;p.(Ile219Asn)) was identified in two Arab families with lactic acidosis and borderline microcephaly. Diagnosed with 'UQCC1-related mitochondrial energy disorder'. 1 individual was homozygous, and 3 heterozygous for the variant (presuming all 4 are affected?). No segregation or functional evidence provided.
Mitochondrial disorder with complex III deficiency v2.9 UQCC1 Ida Ertmanska edited their review of gene: UQCC1: Changed rating: AMBER
Mitochondrial disorder with complex III deficiency v2.9 UQCC1 Ida Ertmanska reviewed gene: UQCC1: Rating: RED; Mode of pathogenicity: None; Publications: 39504961; Phenotypes: mitochondrial respiratory chain complex deficiency, MONDO:0000066; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v8.11 RIC1 Luke Stuart changed review comment from: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026).

Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate.

Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. 7/8 patients ahd cataract. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect.

Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded.

Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting, as well as in structural brain development. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating for bilateral congenital cataracts is reiterated.; to: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026).

Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate.

Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. 7/8 patients had cataract. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect.

Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded.

Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting, as well as in structural brain development. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating for bilateral congenital cataracts is reiterated.
Intellectual disability v11.25 RIC1 Luke Stuart reviewed gene: RIC1: Rating: ; Mode of pathogenicity: None; Publications: 27878435, 31932796, 36493769; Phenotypes: CATIFA syndrome, OMIM:618761, Catifa syndrome, MONDO:0032901; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v8.11 RIC1 Luke Stuart changed review comment from: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026).

Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate.

Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect.

Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded.

Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating for intellectual disability is reiterated.; to: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026).

Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate.

Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. 7/8 patients ahd cataract. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect.

Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded.

Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting, as well as in structural brain development. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating for bilateral congenital cataracts is reiterated.
Bilateral congenital or childhood onset cataracts v8.11 RIC1 Luke Stuart reviewed gene: RIC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27878435, 31932796, 36493769; Phenotypes: CATIFA syndrome, OMIM:618761, Catifa syndrome, MONDO:0032901; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v6.18 PTPRO Luke Stuart changed review comment from: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026)

Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858).

Wharram et al., 2000 (PMID 11086029): Ptpro-/- mice show altered podocyte structure- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by scanning and transmission electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and a filtration/pressure regulation defect rather than overt proteinuria in mice.; to: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026)

Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858).

Wharram et al., 2000 (PMID 11086029): Ptpro-/- mice show altered podocyte structure, consistent with human disease subjects- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and might reduce renal functional reserve.

An amber rating with watchlist designation is appropriate, given 2 unrelated families with segregation, plus an animal model partially recapitulating the phenotype seen in humans disease subjects.
Clefting v7.10 RIC1 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family, with a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.; to: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family with a founder variant, plus a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.
Clefting v7.10 RIC1 Ida Ertmanska Tag founder-effect tag was added to gene: RIC1.
Intellectual disability v11.25 RIC1 Ida Ertmanska Phenotypes for gene: RIC1 were changed from CATIFA syndrome 618761; Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD to CATIFA syndrome, OMIM:618761; Catifa syndrome, MONDO:0032901
Clefting v7.10 RIC1 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 consanguineous family, with a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.; to: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family, with a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.
Clefting v7.10 RIC1 Ida Ertmanska Tag watchlist tag was added to gene: RIC1.
Clefting v7.10 RIC1 Ida Ertmanska Classified gene: RIC1 as Amber List (moderate evidence)
Clefting v7.10 RIC1 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 consanguineous family, with a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.
Clefting v7.10 RIC1 Ida Ertmanska Gene: ric1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v11.24 GIGYF1 Achchuthan Shanmugasundram Publications for gene: GIGYF1 were set to 33057194; 35917186; 36924980
Intellectual disability v11.23 GIGYF1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is identified with significant enrichment in multiple large cohorts of autism spectrum disorder patients. Detailed clinical information was only available for a small subset of patients, from which intellectual disability was reported in 11/25 patients. However, severity of ID was not provided for any of these patients. Hence, this gene is rated amber with 'watchlist' tag added.; to: Comment on list classification: GIGYF1 shows statistically robust de novo enrichment for a complex neurodevelopmental disorder across three large cohorts of autism spectrum disorder patients (PMID:33057194, PMID:35917192, PMID:36924980), with supporting functional data in cell and animal models. However, only 25 individuals across the literature have detailed clinical phenotyping, of whom 11 had confirmed ID (no severity reported).

Although ClinGen rated it 'Definitive' for complex neurodevelopmental disorder, ClinGen's own review flags unresolved penetrance given recurrence of variants in unaffected parents/population controls. Gene2Phenotype recently downgraded this gene from 'moderate' to 'limited' confidence on the DD panel, and OMIM has no phenotype association as of August 2026.

Hence, this gene is rated amber based on all these evidences. The 'watchlist' tag has been added as recommendation for re-review as additional deeply phenotyped ID/GDD cases are published.
Clefting v7.9 RIC1 Luke Stuart gene: RIC1 was added
gene: RIC1 was added to Clefting. Sources: Literature
Mode of inheritance for gene: RIC1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: RIC1 were set to 27878435; 31932796; 36493769
Phenotypes for gene: RIC1 were set to CATIFA syndrome, OMIM:618761; Catifa syndrome, MONDO:0032901
Review for gene: RIC1 was set to AMBER
Added comment: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026).

Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate.

Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect.

Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded.

Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating with BOTH monoallelic and biallelic inheritance is recommended for clefting.
Sources: Literature
Intellectual disability v11.23 GIGYF1 Achchuthan Shanmugasundram changed review comment from: PMID:33057194 (2020) - This gene has been identified with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).

PMID:35917186 (2022) - 60 individuals carrying 35 distinct GIGYF1 likely gene-disruptive (LGD) variants, identified from SPARK/SSC autism cohorts (20,452 trios + 12,227 singletons) plus 7 additional GeneMatcher-ascertained probands. This cohort was ascertained specifically through ASD registries, so detailed non-ASD clinical/developmental phenotyping (including formal ID assessment) was not systematically reported for most of the 60 individuals. However, detailed clinical information was available for 11 patients, of which 9 patients had ASD, 10 had speech-language issues, 3 had motor delays, and 6 had ID. Severity of ID has not been provided for any of these patients.

PMID:36924980 (2023) - 26 de novo variants identified across a combined 44,665 NDD trios (ASD-primary and DD-primary cohorts). Of these, detailed clinical information was obtained for only 14 probands, of which 12 had ASD, 5 had DD, 5 had ID, 3 had motor delay and 8 had speech delay. Severity of ID has not been provided for any of these patients.

This gene has not yet been associated with any relevant phenotype in OMIM (last accessed 16 August 2026), but associated with GIGYF1-related developmental disorder with 'limited' rating on the DD panel of Gene2Phenotype. This gene has been associated with 'Definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Intellectual Disability and Autism GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009351).; to: PMID:33057194 (2020) - This gene has been identified with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).

PMID:35917186 (2022) - 60 individuals carrying 35 distinct GIGYF1 likely gene-disruptive (LGD) variants, identified from SPARK/SSC autism cohorts (20,452 trios + 12,227 singletons) plus 7 additional GeneMatcher-ascertained probands. This cohort was ascertained specifically through ASD registries, so detailed non-ASD clinical/developmental phenotyping (including formal ID assessment) was not systematically reported for most of the 60 individuals. However, detailed clinical information was available for 11 patients, of which 9 patients had ASD, 10 had speech-language issues, 3 had motor delays, and 6 had ID. Severity of ID has not been provided for any of these patients.

PMID:36924980 (2023) - 26 de novo variants identified across a combined 44,665 NDD trios (ASD-primary and DD-primary cohorts). Of these, detailed clinical information was obtained for only 14 probands, of which 12 had ASD, 5 had DD, 5 had ID, 3 had motor delay and 8 had speech delay. Severity of ID has not been provided for any of these patients.

The pLI = 0 in gnomAD v4.1.1 for GIGYF indicating lack of constraint against LOF.

This gene has not yet been associated with any relevant phenotype in OMIM (last accessed 16 August 2026), but associated with GIGYF1-related developmental disorder with 'limited' rating on the DD panel of Gene2Phenotype. This gene was previously rated 'moderate/ on the DD panel in G2P and has been demoted in the last year.

This gene has been associated with 'Definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Intellectual Disability and Autism GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009351). However, ClinGen review noted that individuals with similar variants have also been observed in the general population or in reportedly unaffected parents of affected individuals, and deep phenotyping of parents in these studies is often unavailable. In addition, the extent of reduced penetrance and variable expressivity is currently unknown (PMID:35917186).
Nephrocalcinosis or nephrolithiasis v6.3 ABCC6 John Sayer gene: ABCC6 was added
gene: ABCC6 was added to Nephrocalcinosis or nephrolithiasis. Sources: Other
Mode of inheritance for gene: ABCC6 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ABCC6 were set to PMID: 41908612; 33820832
Phenotypes for gene: ABCC6 were set to nephrolithiasis; nephrocalcinosis
Penetrance for gene: ABCC6 were set to Incomplete
Review for gene: ABCC6 was set to GREEN
Added comment: ABCC6 causes autosomal recessive pseudoxanthoma elasticum which can include vascular and tissue calcification including kidney
Emergin evidence of het carriers with nephrolithiasis and nephrocalcinosis phenotypes.
Sources: Other
Leukodystrophy, adult onset v7.9 CTSA Lauren Turton reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Proteinuric renal disease v6.18 NUP205 Ida Ertmanska Mode of pathogenicity for gene: NUP205 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Proteinuric renal disease v6.17 NUP205 Ida Ertmanska Mode of pathogenicity for gene: NUP205 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v8.5 MMP9 Ida Ertmanska Tag Q3_26_promote_green was removed from gene: MMP9.
Fetal anomalies v8.5 MMP9 Ida Ertmanska Publications for gene: MMP9 were set to
Fetal anomalies v8.4 MMP9 Ida Ertmanska Deleted their review
Fetal anomalies v8.4 MMP9 Ida Ertmanska Deleted their comment
Proteinuric renal disease v6.16 PTPRO Luke Stuart changed review comment from: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026)

Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858).

Ptpro-/- mice show altered podocyte structure- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by scanning and transmission electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and a filtration/pressure regulation defect rather than overt proteinuria in mice.; to: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026)

Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858).

Wharram et al., 2000 (PMID 11086029): Ptpro-/- mice show altered podocyte structure- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by scanning and transmission electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and a filtration/pressure regulation defect rather than overt proteinuria in mice.
Proteinuric renal disease v6.16 PTPRO Luke Stuart changed review comment from: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026)

Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858).; to: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026)

Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858).

Ptpro-/- mice show altered podocyte structure- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by scanning and transmission electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and a filtration/pressure regulation defect rather than overt proteinuria in mice.
Proteinuric renal disease v6.16 PTPRO Luke Stuart reviewed gene: PTPRO: Rating: AMBER; Mode of pathogenicity: None; Publications: 34546508, 21722858; Phenotypes: Nephrotic syndrome, type 6, OMIM:614196; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease - additional genes v2.7 ROBO2 Ida Ertmanska Publications for gene: ROBO2 were set to 27002985; 29194579; 32041992; 34059960
Unexplained young onset end-stage renal disease - additional genes v2.6 ROBO2 Ida Ertmanska edited their review of gene: ROBO2: Changed publications to: 17357069, 23536131, 26026792, 27002985, 29194579, 32041992, 34059960
Unexplained young onset end-stage renal disease - additional genes v2.6 ROBO2 Ida Ertmanska changed review comment from: PMID: 34059960 Liu et al., 2021
Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux.
Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1)
Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1)
Both classified VUS in the paper according to ACMG criteria.

PMID: 32041992 Darlow et al., 2020
Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants.
Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2.

PMID: 29194579 Rasmussen et al., 2018
Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect.

PMID: 27002985 Mitsioni et al., 2016
103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were NOT found to be associated with nonsyndromic VUR or VUR-RHD.

PMID: 24429398 Hwang et al., 2014
Cohort of 749 individuals from 650 different families with CAKUT, mostly from Eastern Europe (63%). 4 families had variants in ROBO2 - 2 of Indian origin, and 2 Eastern European. 4 unique ROBO2 missense variants were detected. Specific diagnoses of the 4 probands included Multicystic dysplastic kidney, Posterior urethral valves, Vesicoureteral reflux, and Ureteropelvic junction obstruction.

ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026).; to: PMID: 34059960 Liu et al., 2021
Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux.
Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1)
Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1)
Both classified VUS in the paper according to ACMG criteria.

PMID: 32041992 Darlow et al., 2020
Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants.
Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2.

PMID: 29194579 Rasmussen et al., 2018
Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect.

PMID: 27002985 Mitsioni et al., 2016
103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were not found to be associated with nonsyndromic VUR or VUR-RHD in this cohort.

PMID: 24429398 Hwang et al., 2014
Cohort of 749 individuals from 650 different families with CAKUT, mostly from Eastern Europe (63%). 4 families had variants in ROBO2 - 2 of Indian origin, and 2 Eastern European. 4 unique ROBO2 missense variants were detected. Specific diagnoses of the 4 probands included Multicystic dysplastic kidney, Posterior urethral valves, Vesicoureteral reflux, and Ureteropelvic junction obstruction.

PMID: 23536131 Dobson et al., 2013
'Heterozygous non-synonymous ROBO2 variants are unlikely to be sufficient to cause familial vesicoureteric reflux'. Sequenced 227 index cases with primary VUR in an Irish population and found ROBO2 55 variants, of which 20 were novel. Only p.Pro522Thr and p.Val799Ile segregated with the disorder. Authors pose ROBO2 variants are more likely to act as modifiers, causing VUR with digenic or oligogenic inheritance.

PMID: 17357069 - Lu et al., 2007
Report of a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2.

FUNCTIONAL EVIDENCE: Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage exhibit striking CAKUT-VUR phenotypes. Robo2del5/del5 homozygotes uniformly died shortly after birth with multiplex, dysplastic kidneys and short ureters. 4 (15%) of 26 Robo2del5/+ heterozygous newborns exhibited a unilateral CAKUT-VUR phenotype. With gene dosage reduced further, up to 40-70% of the heterozygous knock-down mice exhibited CAKUT-VUR.

ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026). ROBO2 is also Green on Congenital anomalies of the kidney and urinary tract (CAKUT) in PanelApp Australia (accessed 17th Aug 2026).
Unexplained young onset end-stage renal disease - additional genes v2.6 ROBO2 Ida Ertmanska changed review comment from: PMID: 34059960 Liu et al., 2021
Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux.
Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1)
Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1)
Both classified VUS in the paper according to ACMG criteria.

PMID: 32041992 Darlow et al., 2020
Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants.
Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2.

PMID: 29194579 Rasmussen et al., 2018
Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect.

PMID: 27002985 Mitsioni et al., 2016
103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were NOT found to be associated with nonsyndromic VUR or VUR-RHD.

ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026).; to: PMID: 34059960 Liu et al., 2021
Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux.
Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1)
Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1)
Both classified VUS in the paper according to ACMG criteria.

PMID: 32041992 Darlow et al., 2020
Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants.
Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2.

PMID: 29194579 Rasmussen et al., 2018
Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect.

PMID: 27002985 Mitsioni et al., 2016
103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were NOT found to be associated with nonsyndromic VUR or VUR-RHD.

PMID: 24429398 Hwang et al., 2014
Cohort of 749 individuals from 650 different families with CAKUT, mostly from Eastern Europe (63%). 4 families had variants in ROBO2 - 2 of Indian origin, and 2 Eastern European. 4 unique ROBO2 missense variants were detected. Specific diagnoses of the 4 probands included Multicystic dysplastic kidney, Posterior urethral valves, Vesicoureteral reflux, and Ureteropelvic junction obstruction.

ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026).
Unexplained young onset end-stage renal disease - additional genes v2.6 ROBO2 Ida Ertmanska Classified gene: ROBO2 as Red List (low evidence)
Unexplained young onset end-stage renal disease - additional genes v2.6 ROBO2 Ida Ertmanska Added comment: Comment on list classification: While there are more than 3 cases reported in literature with ROBO2 variants and vesicoureteral reflux, the evidence for this gene-disease association is limited and sometimes conflicting. Hence, this gene should remain Red.
Unexplained young onset end-stage renal disease - additional genes v2.6 ROBO2 Ida Ertmanska Gene: robo2 has been classified as Red List (Low Evidence).
Unexplained young onset end-stage renal disease - additional genes v2.5 ROBO2 Ida Ertmanska Phenotypes for gene: ROBO2 were changed from Vesicoureteral reflux 2, OMIM:610878 to Vesicoureteral reflux 2, OMIM:610878; vesicoureteral reflux 2, MONDO:0012573
Unexplained young onset end-stage renal disease - additional genes v2.4 ROBO2 Ida Ertmanska Publications for gene: ROBO2 were set to
Unexplained young onset end-stage renal disease - additional genes v2.3 ROBO2 Ida Ertmanska Mode of inheritance for gene: ROBO2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.73 WDR4 Ida Ertmanska Classified gene: WDR4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.73 WDR4 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there are now 2 unrelated probands reported in literature with biallelic variants in WDR4 and early-onset seizures. Hence, this gene should be rated Amber, until more evidence emerges.
Early onset or syndromic epilepsy v9.73 WDR4 Ida Ertmanska Gene: wdr4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.72 WDR4 Luke Stuart changed review comment from: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation.
Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity.

Other reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347):

PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy.
PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy.
PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy.

Evidence linking WDR4 to an epilepsy/seizure phenotype (OMIM #618346, MIGSB) rests on a single publication (Shaheen et al. 2015, PMID 26416026) describing two patients from linked consanguineous families with one shared homozygous variant. An amber recommendation for early onset or syndromic epilepsy is recommended.
Sources: Literature; to: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation.
Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity.

Other reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347):

PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy.
PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy.
PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy.

In summary, an epilepsy/seizure phenotype is described in two reports of WDR4-related disease, one comprising two patients from linked consanguineous families with one shared homozygous variant (Shaheen et al. 2015, PMID 26416026). An amber recommendation for early onset or syndromic epilepsy is recommended.
Sources: Literature
Early onset or syndromic epilepsy v9.72 WDR4 Luke Stuart changed review comment from: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation.

Subsequent reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347):

PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy.
PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy.
PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy.

Evidence linking WDR4 to an epilepsy/seizure phenotype (OMIM #618346, MIGSB) rests on a single publication (Shaheen et al. 2015, PMID 26416026) describing two patients from linked consanguineous families with one shared homozygous variant. An amber recommendation for early onset or syndromic epilepsy is recommended.
Sources: Literature; to: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation.
Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity.

Other reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347):

PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy.
PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy.
PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy.

Evidence linking WDR4 to an epilepsy/seizure phenotype (OMIM #618346, MIGSB) rests on a single publication (Shaheen et al. 2015, PMID 26416026) describing two patients from linked consanguineous families with one shared homozygous variant. An amber recommendation for early onset or syndromic epilepsy is recommended.
Sources: Literature
Unexplained young onset end-stage renal disease - additional genes v2.2 ROBO2 Ida Ertmanska edited their review of gene: ROBO2: Changed rating: RED
Unexplained young onset end-stage renal disease - additional genes v2.2 ROBO2 Ida Ertmanska edited their review of gene: ROBO2: Changed publications to: 27002985, 29194579, 32041992, 34059960
Unexplained young onset end-stage renal disease - additional genes v2.2 ROBO2 Ida Ertmanska changed review comment from: PMID: 34059960 Liu et al., 2021
Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux.
Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1)
Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1)
Both classified VUS in the paper according to ACMG criteria.

PMID: 32041992 Darlow et al., 2020
Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants.
Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2.

PMID: 29194579 Rasmussen et al., 2018
Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect.

ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026).; to: PMID: 34059960 Liu et al., 2021
Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux.
Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1)
Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1)
Both classified VUS in the paper according to ACMG criteria.

PMID: 32041992 Darlow et al., 2020
Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants.
Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2.

PMID: 29194579 Rasmussen et al., 2018
Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect.

PMID: 27002985 Mitsioni et al., 2016
103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were NOT found to be associated with nonsyndromic VUR or VUR-RHD.

ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026).
Proteinuric renal disease v6.16 WDR4 Ida Ertmanska Phenotypes for gene: WDR4 were changed from growth deficiency; microcephaly; developmental delay; intellectual disability; proteinuria; nephrotic syndrome to Galloway-Mowat syndrome 6, OMIM:61834; Galloway-Mowat syndrome 6, MONDO:0032691
Proteinuric renal disease v6.15 WDR4 Ida Ertmanska Classified gene: WDR4 as Amber List (moderate evidence)
Proteinuric renal disease v6.15 WDR4 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart and John Sayer, there are now 2 unrelated probands reported in literature with biallelic variants in WDR4 and proteinuria. Hence, this gene should be rated Amber, until more evidence emerges.
Proteinuric renal disease v6.15 WDR4 Ida Ertmanska Gene: wdr4 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v9.7 GLT8D1 Achchuthan Shanmugasundram Classified gene: GLT8D1 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v9.7 GLT8D1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated amber despite having large number of cases and some functional data (zebrafish motor deficits, neuronal cell morphology changes, enzyme activity loss). This is because several reported variants were excluded from scoring due to population frequencies too high to be consistent with disease, gene-wide burden analysis shows no significant ALS association once the exon 4 cluster is excluded, and several cases with p.Arg92Cys variant also co-carrying ARPP21 variant. In addition, this gene is rated as 'Limited' in ClinGen for ALS phenotype.
Neurodegenerative disorders, adult onset v9.7 GLT8D1 Achchuthan Shanmugasundram Gene: glt8d1 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v9.6 GLT8D1 Achchuthan Shanmugasundram Phenotypes for gene: GLT8D1 were changed from familial amyotrophic lateral sclerosis, MONDO:0005144 to amyotrophic lateral sclerosis, MONDO:0004976
Neurodegenerative disorders, adult onset v9.5 GLT8D1 Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients (three of them also had p.Pro529Leu in ARPP21) and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos.

GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles.

PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions.

PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967).; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients (three of them also had p.Pro529Leu in ARPP21) and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles.

Burden analysis showed there is no significant ALS-association within GLT8D1 when exon 4 is excluded. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos.

PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions.

Burden analysis in sALS cohort showed that there is no significant enrichment of rare GLT8D1 variants versus gnomAD East Asian controls at either whole-gene level (4 variants/1,410 combined sALS cases vs 25 variants/9,766 gnomAD controls) or exon 4–specific level (0 variants in sALS vs 3 in controls).

PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967).
Early onset or syndromic epilepsy v9.72 WDR4 Luke Stuart gene: WDR4 was added
gene: WDR4 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: WDR4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR4 were set to 26416026; 28617965; 29597095; 30079490
Phenotypes for gene: WDR4 were set to Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618346; Galloway-Mowat syndrome 6, OMIM:618347
Review for gene: WDR4 was set to AMBER
Added comment: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation.

Subsequent reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347):

PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy.
PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy.
PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy.

Evidence linking WDR4 to an epilepsy/seizure phenotype (OMIM #618346, MIGSB) rests on a single publication (Shaheen et al. 2015, PMID 26416026) describing two patients from linked consanguineous families with one shared homozygous variant. An amber recommendation for early onset or syndromic epilepsy is recommended.
Sources: Literature
Neurodegenerative disorders, adult onset v9.5 GLT8D1 Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients (three of them also had p.Pro529Leu in ARPP21) and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos.

GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles.

PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions.

PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen.; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients (three of them also had p.Pro529Leu in ARPP21) and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos.

GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles.

PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions.

PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967).
Neurodegenerative disorders, adult onset v9.5 GLT8D1 Achchuthan Shanmugasundram reviewed gene: GLT8D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30811981, 33581933, 34746377; Phenotypes: amyotrophic lateral sclerosis, MONDO:0004976; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease - additional genes v2.2 ROBO2 Ida Ertmanska reviewed gene: ROBO2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29194579, 32041992, 34059960; Phenotypes: Vesicoureteral reflux 2, OMIM:610878, vesicoureteral reflux 2, MONDO:0012573; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v8.7 XPNPEP3 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated families reported in literature with biallelic XPNPEP3 variants and paediatric cardiomyopathy (1 from a pre-print article). Hence, this gene should remain Amber until more evidence emerges.; to: Comment on list classification: There are now 3 unrelated families reported in literature with biallelic XPNPEP3 variants and paediatric cardiomyopathy (1 from a pre-print article). Hence, this gene should remain Amber on Paediatric or syndromic cardiomyopathy until more evidence emerges.
Paediatric or syndromic cardiomyopathy v8.7 XPNPEP3 Ida Ertmanska Classified gene: XPNPEP3 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v8.7 XPNPEP3 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated families reported in literature with biallelic XPNPEP3 variants and paediatric cardiomyopathy (1 from a pre-print article). Hence, this gene should remain Amber until more evidence emerges.
Paediatric or syndromic cardiomyopathy v8.7 XPNPEP3 Ida Ertmanska Gene: xpnpep3 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v8.6 XPNPEP3 Ida Ertmanska gene: XPNPEP3 was added
gene: XPNPEP3 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: XPNPEP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XPNPEP3 were set to 20179356; 35328774; 39363162; doi:https://doi.org/10.1101/2025.01.11.25320052
Phenotypes for gene: XPNPEP3 were set to cardiomyopathy, MONDO:0004994
Review for gene: XPNPEP3 was set to AMBER
Added comment: PMID: 20179356 O'Toole et al., 2010
2 affected individuals of kindred F543 (Turkish decent) had a homozygous 4-base deletion in XPNPEP3 c.931_934 delAACA, (p.N311LfsX5). Patient phenotype: Cardiomyopathy, seizure, mental/developmental delay, chronic pancreatitis with pancreatic cysts, mitochondrial disorder.

Kindred A131 - 3 affected individuals (North Finnish) harboured a homozygous splice-site mutation (1357G>T) in XPNPEP3. Patient phenotype: mild form of an NPHP-like kidney disease, with residual kidney function beyond the age of 20 years; hypertension, essential tremor, hearing loss.

PMID: 39363162 Zhen et al., 2024
13-year-old Chinese female patient with intellectual disability presented with a 2-year history of convulsions and fatigue, with a recent episode of swelling, breathlessness, and nocturnal dyspnea. The patient was diagnosed with cardiomyopathy, ventricular tachycardia, heart failure, and kidney failure. WES revealed a homozygous c.970–2A > G mutation in XPNPEP3.

doi:https://doi.org/10.1101/2025.01.11.25320052 Ruijmbeek et al., 2025 - PRE-PRINT
Report of two siblings with renal insufficiency and rapidly progressive cardiomyopathy revealed a novel homozygous variant (NM_022098.4 c.1357G>A) in the XPNPEP3 gene, showed to cause abnormal splicing, leading to an abnormal transcript and loss of XPNPEP3 protein function.

PMID: 35328774 Wachoski-Dark et al., 2022 - review article
XPNPEP3 is a mitochondrial protease that is responsible for the secondary cleavage of proteins localized to the matrix. XPNPEP3-related disease is caused by mitochondrial dysfunction rather than ciliary dysfunction (hypothesised previously).
Sources: Literature
Cutaneous photosensitivity with a likely genetic cause v3.18 UROD Luke Stuart reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: 40534320, 38813949, 9211196, 24175354, 23741761; Phenotypes: Porphyria cutanea tarda, OMIM:176100, Porphyria, hepatoerythropoietic, OMIM:176100, Familial porphyria cutanea tarda, MONDO:0008296, Hepatoerythropoietic porphyria, MONDO:0019799; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Non-acute porphyrias v2.1 UROD Luke Stuart reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: 6112327, 24175354, 39644053, 12735639, 11134514, 9806541; Phenotypes: Porphyria cutanea tarda, OMIM:176100, Porphyria, hepatoerythropoietic, OMIM:176100, Familial porphyria cutanea tarda, MONDO:0008296, Hepatoerythropoietic porphyria, MONDO:0019799; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v11.23 GIGYF1 Achchuthan Shanmugasundram Classified gene: GIGYF1 as Amber List (moderate evidence)
Intellectual disability v11.23 GIGYF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is identified with significant enrichment in multiple large cohorts of autism spectrum disorder patients. Detailed clinical information was only available for a small subset of patients, from which intellectual disability was reported in 11/25 patients. However, severity of ID was not provided for any of these patients. Hence, this gene is rated amber with 'watchlist' tag added.
Intellectual disability v11.23 GIGYF1 Achchuthan Shanmugasundram Gene: gigyf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v11.22 GIGYF1 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: GIGYF1.
Intellectual disability v11.22 GIGYF1 Achchuthan Shanmugasundram Phenotypes for gene: GIGYF1 were changed from Developmental disorder to autism spectrum disorder, MONDO:0005258; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v11.21 GIGYF1 Achchuthan Shanmugasundram Publications for gene: GIGYF1 were set to 33057194
Intellectual disability v11.20 GIGYF1 Achchuthan Shanmugasundram reviewed gene: GIGYF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194, 35917186, 36924980; Phenotypes: autism spectrum disorder, MONDO:0005258, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v8.31 COL6A3 Alexander Rossor gene: COL6A3 was added
gene: COL6A3 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: COL6A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COL6A3 were set to 42520849
Phenotypes for gene: COL6A3 were set to motor neuropathy; myopathy
Mode of pathogenicity for gene: COL6A3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: COL6A3 was set to GREEN
Added comment: Case series of 35 patients showing evidence of both a peripheral motor neuropathy and myopathy
Sources: Expert list
Intellectual disability v11.20 LDB1 Achchuthan Shanmugasundram Phenotypes for gene: LDB1 were changed from Congenital hydrocephalus, MONDO:0016349 to neurodevelopmental disorder, MONDO:0700092; congenital hydrocephalus, MONDO:0016349
Intellectual disability v11.19 LDB1 Achchuthan Shanmugasundram Publications for gene: LDB1 were set to 39680505; 38091987; 33077954
Intellectual disability v11.18 LDB1 Achchuthan Shanmugasundram Mode of pathogenicity for gene: LDB1 was changed from None to Other
Hydrocephalus v5.18 LDB1 Achchuthan Shanmugasundram changed review comment from: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, distinguishing two variant classes with distinct phenotypic and mechanistic consequences. Ventriculomegaly/enlarged ventricles was observed in 9/9 individuals with detailed clinical data who carried C-terminal LID-disrupting (frameshift/nonsense/splice-site) variants, versus only 1/7 individuals with N-terminal LGD or DD-missense variants. Four C-terminal LID-disrupting LGD variants (p.Ser317Argfs21, p.Gln333, p.Glu349Serfs134, p.Arg356Serfs127) and one LID missense variant (p.Thr359Pro) were newly reported, in addition to prior literature reports of 8 C-terminal LGD + 1 missense variant. All these evidence support a genotype-specific association between C-terminal LDB1 variants and hydrocephalus/ventriculomegaly.

C-terminal LID-affecting LDB1 variants abolished LHX2 binding and act dominant-negatively, suppressing wild-type LDB1–LHX2 interaction below expected levels while also showing increased protein stability and nuclear aggregate formation unlike N-terminal variants. This dominant-negative mechanism was also confirmed in vivo, as C-terminal variants worsened viability upon overexpression and failed to rescue (or exacerbated) chi loss-of-function phenotypes in Drosophila, in contrast to N-terminal variants.; to: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, distinguishing two variant classes with distinct phenotypic and mechanistic consequences. Ventriculomegaly/enlarged ventricles was observed in 9/9 individuals with detailed clinical data who carried C-terminal LID-disrupting (frameshift/nonsense/splice-site) variants, versus only 1/7 individuals with N-terminal LGD or DD-missense variants. Four C-terminal LID-disrupting LGD variants (p.Ser317Argfs21, p.Gln333, p.Glu349Serfs134, p.Arg356Serfs127) and one LID missense variant (p.Thr359Pro) were newly reported, in addition to prior literature reports of 8 C-terminal LGD + 1 missense variant. All these evidence support a genotype-specific association between C-terminal LDB1 variants and hydrocephalus/ventriculomegaly.

C-terminal LID-affecting LDB1 variants abolished LHX2 binding and act dominant-negatively, suppressing wild-type LDB1–LHX2 interaction below expected levels while also showing increased protein stability and nuclear aggregate formation unlike N-terminal variants. This dominant-negative mechanism was also confirmed in vivo, as C-terminal variants worsened viability upon overexpression and failed to rescue (or exacerbated) chi loss-of-function phenotypes in Drosophila, in contrast to N-terminal variants.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 16 August 2026).
Intellectual disability v11.17 LDB1 Achchuthan Shanmugasundram changed review comment from: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, of which 14 patients presented with developmental delay, 13 patients with speech delay and 8 patients with motor delay. There were eight other patients reported previously. Developmental delay was present in 9/11 individuals with N-terminal LGD/DD missense variants and 7/7 individuals with C-terminal LID-affecting variants, speech delay present in 10/10 and 5/5, and motor delay present in 5/9 and 5/5 respectively. Unlike the ventriculomegaly phenotype, developmental delay occurs across both N-terminal and C-terminal variant classes, indicating it is a core, mechanism-independent feature of LDB1-related neurodevelopmental disorder.

N-terminal DD missense variants impair LDB1 homodimerization through loss-of-function, while C-terminal LID variants abolish LHX2 binding via a dominant-negative mechanism, both disrupting transcriptional complexes required for neurogenesis. In Drosophila, neuronal knockdown of the LDB1 ortholog chi impaired motor behavior, and both variant types failed to properly rescue this phenotype, confirming LDB1 dysfunction causally contributes to neurological/developmental impairment.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; to: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, of which 14 patients presented with developmental delay, 13 patients with speech delay and 8 patients with motor delay. There were eight other patients reported previously. Developmental delay was present in 9/11 individuals with N-terminal LGD/DD missense variants and 7/7 individuals with C-terminal LID-affecting variants, speech delay present in 10/10 and 5/5, and motor delay present in 5/9 and 5/5 respectively. Unlike the ventriculomegaly phenotype, developmental delay occurs across both N-terminal and C-terminal variant classes, indicating it is a core, mechanism-independent feature of LDB1-related neurodevelopmental disorder.

N-terminal DD missense variants impair LDB1 homodimerization through loss-of-function, while C-terminal LID variants abolish LHX2 binding via a dominant-negative mechanism, both disrupting transcriptional complexes required for neurogenesis. In Drosophila, neuronal knockdown of the LDB1 ortholog chi impaired motor behavior, and both variant types failed to properly rescue this phenotype, confirming LDB1 dysfunction causally contributes to neurological/developmental impairment.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 16 August 2026).
Intellectual disability v11.17 LDB1 Achchuthan Shanmugasundram reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 42320471; Phenotypes: neurodevelopmental disorder, MONDO:0700092, congenital hydrocephalus, MONDO:0016349; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hydrocephalus v5.18 LDB1 Achchuthan Shanmugasundram Phenotypes for gene: LDB1 were changed from Congenital hydrocephalus, MONDO:0016349 to congenital hydrocephalus, MONDO:0016349; neurodevelopmental disorder, MONDO:0700092
Hydrocephalus v5.17 LDB1 Achchuthan Shanmugasundram Publications for gene: LDB1 were set to 39680505; 38091987; 33077954
Hydrocephalus v5.16 LDB1 Achchuthan Shanmugasundram Mode of pathogenicity for gene: LDB1 was changed from None to Other
Hydrocephalus v5.15 LDB1 Achchuthan Shanmugasundram reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 42320471; Phenotypes: congenital hydrocephalus, MONDO:0016349, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia, adult onset v9.10 ELOVL5 Ida Ertmanska changed review comment from: PMID: 40940404 Watanabe et al., 2025
Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done.

PMID: 32314013 Gazulla et al., 2020
Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease.

PMID: 25065913 DiGregorio et al., 2014
Three SCA-affected Italian families (2 have confirmed shared ancestry, third may be more distantly related or same variant arose spontaneously). ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Disease onset was around 34-45 years of age, with slowly progressive symptoms.
Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. The female proband had ataxia with age of onset 51 years.

FUNCTIONAL EVIDENCE:
PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913
Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%. ; to: PMID: 40940404 Watanabe et al., 2025
Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done.

PMID: 32314013 Gazulla et al., 2020
Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease.

PMID: 25065913 DiGregorio et al., 2014
Three SCA-affected Italian families (2 have confirmed shared ancestry, third may be more distantly related or same variant arose spontaneously). ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Disease onset was around 34-45 years of age, with slowly progressive symptoms.
Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. The female proband had ataxia with age of onset 51 years.

FUNCTIONAL EVIDENCE:
PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913
Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%.

This gene is associated with AD Spinocerebellar ataxia 38, MIM:615957 (OMIM accessed 14th Aug 2026).
Hereditary ataxia, adult onset v9.10 ELOVL5 Ida Ertmanska Phenotypes for gene: ELOVL5 were changed from Spinocerebellar ataxia 38, 615957; Spinocerebellar ataxia 36 615957 to Spinocerebellar ataxia 38, OMIM:615957; spinocerebellar ataxia type 38, MONDO:0014417
Hereditary ataxia, adult onset v9.9 ELOVL5 Ida Ertmanska Publications for gene: ELOVL5 were set to
Hereditary ataxia, adult onset v9.8 ELOVL5 Ida Ertmanska Mode of inheritance for gene: ELOVL5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia, adult onset v9.7 ELOVL5 Ida Ertmanska Mode of pathogenicity for gene: ELOVL5 was changed from Other - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Hereditary ataxia, adult onset v9.6 ELOVL5 Ida Ertmanska Classified gene: ELOVL5 as Amber List (moderate evidence)
Hereditary ataxia, adult onset v9.6 ELOVL5 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated families reported in literature with 3 unique monoallelic ELOVL5 missense variants, affected by adult-onset spinocerebellar ataxia. There is also a fourth pedigree, reported in PMID: 32314013, with a likely benign variant with a high allele frequency in gnomAD (not counted). Based on available evidence, this gene can be promoted to Green at the next update.
Hereditary ataxia, adult onset v9.6 ELOVL5 Ida Ertmanska Gene: elovl5 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v9.5 ELOVL5 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ELOVL5.
Hereditary ataxia, adult onset v9.5 ELOVL5 Ida Ertmanska changed review comment from: PMID: 40940404 Watanabe et al., 2025
Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done.

PMID: 32314013 Gazulla et al., 2020
Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease.

PMID: 25065913 DiGregorio et al., 2014
SCA-affected Italian family. ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1.
Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1.

FUNCTIONAL EVIDENCE:
PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913
Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%.; to: PMID: 40940404 Watanabe et al., 2025
Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done.

PMID: 32314013 Gazulla et al., 2020
Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease.

PMID: 25065913 DiGregorio et al., 2014
Three SCA-affected Italian families (2 have confirmed shared ancestry, third may be more distantly related or same variant arose spontaneously). ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Disease onset was around 34-45 years of age, with slowly progressive symptoms.
Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. The female proband had ataxia with age of onset 51 years.

FUNCTIONAL EVIDENCE:
PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913
Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%.
Hereditary ataxia, adult onset v9.5 ELOVL5 Ida Ertmanska changed review comment from: PMID: 40940404 Watanabe et al., 2025
Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done.

PMID: 32314013 Gazulla et al., 2020
Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote.

PMID: 25065913 DiGregorio et al., 2014
SCA-affected Italian family. ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1.
Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1.

FUNCTIONAL EVIDENCE:
PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913
Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%.; to: PMID: 40940404 Watanabe et al., 2025
Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done.

PMID: 32314013 Gazulla et al., 2020
Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease.

PMID: 25065913 DiGregorio et al., 2014
SCA-affected Italian family. ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1.
Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1.

FUNCTIONAL EVIDENCE:
PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913
Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%.
Hereditary ataxia, adult onset v9.5 ELOVL5 Ida Ertmanska edited their review of gene: ELOVL5: Changed publications to: 25065913, 32314013, 37199746, 40940404
Hereditary ataxia, adult onset v9.5 ELOVL5 Ida Ertmanska changed review comment from: PMID: 40940404 Watanabe et al., 2025
Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected.; to: PMID: 40940404 Watanabe et al., 2025
Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done.

PMID: 32314013 Gazulla et al., 2020
Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote.

PMID: 25065913 DiGregorio et al., 2014
SCA-affected Italian family. ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1.
Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1.

FUNCTIONAL EVIDENCE:
PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913
Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%.
Proteinuric renal disease v6.14 WDR4 Luke Stuart changed review comment from: Renal features including proteinuria and nephrotic syndrome have been noted in a subset of Galloway Mowat Syndrome 6 (GAMOS6) patients:

Braun et al., 2018 (PMID 30079490): A GAMOS family was investigated via WES. WDR4 c.454-2A>C (homozygous) segregated with disease in four siblings, three of whom demonstrated renal involvement (nephrotic range proteinuria). Severity was variable; only one child (B1028-21) developed overt nephrotic syndrome including edema and hypalbuminemia.

Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity. At 5 years, the patient developed occasional mild proteinuria (1+) with no associated symptoms, progressing to hypoalbuminemia (2.5 mg/dL), proteinuria (3+) and increased urine protein-to-creatinine ratio (3.0) at 6 years. Nephrotic syndrome was diagnosed.

Emerging evidence suggests renal abnormalities as a component of the GAMOS6 phenotype. An amber classification is recommended based on the observation of four individuals from two independent families presenting with proteinuria, two of whom developed overt nephrotic syndrome. Characterisation of additional WDR4-related GAMOS patients is necessary to establish a clear relationship.

WDR4 is associated with Galloway-Mowat syndrome 6 (OMIM #61834) and Microcephaly, growth deficiency, seizures, and brain malformations (OMIM #618346), accessed 08/2026.; to: WDR4 is associated with Galloway-Mowat syndrome 6 (OMIM #61834) and Microcephaly, growth deficiency, seizures, and brain malformations (OMIM #618346), accessed 08/2026.

Renal features including proteinuria and nephrotic syndrome have been noted in a subset of Galloway Mowat Syndrome 6 (GAMOS6) patients:

Braun et al., 2018 (PMID 30079490): A GAMOS family was investigated via WES. WDR4 c.454-2A>C (homozygous) segregated with disease in four siblings, three of whom demonstrated renal involvement (nephrotic range proteinuria). Severity was variable; only one child (B1028-21) developed overt nephrotic syndrome including edema and hypalbuminemia.

Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity. At 5 years, the patient developed occasional mild proteinuria (1+) with no associated symptoms, progressing to hypoalbuminemia (2.5 mg/dL), proteinuria (3+) and increased urine protein-to-creatinine ratio (3.0) at 6 years. Nephrotic syndrome was diagnosed.

Emerging evidence suggests renal abnormalities as a component of the GAMOS6 phenotype. An amber classification is recommended based on the observation of four individuals from two independent families presenting with proteinuria, two of whom developed overt nephrotic syndrome. Characterisation of additional WDR4-related GAMOS patients is necessary to establish a clear relationship.

Proteinuric renal disease v6.14 WDR4 Luke Stuart reviewed gene: WDR4: Rating: AMBER; Mode of pathogenicity: None; Publications: 30079490; Phenotypes: Galloway-Mowat syndrome 6, OMIM:61834, Galloway-Mowat syndrome 6, MONDO:0032691; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v9.5 ELOVL5 Ida Ertmanska reviewed gene: ELOVL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40940404; Phenotypes: Spinocerebellar ataxia 38, OMIM:615957, spinocerebellar ataxia type 38, MONDO:0014417; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v9.30 GPN2 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Luke Stuart, there are now 2 pedigrees reported where individuals harbouring biallelic GPN2 variants presented with ataxia (2 sibs, age of onset not specified), and cerebellar atrophy (both families). Based on available evidence, this gene can only be rated Amber.; to: Comment on list classification: As reviewed by Luke Stuart, there are now 2 pedigrees reported where individuals harbouring biallelic GPN2 variants presented with ataxia (2 sibs, age of onset not specified), and cerebellar atrophy (both families). These families were found to have shared ancestry - counted as 1 family. Based on available evidence, this gene can only be rated Red.
Ataxia and cerebellar anomalies - childhood onset v9.30 GPN2 Ida Ertmanska Tag founder-effect tag was added to gene: GPN2.
Ataxia and cerebellar anomalies - childhood onset v9.30 GPN2 Ida Ertmanska Classified gene: GPN2 as Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v9.30 GPN2 Ida Ertmanska Gene: gpn2 has been classified as Red List (Low Evidence).
Skeletal dysplasia v10.5 LONP1 Ida Ertmanska Phenotypes for gene: LONP1 were changed from CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879
Skeletal dysplasia v10.4 LONP1 Ida Ertmanska Phenotypes for gene: LONP1 were changed from CODAS (Cerebral, Ocular, Dental, Auricular and Skeletal anomalies) syndrome 600373 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092
Severe microcephaly v9.26 CDK6 Ida Ertmanska Tag watchlist tag was added to gene: CDK6.
Severe microcephaly v9.26 CDK6 Ida Ertmanska Publications for gene: CDK6 were set to 25951892; 25548773; 23918663
Severe microcephaly v9.25 CDK6 Ida Ertmanska Phenotypes for gene: CDK6 were changed from Autosomal recessive primary microcephaly (MCPH) ; ?Microcephaly 12, primary, autosomal recessive, 616080 to ?Microcephaly 12, primary, autosomal recessive, OMIM:616080; microcephaly 12, primary, autosomal recessive, MONDO:0014484
Severe microcephaly v9.24 CDK6 Ida Ertmanska Classified gene: CDK6 as Amber List (moderate evidence)
Severe microcephaly v9.24 CDK6 Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported in literature with biallelic CDK6 variants and severe microcephaly (more than 3SD below average). Hence, this gene can be rated Amber with current evidence. A 'watchlist' tag was added in anticipation of further reports.
Severe microcephaly v9.24 CDK6 Ida Ertmanska Gene: cdk6 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v10.3 LONP1 Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v9.23 CDK6 Ida Ertmanska edited their review of gene: CDK6: Changed publications to: 23918663, 41856556
Severe microcephaly v9.23 CDK6 Ida Ertmanska changed review comment from: PMID: 41856556 Isik et al., 2026
Report of a female child (Case 3, 7.5 yrs old) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Parents are consanguineous.
Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.; to: PMID: 41856556 Isik et al., 2026
Report of a female child (Case 3, 7.5 yrs old) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Parents are consanguineous.
Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.

Individuals in PMID:23918663 (see review by Rebecca Foulger) had severe microcephaly of -4 SD and -6SD.
Severe microcephaly v9.23 CDK6 Ida Ertmanska changed review comment from: PMID: 41856556 Isik et al., 2026
Report of a female child (Case 3) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq.
Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.; to: PMID: 41856556 Isik et al., 2026
Report of a female child (Case 3, 7.5 yrs old) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Parents are consanguineous.
Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.
Severe microcephaly v9.23 CDK6 Ida Ertmanska reviewed gene: CDK6: Rating: AMBER; Mode of pathogenicity: None; Publications: 41856556; Phenotypes: ?Microcephaly 12, primary, autosomal recessive, OMIM:616080, microcephaly 12, primary, autosomal recessive, MONDO:0014484; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pyruvate dehydrogenase (PDH) deficiency v1.44 LONP1 Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS syndrome OMIM:600373; CODAS syndrome MONDO:0010879 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092
Pyruvate dehydrogenase (PDH) deficiency v1.43 LONP1 Achchuthan Shanmugasundram Publications for gene: LONP1 were set to 30304514
Bilateral congenital or childhood onset cataracts v8.11 LONP1 Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS syndrome, 600373 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879
Bilateral congenital or childhood onset cataracts v8.10 LONP1 Achchuthan Shanmugasundram Publications for gene: LONP1 were set to 25574826; 26622071; 27878435; 29408517; 25808063; 28148925
Pyruvate dehydrogenase (PDH) deficiency v1.42 LONP1 Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.51 ZNHIT3 Ida Ertmanska changed review comment from: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including optic atrophy. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation, though optic atrophy is not specifically mentioned. Hence, this gene can only be rated Amber on Optic neuropathy with the current evidence.; to: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including optic atrophy. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation, though optic atrophy is not specifically mentioned. Hence, this gene can only be rated Amber on Optic neuropathy with the current evidence. It was tagged for promotion to Green on Paediatric disorders - additional genes, to ensure inclusion on R27.
Severe microcephaly v9.23 ZNHIT3 Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3.
Severe microcephaly v9.23 ZNHIT3 Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence)
Severe microcephaly v9.23 ZNHIT3 Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including microcephaly. However, the severity is not stated in PMID: 28335020. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation with microcephaly. Hence, this gene can only be rated Amber with the current evidence. It was tagged for promotion to Green on Paediatric disorders - additional genes, to ensure inclusion on R27.
Severe microcephaly v9.23 ZNHIT3 Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v8.4 ZNHIT3 Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3.
Paediatric disorders - additional genes v8.13 ZNHIT3 Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3.
Paediatric disorders - additional genes v8.13 ZNHIT3 Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v8.13 ZNHIT3 Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including childhood-onset cerebellar atrophy, optic atrophy, oedema, microcephaly, infantile spasms, and profound developmental delay. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation similar to reported patients. Hence, this gene can be promoted to Green at the next update.
Paediatric disorders - additional genes v8.13 ZNHIT3 Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v8.9 LONP1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are >3 patients reported with biallelic variants and congenital cataracts. However, only one patient with monoallelic variant presented with cataracts. Hence, the MOI should remain as BIALLELIC.
Bilateral congenital or childhood onset cataracts v8.9 LONP1 Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v9.29 ZNHIT3 Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3.
Bilateral congenital or childhood onset cataracts v8.8 LONP1 Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v9.29 ZNHIT3 Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v9.29 ZNHIT3 Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including childhood-onset cerebellar atrophy. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation with structural cerebellar anomalies. Hence, this gene can be promoted to Green at the next update.
Ataxia and cerebellar anomalies - childhood onset v9.29 ZNHIT3 Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.51 ZNHIT3 Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3.
Optic neuropathy v6.51 ZNHIT3 Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence)
Optic neuropathy v6.51 ZNHIT3 Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including optic atrophy. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation, though optic atrophy is not specifically mentioned. Hence, this gene can only be rated Amber on Optic neuropathy with the current evidence.
Optic neuropathy v6.51 ZNHIT3 Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v5.7 ZNHIT3 Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence)
Primary lymphoedema v5.7 ZNHIT3 Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including oedema. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation with pericardiac oedema. Hence, this gene can be promoted to Green at the next update.
Primary lymphoedema v5.7 ZNHIT3 Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v5.6 ZNHIT3 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ZNHIT3.
Optic neuropathy v6.50 ZNHIT3 Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: AMBER
Paediatric disorders - additional genes v8.12 ZNHIT3 Ida Ertmanska gene: ZNHIT3 was added
gene: ZNHIT3 was added to Paediatric disorders - additional genes. Sources: Literature
Q3_26_promote_green tags were added to gene: ZNHIT3.
Mode of inheritance for gene: ZNHIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNHIT3 were set to 28335020; 31048081; 39252897; 40178020
Phenotypes for gene: ZNHIT3 were set to PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841
Review for gene: ZNHIT3 was set to GREEN
Added comment: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Brain MRI showed cerebral, cerebellar and brainstem atrophy and thin corpus callosum. Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.
Sources: Literature
Severe microcephaly v9.22 ZNHIT3 Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: AMBER
Ataxia and cerebellar anomalies - childhood onset v9.28 ZNHIT3 Ida Ertmanska gene: ZNHIT3 was added
gene: ZNHIT3 was added to Ataxia and cerebellar anomalies - childhood onset. Sources: Literature
Q3_26_promote_green tags were added to gene: ZNHIT3.
Mode of inheritance for gene: ZNHIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNHIT3 were set to 28335020; 31048081; 39252897; 40178020
Phenotypes for gene: ZNHIT3 were set to PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841
Review for gene: ZNHIT3 was set to GREEN
Added comment: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Brain MRI showed cerebral, cerebellar and brainstem atrophy and thin corpus callosum. Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.
Sources: Literature
Severe microcephaly v9.22 ZNHIT3 Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence)
Severe microcephaly v9.22 ZNHIT3 Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v5.6 ZNHIT3 Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence)
Primary lymphoedema v5.6 ZNHIT3 Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v9.21 ZNHIT3 Ida Ertmanska changed review comment from: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.; to: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Brain MRI showed cerebral, cerebellar and brainstem atrophy and thin corpus callosum. Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.
Primary lymphoedema v5.5 ZNHIT3 Ida Ertmanska Phenotypes for gene: ZNHIT3 were changed from PEHO syndrome, 260565 to PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841
Primary lymphoedema v5.4 ZNHIT3 Ida Ertmanska Publications for gene: ZNHIT3 were set to 28335020
Primary lymphoedema v5.3 ZNHIT3 Ida Ertmanska reviewed gene: ZNHIT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28335020, 31048081, 39252897, 40178020; Phenotypes: PEHO syndrome, OMIM:260565, PEHO syndrome, MONDO:0009841; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v9.21 ZNHIT3 Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: GREEN; Changed publications to: 28335020, 31048081, 39252897, 40178020; Changed phenotypes to: PEHO syndrome, OMIM:260565, PEHO syndrome, MONDO:0009841; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v9.21 ZNHIT3 Ida Ertmanska commented on gene: ZNHIT3
Severe microcephaly v9.21 ZNHIT3 Ida Ertmanska Publications for gene: ZNHIT3 were set to 28335020
Severe microcephaly v9.20 ZNHIT3 Ida Ertmanska Phenotypes for gene: ZNHIT3 were changed from PEHO syndrome, 260565; microcephaly to Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy; PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841
Optic neuropathy v6.50 ZNHIT3 Ida Ertmanska Phenotypes for gene: ZNHIT3 were changed from Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) 260565 to Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy; PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841
Optic neuropathy v6.49 ZNHIT3 Ida Ertmanska Publications for gene: ZNHIT3 were set to 28335020
Optic neuropathy v6.48 ZNHIT3 Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence)
Optic neuropathy v6.48 ZNHIT3 Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.47 ZNHIT3 Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: GREEN
Optic neuropathy v6.47 ZNHIT3 Ida Ertmanska changed review comment from: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.; to: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.
Optic neuropathy v6.47 ZNHIT3 Ida Ertmanska edited their review of gene: ZNHIT3: Changed publications to: 28335020, 31048081, 39252897, 40178020
Ataxia and cerebellar anomalies - childhood onset v9.27 GPN2 Achchuthan Shanmugasundram Phenotypes for gene: GPN2 were changed from Cerebellar ataxia (MONDO:0000437) to Cerebellar ataxia, MONDO:0000437
Optic neuropathy v6.47 ZNHIT3 Ida Ertmanska changed review comment from: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each.
She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.; to: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.
Intellectual disability v11.17 GPN2 Achchuthan Shanmugasundram Phenotypes for gene: GPN2 were changed from Intellectual disability (MONDO:0001071) to Intellectual disability, MONDO:0001071
Monogenic hearing loss v6.42 GPN2 Achchuthan Shanmugasundram Phenotypes for gene: GPN2 were changed from Sensorineural hearing loss disorder (MONDO:0020678) to Sensorineural hearing loss disorder, MONDO:0020678
Hereditary ataxia, adult onset v9.5 OGDH Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases reported with monoallelic OGDH variants and with cerebellar ataxia. There is also some functional evidence available from Drosophila showing a role for reported variants in late-onset locomotion defects.

Hence, this gene can be rated amber with 'watchlist' tag added to review gene rating in light of any new evidence.; to: Comment on list classification: There are two unrelated cases reported with monoallelic OGDH variants and with cerebellar ataxia. There is also functional evidence available from Drosophila showing a role for reported variants in late-onset locomotion defects.

Hence, this gene can be rated green in the next GMS update.
Hereditary ataxia, adult onset v9.5 OGDH Achchuthan Shanmugasundram Tag watchlist was removed from gene: OGDH.
Tag Q3_26_NHS_review tag was added to gene: OGDH.
Tag Q3_26_promote_green tag was added to gene: OGDH.
Hereditary ataxia, adult onset v9.5 OGDH Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: GREEN
Bilateral congenital or childhood onset cataracts v8.8 COPB1 Achchuthan Shanmugasundram Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly to Baralle-Macken syndrome, OMIM:619255; Baralle-Macken syndrome, MONDO:0031002
Severe microcephaly v9.19 COPB1 Achchuthan Shanmugasundram Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly to Baralle-Macken syndrome, OMIM:619255; Baralle-Macken syndrome, MONDO:0031002
Intellectual disability v11.16 COPB1 Achchuthan Shanmugasundram Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly to Baralle-Macken syndrome, OMIM:619255; Baralle-Macken syndrome, MONDO:0031002
Early onset or syndromic epilepsy v9.72 DHX16 Achchuthan Shanmugasundram Phenotypes for gene: DHX16 were changed from Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733 neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890 to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890
Intellectual disability v11.15 COPB1 Luke Stuart changed review comment from: Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). All six patients had severe intellectual disability. In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability.

Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 variant, c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts.

A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.; to: COPB1 is associated with Baralle-Macken syndrome, OMIM:619255 (accessed 08/ 2026)

Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). All six patients had severe intellectual disability. In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability.

Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 variant, c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts.

A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.
Intellectual disability v11.15 COPB1 Luke Stuart edited their review of gene: COPB1: Changed phenotypes to: Baralle-Macken syndrome, OMIM:619255, Baralle-Macken syndrome, MONDO:0031002
Severe microcephaly v9.18 COPB1 Luke Stuart edited their review of gene: COPB1: Changed phenotypes to: Baralle-Macken syndrome, OMIM:619255, Baralle-Macken syndrome, MONDO:0031002
Severe microcephaly v9.18 COPB1 Luke Stuart changed review comment from: Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability.

Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts.

A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.; to: COPB1 is associated with Baralle-Macken syndrome, OMIM:619255 (accessed 08/2026).

Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability.

Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts.

A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.
Bilateral congenital or childhood onset cataracts v8.7 COPB1 Luke Stuart changed review comment from: Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability.

Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts.

All eight paediatric patients reported to date had severe early-onset cataracts (Khalid et al., 2025 (PMID 40396222); Macken et al., 2021 (PMID 33632302).

A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.; to: Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability.

Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts.

All eight paediatric patients reported to date had severe early-onset cataracts (Khalid et al., 2025 (PMID 40396222); Macken et al., 2021 (PMID 33632302).

COPB1 is associated with Baralle-Macken syndrome, OMIM:619255 (accessed 08/2026).

A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.
Bilateral congenital or childhood onset cataracts v8.7 COPB1 Luke Stuart edited their review of gene: COPB1: Changed phenotypes to: Baralle-Macken syndrome, OMIM:619255, Baralle-Macken syndrome, MONDO:0031002
Early onset or syndromic epilepsy v9.71 DHX16 Ida Ertmanska Phenotypes for gene: DHX16 were changed from Neuromuscular disease and ocular or auditory anomalies with or without seizures 618733 to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733 neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890
Early onset or syndromic epilepsy v9.70 DHX16 Ida Ertmanska edited their review of gene: DHX16: Changed phenotypes to: Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733 neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890
Early onset or syndromic epilepsy v9.70 DHX16 Achchuthan Shanmugasundram Publications for gene: DHX16 were set to 31256877
Early onset or syndromic epilepsy v9.69 DHX16 Achchuthan Shanmugasundram Mode of inheritance for gene: DHX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v11.15 PDCD6IP Achchuthan Shanmugasundram Phenotypes for gene: PDCD6IP were changed from microcephaly; Intellectual disability to ?Microcephaly 29, primary, autosomal recessive, OMIM:620047; microcephaly 29, primary, autosomal recessive, MONDO:0031060
Intellectual disability v11.14 PDCD6IP Achchuthan Shanmugasundram Publications for gene: PDCD6IP were set to 32286682
Arthrogryposis v10.20 NFATC2 Achchuthan Shanmugasundram Classified gene: NFATC2 as Red List (low evidence)
Arthrogryposis v10.20 NFATC2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one patient reported with biallelic NFATC2 variants and with joint contractures. Hence, this gene should be rated red with the current evidence.
Arthrogryposis v10.20 NFATC2 Achchuthan Shanmugasundram Gene: nfatc2 has been classified as Red List (Low Evidence).
Arthrogryposis v10.19 NFATC2 Achchuthan Shanmugasundram Phenotypes for gene: NFATC2 were changed from ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369; lymphoproliferative syndrome, MONDO:0016537 to ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369
Arthrogryposis v10.18 NFATC2 Achchuthan Shanmugasundram Tag watchlist was removed from gene: NFATC2.
Arthrogryposis v10.18 NFATC2 Achchuthan Shanmugasundram changed review comment from: PMID:35789258 (2022) reported the first patient with complete NFAT1 (NFATC2) deficiency identified with a homozygous frameshift variant (c.2023_2026delTACC; p.Tyr675Thrfs*18). The patient presented with presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma, and immune profile showed accumulation of naïve B cells with oncogenic signatures (MYC, JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, aberrant CD8+ T cells.

PMID:38427060 (2024) reported a 12-year-old female patient identified with a homozygous 6bp in-frame deletion (c.340_345delGAGATC; p.Glu114_Ile115del) and presenting with EBV-associated lymphoproliferation without skeletal involvement. This patient had recurrent chest infections, chronic wet cough, failure to thrive, generalised lymphadenopathy and severe hypogammaglobulinemia. The father and the healthy brother of the patient were heterozygous for the variant.

As reviewed by Boaz Palterer, Bustamante-Ogando et al (2025) reported in a conference abstract (NOT a peer-reviewed manuscript) of a 12-year-old female patient with a severe, early-onset immunodeficiency characterised by recurrent sinopulmonary infections, bloody diarrhoea, chronic lung disease, and profound failure to thrive. Immunological analysis revealed anaemia and thrombocytosis, as well as pan-hypogammaglobulinemia, with reduced CD4+ and CD8+ T cells. Whole exome sequencing identified two novel, ultra-rare, highly conserved compound heterozygous missense variants in NFATC2 (p.Gly408Arg & p.Arg646Gln).

This gene has been provisionally associated with MIM #620232 in OMIM (last accessed 11 August 2024).; to: PMID:35789258 (2022) reported the first patient with complete NFAT1 (NFATC2) deficiency identified with a homozygous frameshift variant (c.2023_2026delTACC; p.Tyr675Thrfs*18). The patient presented with presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma, and immune profile showed accumulation of naïve B cells with oncogenic signatures (MYC, JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, aberrant CD8+ T cells.

PMID:38427060 (2024) reported a 12-year-old female patient identified with a homozygous 6bp in-frame deletion (c.340_345delGAGATC; p.Glu114_Ile115del) and presenting with EBV-associated lymphoproliferation without skeletal involvement. This patient had recurrent chest infections, chronic wet cough, failure to thrive, generalised lymphadenopathy and severe hypogammaglobulinemia. The father and the healthy brother of the patient were heterozygous for the variant.

As reviewed by Boaz Palterer, Bustamante-Ogando et al (2025) reported in a conference abstract (NOT a peer-reviewed manuscript) of a 12-year-old female patient with a severe, early-onset immunodeficiency characterised by recurrent sinopulmonary infections, bloody diarrhoea, chronic lung disease, and profound failure to thrive. Immunological analysis revealed anaemia and thrombocytosis, as well as pan-hypogammaglobulinemia, with reduced CD4+ and CD8+ T cells. Whole exome sequencing identified two novel, ultra-rare, highly conserved compound heterozygous missense variants in NFATC2 (p.Gly408Arg & p.Arg646Gln).

This gene has been provisionally associated with MIM #620232 in OMIM (last accessed 11 August 2024).
Arthrogryposis v10.18 NFATC2 Achchuthan Shanmugasundram Deleted their comment
Arthrogryposis v10.18 NFATC2 Achchuthan Shanmugasundram edited their review of gene: NFATC2: Changed rating: RED; Changed phenotypes to: ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232, joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369
Arthrogryposis v10.18 NFATC2 Achchuthan Shanmugasundram Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v9.102
Arthrogryposis v10.18 NFATC2 Achchuthan Shanmugasundram gene: NFATC2 was added
gene: NFATC2 was added to Arthrogryposis. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: NFATC2.
Mode of inheritance for gene: NFATC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFATC2 were set to 35789258; 38427060
Phenotypes for gene: NFATC2 were set to ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369; lymphoproliferative syndrome, MONDO:0016537
Penetrance for gene: NFATC2 were set to unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 NFATC2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are only two unrelated cases published with biallelic NFATC2 variants and with a relevant phenotype. They displayed phenotypic variability with both displaying lymphoproliferative disorder, but only one with skeletal phenotype. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are only two unrelated cases published with biallelic NFATC2 variants and with a relevant phenotype. They displayed phenotypic variability with both displaying lymphoproliferative disorder, but only one with skeletal phenotype. Hence, this gene should be rated amber with the current evidence.

The 'watchlist' tag has been added as there is an additional patient reported in a conference abstract with relevant phenotype. Hence, this gene should be reviewed and updated when additional published evidence become available.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 NFATC2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: NFATC2.
Fetal anomalies v8.4 PCLO Achchuthan Shanmugasundram Phenotypes for gene: PCLO were changed from Pontocerebellar hypoplasia, type 3, OMIM:608027 to Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy
Optic neuropathy v6.47 ZNHIT3 Ida Ertmanska edited their review of gene: ZNHIT3: Changed phenotypes to: PEHO syndrome, OMIM:260565, PEHO syndrome, MONDO:0009841
Optic neuropathy v6.47 ZNHIT3 Ida Ertmanska edited their review of gene: ZNHIT3: Changed publications to: 31048081, 39252897
Optic neuropathy v6.47 ZNHIT3 Ida Ertmanska changed review comment from: PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each.
She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.; to: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each.
She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.
Intellectual disability v11.13 PCLO Achchuthan Shanmugasundram Publications for gene: PCLO were set to 25832664
Intellectual disability v11.12 PCLO Achchuthan Shanmugasundram Phenotypes for gene: PCLO were changed from Pontocerebellar hypoplasia, type 3 to Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy
Optic neuropathy v6.47 ZNHIT3 Ida Ertmanska changed review comment from: PMID: 31048081 Õunap et al., 2019
Report of a female patient (non-Finnish) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each.
She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.; to: PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each.
She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.
Optic neuropathy v6.47 ZNHIT3 Ida Ertmanska reviewed gene: ZNHIT3: Rating: AMBER; Mode of pathogenicity: None; Publications: 31048081; Phenotypes: PEHO syndrome, OMIM:260565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v11.11 VWA8 Ida Ertmanska Classified gene: VWA8 as Red List (low evidence)
Intellectual disability v11.11 VWA8 Ida Ertmanska Added comment: Comment on list classification: There is one family reported in literature with a biallelic missense variant in VWA8 segregating with a complex neurodevelopmental disorder (PMID: 34660594). Other reports describe individuals with retinitis pigmentosa and monoallelic nonsense variants. Hence, this gene can only be rated Red on Intellectual disability with the current evidence.
Intellectual disability v11.11 VWA8 Ida Ertmanska Gene: vwa8 has been classified as Red List (Low Evidence).
Intellectual disability v11.10 VWA8 Ida Ertmanska gene: VWA8 was added
gene: VWA8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: VWA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VWA8 were set to 34660594; 37012052; 40638000; 42120427
Phenotypes for gene: VWA8 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: VWA8 was set to RED
Added comment: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 37012052 Kong et al., 2023
A single family with 11 individuals all presenting initial symptoms of visual defects which later progressed to macular changes, including macular degeneration and dystrophy. Two variants (c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter)) on the same allele of the VWA8 gene were found to segregate with disease. Expression studies showed reduced protein expression. Zebrafish knockdown model displayed a similar phenotype to that of humans.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish.

PMID: 42120427 Kong et al., 2026 - Functional evidence - same research group as first patient report in PMID: 37012052
Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice.
The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation.
Sources: Literature
Retinal disorders v9.19 VWA8 Ida Ertmanska commented on gene: VWA8: Comment on list classification: There are now 2 unrelated probands reported in literature with monoallelic nonsense variants in VWA8 and retinitis pigmentosa. A mouse model presented in PMID: 42120427 (Kong et al., 2026) is supportive of this disease association. Homozygous knockout mice had a more severe retinal phenotype than heterozygous mutants (though biallelic cases not yet reported in human). There is one pedigree reported with a bialellic VWA8 missense variant segregating with a complex neurodevelopmental disorder without retinal disease - potentially resulting from a different disease mechanism. Based on available evidence, this gene can be promoted to Green on Retinal disorders with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Retinal disorders v9.19 VWA8 Ida Ertmanska Phenotypes for gene: VWA8 were changed from ?Retinitis pigmentosa 97, OMIM:620422 to ?Retinitis pigmentosa 97, OMIM:620422; retinitis pigmentosa 97, MONDO:0957314
Retinal disorders v9.18 VWA8 Ida Ertmanska Publications for gene: VWA8 were set to 37012052
Retinal disorders v9.17 VWA8 Ida Ertmanska Tag watchlist was removed from gene: VWA8.
Tag Q3_26_promote_green tag was added to gene: VWA8.
Retinal disorders v9.17 VWA8 Ida Ertmanska changed review comment from: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish

PMID: 42120427 Kong et al., 2026 - Functional evidence
Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice.
The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation.; to: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish

PMID: 42120427 Kong et al., 2026 - Functional evidence - same research group as first patient report in PMID: 37012052
Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice.
The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation.
Retinal disorders v9.17 VWA8 Ida Ertmanska edited their review of gene: VWA8: Changed publications to: 34660594, 40638000, 42120427
Retinal disorders v9.17 VWA8 Ida Ertmanska changed review comment from: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish.; to: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish

PMID: 42120427 Kong et al., 2026 - Functional evidence
Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice.
The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation.
Autoinflammatory disorders v3.21 PSMB8 Achchuthan Shanmugasundram Mode of pathogenicity for gene: PSMB8 was changed from to Other
Autoinflammatory disorders v3.20 PSMB8 Achchuthan Shanmugasundram edited their review of gene: PSMB8: Changed mode of pathogenicity: Other
Retinal disorders v9.17 VWA8 Ida Ertmanska edited their review of gene: VWA8: Changed publications to: 34660594, 40638000
Retinal disorders v9.17 VWA8 Ida Ertmanska changed review comment from: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.; to: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish.
Retinal disorders v9.17 VWA8 Ida Ertmanska reviewed gene: VWA8: Rating: GREEN; Mode of pathogenicity: None; Publications: 40638000; Phenotypes: ?Retinitis pigmentosa 97, OMIM:620422, retinitis pigmentosa 97, MONDO:0957314; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.68 SEC31A Ida Ertmanska Tag watchlist was removed from gene: SEC31A.
Fetal anomalies v8.3 SEC31A Ida Ertmanska Classified gene: SEC31A as Amber List (moderate evidence)
Fetal anomalies v8.3 SEC31A Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated probands reported with 3 unique homozygous variants in SEC31A and a highly syndromic presentation, resulting in early lethality. Two individuals had IUGR. In addition, a neuron-specific sec31a knock-down in Drosophila recapitulated early lethality seen in the patients. Based on available evidence, this gene should be Green on Fetal anomalies.
Fetal anomalies v8.3 SEC31A Ida Ertmanska Gene: sec31a has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v8.11 SEC31A Ida Ertmanska Classified gene: SEC31A as Amber List (moderate evidence)
Paediatric disorders - additional genes v8.11 SEC31A Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated probands reported with 3 unique homozygous variants in SEC31A and a highly syndromic presentation, resulting in early lethality. A neuron-specific sec31a knock-down in Drosophila recapitulated early lethality seen in the patients. Based on available evidence, this gene should be Green on Paediatric disorders - additional genes.
Paediatric disorders - additional genes v8.11 SEC31A Ida Ertmanska Gene: sec31a has been classified as Amber List (Moderate Evidence).
Fetal anomalies v8.2 SEC31A Ida Ertmanska gene: SEC31A was added
gene: SEC31A was added to Fetal anomalies. Sources: Literature
Q3_26_promote_green tags were added to gene: SEC31A.
Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEC31A were set to 30464055; 39725565; 40508110
Phenotypes for gene: SEC31A were set to ?Halperin-Birk syndrome, OMIM:618651; neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849
Review for gene: SEC31A was set to GREEN
Added comment: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp) - variant not in gnomAD v4.1.1. Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant - not in gnomAD v4.1.1.

Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.
Sources: Literature
Paediatric disorders - additional genes v8.10 SEC31A Ida Ertmanska gene: SEC31A was added
gene: SEC31A was added to Paediatric disorders - additional genes. Sources: Literature
Q3_26_promote_green tags were added to gene: SEC31A.
Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEC31A were set to 30464055; 39725565; 40508110
Phenotypes for gene: SEC31A were set to ?Halperin-Birk syndrome, OMIM:618651; neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849
Review for gene: SEC31A was set to GREEN
Added comment: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp) - variant not in gnomAD v4.1.1. Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant - not in gnomAD v4.1.1.

Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.
Sources: Literature
Intellectual disability v11.9 SEC31A Ida Ertmanska edited their review of gene: SEC31A: Changed publications to: 30464055, 39725565, 40508110
Intellectual disability v11.9 SEC31A Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.; to: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp) - variant not in gnomAD v4.1.1. Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant - not in gnomAD v4.1.1.

Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.
Early onset or syndromic epilepsy v9.68 SEC31A Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant.
Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.; to: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp) - variant not in gnomAD v4.1.1. Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant - not in gnomAD v4.1.1.
Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.
Early onset or syndromic epilepsy v9.68 SEC31A Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. Parents confirmed to be consanguineous.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant.
Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.; to: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant.
Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.
Early onset or syndromic epilepsy v9.68 SEC31A Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant.
Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.; to: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. Parents confirmed to be consanguineous.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant.
Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.
Early onset or syndromic epilepsy v9.68 SEC31A Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Focal and generalised tonic-clonic seizures were seen from birth. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant.
Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.; to: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant.
Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.
Early onset or syndromic epilepsy v9.68 SEC31A Ida Ertmanska edited their review of gene: SEC31A: Changed publications to: 30464055, 39725565, 40508110
Early onset or syndromic epilepsy v9.68 SEC31A Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.; to: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.

PMID: 30464055 Halperin et al., 2018
2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Focal and generalised tonic-clonic seizures were seen from birth. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant.
Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.
Early onset or syndromic epilepsy v9.68 SEC31A Ida Ertmanska Phenotypes for gene: SEC31A were changed from Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies 618651 to ?Halperin-Birk syndrome, OMIM:618651; neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849
Early onset or syndromic epilepsy v9.67 SEC31A Ida Ertmanska Publications for gene: SEC31A were set to 30464055; 39725565; 40508110
Early onset or syndromic epilepsy v9.67 SEC31A Ida Ertmanska Publications for gene: SEC31A were set to 30464055
Early onset or syndromic epilepsy v9.66 SEC31A Ida Ertmanska Classified gene: SEC31A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.66 SEC31A Ida Ertmanska Gene: sec31a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.65 SEC31A Ida Ertmanska reviewed gene: SEC31A: Rating: AMBER; Mode of pathogenicity: None; Publications: 39725565, 40508110; Phenotypes: ?Halperin-Birk syndrome, OMIM:618651, neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v11.9 SEC31A Ida Ertmanska Publications for gene: SEC31A were set to 30464055
Intellectual disability v11.8 SEC31A Ida Ertmanska Phenotypes for gene: SEC31A were changed from Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies 618651 to ?Halperin-Birk syndrome, OMIM:618651; neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849
Intellectual disability v11.7 SEC31A Ida Ertmanska edited their review of gene: SEC31A: Changed publications to: 39725565, 40508110
Intellectual disability v11.7 SEC31A Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.; to: PMID: 39725565 Almontashiri et al., 2025
Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is
Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.

PMID: 40508110 AlTassan et al., 2025
Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.
Intellectual disability v11.7 SEC31A Ida Ertmanska reviewed gene: SEC31A: Rating: AMBER; Mode of pathogenicity: None; Publications: 39725565; Phenotypes: ?Halperin-Birk syndrome, OMIM:618651, neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v11.7 PDCD6IP Ida Ertmanska reviewed gene: PDCD6IP: Rating: AMBER; Mode of pathogenicity: None; Publications: 28322231, 32286682, 40897677; Phenotypes: ?Microcephaly 29, primary, autosomal recessive, OMIM:620047, microcephaly 29, primary, autosomal recessive, MONDO:0031060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v9.18 PDCD6IP Ida Ertmanska Publications for gene: PDCD6IP were set to 32286682; 40897677
Severe microcephaly v9.17 PDCD6IP Ida Ertmanska edited their review of gene: PDCD6IP: Changed phenotypes to: ?Microcephaly 29, primary, autosomal recessive, OMIM:620047, microcephaly 29, primary, autosomal recessive, MONDO:0031060
Severe microcephaly v9.17 PDCD6IP Ida Ertmanska edited their review of gene: PDCD6IP: Changed publications to: 28322231, 32286682, 40897677
Severe microcephaly v9.17 PDCD6IP Ida Ertmanska changed review comment from: Comment on list classification: There are now 2 unrelated probands with severe microcephaly (1 progressive post-natally). A supportive animal model recaptiulating microcephaly is also available. Hence, this gene can now be promoted to Green.; to: Comment on list classification: There are now 2 unrelated probands with severe microcephaly (1 progressive post-natally). A supportive mouse model recapitulating microcephaly is also available (PMID: 28322231, old gene name Alix). Hence, this gene can now be promoted to Green.
Severe microcephaly v9.17 PDCD6IP Ida Ertmanska commented on gene: PDCD6IP: Comment on list classification: There are now 2 unrelated probands with severe microcephaly (1 progressive post-natally). A supportive animal model recaptiulating microcephaly is also available. Hence, this gene can now be promoted to Green.
Severe microcephaly v9.17 PDCD6IP Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th Aug 2026.
Severe microcephaly v9.17 PDCD6IP Ida Ertmanska Phenotypes for gene: PDCD6IP were changed from Primary microcephaly to ?Microcephaly 29, primary, autosomal recessive, OMIM:620047; microcephaly 29, primary, autosomal recessive, MONDO:0031060
Severe microcephaly v9.16 PDCD6IP Ida Ertmanska Publications for gene: PDCD6IP were set to 32286682
Severe microcephaly v9.15 PDCD6IP Ida Ertmanska Tag watchlist was removed from gene: PDCD6IP.
Tag Q3_26_promote_green tag was added to gene: PDCD6IP.
Severe microcephaly v9.15 PDCD6IP Ida Ertmanska changed review comment from: PMID: 40897677 D'Alessio et al., 2025
Report of a male individual with mild intellectual disability and microcephaly carrying a homozygous nonsense variant in PDCD6IP: NM_013374.6 c.964C>T p.(Arg322*). Heterozygous family members unaffected. Additional features of strabismus and thrombocytopenia was also noted. Proband OFC listed as 52.7cm (−2.5 SD) in table 1. At birth, his OFC was 34 cm (−0.78 SD), but at age 25 yrs, his OFC was 51.6 cm (−3.1 SD).; to: PMID: 40897677 D'Alessio et al., 2025
Report of a male individual with mild intellectual disability and acquired microcephaly carrying a homozygous nonsense variant in PDCD6IP: NM_013374.6 c.964C>T p.(Arg322*). Heterozygous family members unaffected. Additional features of strabismus and thrombocytopenia was also noted. No seizures present. Proband OFC listed as 52.7cm (−2.5 SD) in table 1. At birth, his OFC was 34 cm (−0.78 SD), but at age 25 yrs, his OFC was 51.6 cm (−3.1 SD).
Severe microcephaly v9.15 PDCD6IP Ida Ertmanska reviewed gene: PDCD6IP: Rating: GREEN; Mode of pathogenicity: None; Publications: 40897677; Phenotypes: ?Microcephaly 29, primary, autosomal recessive, OMIM:620047; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v9.26 PCLO Ida Ertmanska changed review comment from: PMID: 42038819 Baneshi et al., 2025
Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES.
CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed.

PMID: 40661989 Lertsakulbunlue et al., 2025
Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis.

PMID: 30287594 Chitre et al., 2018
Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19).
Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter).
Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs.

PMID: 25832664 Ahmed et al., 2015
Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant.

FUNCTIONAL EVIDENCE:
PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Seizures were also present in the mutated rats.

PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).; to: PMID: 42038819 Baneshi et al., 2025
Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia (usure on age of onset), behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES.
CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed.

PMID: 40661989 Lertsakulbunlue et al., 2025
Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis.

PMID: 30287594 Chitre et al., 2018
Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19).
Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter).
Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs.

PMID: 25832664 Ahmed et al., 2015
Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant.

FUNCTIONAL EVIDENCE:
PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Seizures were also present in the mutated rats.

PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).
Early onset or syndromic epilepsy v9.65 PCLO Ida Ertmanska changed review comment from: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and early-onset epilepsy. There is a supportive rat model showing that pclo knock-out results in reduced brain size, impaired motor coordination, and seizures. Hence, this gene can be promoted to Green at the next update.
Ataxia and cerebellar anomalies - childhood onset v9.26 PCLO Ida Ertmanska changed review comment from: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and cerebellar atrophy / hypoplasia, plus 1 additional case with mild ataxia. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and cerebellar atrophy / hypoplasia, plus 1 additional case with mild ataxia. There is a supportive rat model showing that pclo knock-out results in reduced brain size and impaired motor coordination. Hence, this gene can be promoted to Green at the next update.
Ataxia and cerebellar anomalies - childhood onset v9.26 PCLO Ida Ertmanska Phenotypes for gene: PCLO were changed from Pontocerebellar Hypoplasia type 3; Pontocerebellar hypoplasia 3 homozygous non-sense variant identified in the affected individuals of a single pedigree. to Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy
Ataxia and cerebellar anomalies - childhood onset v9.25 PCLO Ida Ertmanska Publications for gene: PCLO were set to PMID: 25832664
Ataxia and cerebellar anomalies - childhood onset v9.24 PCLO Ida Ertmanska Classified gene: PCLO as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v9.24 PCLO Ida Ertmanska Gene: pclo has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v9.23 PCLO Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: PCLO.
Ataxia and cerebellar anomalies - childhood onset v9.23 PCLO Ida Ertmanska commented on gene: PCLO: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and cerebellar atrophy / hypoplasia, plus 1 additional case with mild ataxia. Hence, this gene can be promoted to Green at the next update.
Ataxia and cerebellar anomalies - childhood onset v9.23 PCLO Ida Ertmanska reviewed gene: PCLO: Rating: GREEN; Mode of pathogenicity: None; Publications: 25832664, 30287594, 32122952, 40661989, 42038819; Phenotypes: Pontocerebellar hypoplasia, type 3, OMIM:608027, PEHO syndrome, MONDO:0009841, progressive encephalopathy with edema, hypsarrhythmia and optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v11.7 PCLO Ida Ertmanska commented on gene: PCLO: Comment on list classification: Though there are now at least 3 unrelated families reported in literature with biallelic PCLO variants and severe psychomotor developmental delay, this is likely secondary to pontocerebellar hypoplasia and early-onset epilepsy. Hence, this gene should remain Red on the Intellectual disability panel.
Intellectual disability v11.7 PCLO Ida Ertmanska reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: None; Publications: 25832664, 30287594, 32122952, 40661989, 42038819; Phenotypes: Pontocerebellar hypoplasia, type 3, OMIM:608027, PEHO syndrome, MONDO:0009841, progressive encephalopathy with edema, hypsarrhythmia and optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.65 PCLO Ida Ertmanska changed review comment from: PMID: 42038819 Baneshi et al., 2025
Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES.
CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed.

PMID: 40661989 Lertsakulbunlue et al., 2025
Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis.

PMID: 30287594 Chitre et al., 2018
Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19).
Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter).
Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs.

PMID: 25832664 Ahmed et al., 2015
Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant.

FUNCTIONAL EVIDENCE:
PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion.

PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).; to: PMID: 42038819 Baneshi et al., 2025
Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES.
CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed.

PMID: 40661989 Lertsakulbunlue et al., 2025
Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis.

PMID: 30287594 Chitre et al., 2018
Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19).
Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter).
Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs.

PMID: 25832664 Ahmed et al., 2015
Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant.

FUNCTIONAL EVIDENCE:
PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Seizures were also present in the mutated rats.

PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).
Early onset or syndromic epilepsy v9.65 PCLO Ida Ertmanska edited their review of gene: PCLO: Changed publications to: 25832664, 30287594, 32122952, 40661989, 42038819
Early onset or syndromic epilepsy v9.65 PCLO Ida Ertmanska changed review comment from: PMID: 42038819 Baneshi et al., 2025
Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES.
CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed.

PMID: 40661989 Lertsakulbunlue et al., 2025
Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis.

PMID: 30287594 Chitre et al., 2018
Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19).
Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter).
Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs.

PMID: 25832664 Ahmed et al., 2015
Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant.

PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).; to: PMID: 42038819 Baneshi et al., 2025
Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES.
CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed.

PMID: 40661989 Lertsakulbunlue et al., 2025
Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis.

PMID: 30287594 Chitre et al., 2018
Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19).
Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter).
Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs.

PMID: 25832664 Ahmed et al., 2015
Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant.

FUNCTIONAL EVIDENCE:
PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion.

PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).
Early onset or syndromic epilepsy v9.65 PCLO Ida Ertmanska Phenotypes for gene: PCLO were changed from to Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy
Early onset or syndromic epilepsy v9.64 PCLO Ida Ertmanska Publications for gene: PCLO were set to
Early onset or syndromic epilepsy v9.63 PCLO Ida Ertmanska Mode of inheritance for gene: PCLO was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.62 PCLO Ida Ertmanska Classified gene: PCLO as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.62 PCLO Ida Ertmanska Added comment: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.62 PCLO Ida Ertmanska Gene: pclo has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.61 PCLO Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: PCLO.
Early onset or syndromic epilepsy v9.61 PCLO Ida Ertmanska reviewed gene: PCLO: Rating: GREEN; Mode of pathogenicity: None; Publications: 25832664, 30287594, 40661989, 42038819; Phenotypes: Pontocerebellar hypoplasia, type 3, OMIM:608027, PEHO syndrome, MONDO:0009841, progressive encephalopathy with edema, hypsarrhythmia and optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arrhythmogenic right ventricular cardiomyopathy v3.18 JUP Matthew Edwards changed review comment from: On CGGL Royal Brompton ACM panel (although only VUS reported so far). Definitive ARVC gene; to: On CGGL Royal Brompton ACM panel (although only VUS reported so far). Definitive ARVC/NAXOS disease gene, although unclear if definitively causes dominant disease
Severe insulin resistance and lipodystrophy syndromes v5.4 PSMB8 Achchuthan Shanmugasundram Phenotypes for gene: PSMB8 were changed from Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040 to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; proteasome-associated autoinflammatory syndrome 1, MONDO:0054698
Severe insulin resistance and lipodystrophy syndromes v5.3 PSMB8 Achchuthan Shanmugasundram edited their review of gene: PSMB8: Changed phenotypes to: Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040, proteasome-associated autoinflammatory syndrome 1, MONDO:0054698
Autoinflammatory disorders v3.20 PSMB8 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available (>10 unrelated families and functional work) for the association of monoallelic PSMB8 variants with proteasome-associated autoinflammatory syndrome and immunodeficiency.

Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Autoinflammatory disorders v3.20 PSMB8 Achchuthan Shanmugasundram Mode of inheritance for gene: PSMB8 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory disorders v3.19 PSMB8 Achchuthan Shanmugasundram Phenotypes for gene: PSMB8 were changed from Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040 to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; proteasome-associated autoinflammatory syndrome 1, MONDO:0054698; Immunodeficiency, HP:0002721
Autoinflammatory disorders v3.18 PSMB8 Achchuthan Shanmugasundram Publications for gene: PSMB8 were set to 21852578; 21953331; 20534754; 20159315; 21881205; 21129723
Autoinflammatory disorders v3.17 PSMB8 Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: PSMB8.
Autoinflammatory disorders v3.17 PSMB8 Achchuthan Shanmugasundram reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: 41253591, 42167218; Phenotypes: Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040, proteasome-associated autoinflammatory syndrome 1, MONDO:0054698, Immunodeficiency, HP:0002721; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 PSMB8 Achchuthan Shanmugasundram changed review comment from: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).

PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE.

Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency.

PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease.

Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID.

Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).; to: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).

PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE.

Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes, directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency.

PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease.

Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID.

Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 PSMB8 Achchuthan Shanmugasundram Publications for gene: PSMB8 were set to 21881205; 20159315; 21953331; 21129723; 20534754; 21852578; 42167218
Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 PSMB8 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence available (>10 unrelated families and functional work) for the association of monoallelic PSMB8 variants with immunodeficiency and inflammation.

Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.; to: Comment on mode of inheritance: There is sufficient evidence available (>10 unrelated families and functional work) for the association of monoallelic PSMB8 variants with proteasome-associated autoinflammatory syndrome and immunodeficiency.

Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 PSMB8 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence available (>3 unrelated families and functional work) for the association of monoallelic PSMB8 variants with immunodeficiency and inflammation.

Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.; to: Comment on mode of inheritance: There is sufficient evidence available (>10 unrelated families and functional work) for the association of monoallelic PSMB8 variants with immunodeficiency and inflammation.

Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 PSMB8 Achchuthan Shanmugasundram changed review comment from: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).

PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency.

PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease.

Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID.

Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).; to: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).

PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE.

Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency.

PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease.

Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID.

Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 PSMB8 Achchuthan Shanmugasundram changed review comment from: PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease.

Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID.

There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with definitive rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).; to: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).

PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency.

PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease.

Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID.

Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 PSMB8 Achchuthan Shanmugasundram edited their review of gene: PSMB8: Changed publications to: 41253591, 42167218
Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 PSMB8 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available (>3 unrelated families and functional work) for the association of monoallelic PSMB8 variants with immunodeficiency and inflammation.

Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 PSMB8 Achchuthan Shanmugasundram Mode of inheritance for gene: PSMB8 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.100 PSMB8 Achchuthan Shanmugasundram Mode of pathogenicity for gene: PSMB8 was changed from None to Other
Primary immunodeficiency or monogenic inflammatory bowel disease v9.99 PSMB8 Achchuthan Shanmugasundram changed review comment from: PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease.

There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with definitive rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).; to: PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease.

Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID.

There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with definitive rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.99 PSMB8 Achchuthan Shanmugasundram edited their review of gene: PSMB8: Changed mode of pathogenicity: Other
Primary immunodeficiency or monogenic inflammatory bowel disease v9.99 PSMB8 Achchuthan Shanmugasundram Publications for gene: PSMB8 were set to 21881205; 20159315; 21953331; 21129723; 20534754; 21852578
Primary immunodeficiency or monogenic inflammatory bowel disease v9.98 PSMB8 Achchuthan Shanmugasundram Phenotypes for gene: PSMB8 were changed from Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; Autoinflammation, lipodystrophy, and dermatosis syndrome; Contractures, panniculitis, ICC, fevers; Autoinflammatory Disorders; CANDLE syndrome to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; proteasome-associated autoinflammatory syndrome 1, MONDO:0054698; Immunodeficiency, HP:0002721
Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 PSMB8 Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: PSMB8.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 PSMB8 Achchuthan Shanmugasundram reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: 42167218; Phenotypes: Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040, proteasome-associated autoinflammatory syndrome 1, MONDO:0054698, Immunodeficiency, HP:0002721; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cardiac arrhythmias - additional genes v3.13 STS William Davies gene: STS was added
gene: STS was added to Cardiac arrhythmias - additional genes. Sources: Research,Literature
Mode of inheritance for gene: STS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: STS were set to PMIDs: 32139392; 36379544; 39158681; 39150468; 40688208; 40062371; 39912958; 28795252 and doi: 10.64898/2026.07.22.739997v1
Phenotypes for gene: STS were set to Atrial fibrillation/flutter; supraventricular tachycardia; bradycardia; ventricular ectopic beats; QT interval alteration
Penetrance for gene: STS were set to Incomplete
Mode of pathogenicity for gene: STS was set to Other
Review for gene: STS was set to RED
Added comment: Four independent and converging lines of evidence currently support inclusion of STS (Xp22.31) as a novel candidate gene for arrhythmias (particularly in males):

1. Deletion Copy Number Variants encompassing STS are associated with increased risk of a variety of heart rhythm abnormalities:

• Middle-aged male deletion carriers are at ~4x risk of being diagnosed with atrial fibrillation compared to age/sex-matched non-carriers, and self-report higher levels of arrhythmia/atrial flutter (PMID: 32139392)
• Paroxysmal supraventricular tachycardia in 2 year old male deletion carrier (PMID: 29569268)
• Diagnoses of brady- and tachycardia and atrial fibrillation self-reported by male and female deletion carriers (PMID: 36379544)
• Exercise-induced atrial fibrillation presenting at 16 and 23 years in 25 year old male deletion carrier with ongoing sinus bradycardia (PMIDs: 39158681 and 39150468)
• 16 year old male deletion carrier presenting with history of sinus bradycardia from 5 years, shortened QT interval and polymorphic ventricular extrasystole (up to 9% of heartbeats); 2.5 year old male deletion carrier with supraventricular pacemaker migration, mild bradycardia with shortened QT interval, and significant arrhythmia with a heart rate ranging from 76–118 bpm (PMID: 40688208)
• Sudden cardiac arrest with ventricular fibrillation in 17 year old male deletion carrier. ECG showed a wandering atrial pacemaker, ST-segment elevation, and T-wave inversion, frequent polymorphic ventricular extrasystoles (VES), ventricular couplet, 1 3-beat 160/min ventricular tachycardia, and 131 ventricular bigeminies (PMID: 40062371)
• Three adult male deletion carriers with a history of (paroxysmal) atrial fibrillation and supraventricular ectopic beats; two presented with ongoing frequent ventricular ectopic beats (PMID: 39912958)

2. Genetic association analysis across Xp22.31 highlights an excess of common risk variants for idiopathic atrial fibrillation within STS in a large middle-aged male sample of 4556 cases and 163,499 controls (PMID: 36379544)

3. Systemic inhibition of the STS enzyme in a cohort of 10 patients with early breast cancer pre-screened to exclude a history of cardiac arrhythmia resulted in three Grade 2 adverse events (two related to abnormal ECG and one to tachycardia) and one Grade 1 adverse event (prolonged QT)(PMID: 28795252).

4. In ex vivo ECG, the hearts of mice with a small Sts-specific genetic deletion and >95% loss of enzyme activity show evidence for an increased frequency of abnormal rhythms (notably ventricular ectopics) and for longer runs of abnormal beats (doi:10.64898/2026.07.22.739997v1)
Sources: Research, Literature
Early onset or syndromic epilepsy v9.61 ELAVL2 Achchuthan Shanmugasundram Classified gene: ELAVL2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.61 ELAVL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (at least four unrelated cases and functional studies) available for the association of monoallelic ELAVL2 variants with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v9.61 ELAVL2 Achchuthan Shanmugasundram Gene: elavl2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.60 ELAVL2 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: ELAVL2.
Fetal anomalies v8.1 MMP9 Ida Ertmanska reviewed gene: MMP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19615667, 28342220, 34407464, 36035187; Phenotypes: Metaphyseal anadysplasia 2, OMIM:613073, metaphyseal anadysplasia 2, MONDO:0013113; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v10.3 MMP9 Ida Ertmanska commented on gene: MMP9: Comment on list classification: There are now 4 unrelated individuals reported with biallelic MMP9 variants and Metaphyseal anadysplasia. Hence, this gene can be promoted to Green at the next update.
Fetal anomalies v8.1 MMP9 Ida Ertmanska Deleted their review
Fetal anomalies v8.1 MMP9 Ida Ertmanska Deleted their comment
Fetal anomalies v8.1 MMP9 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: MMP9.
Fetal anomalies v8.1 MMP9 Ida Ertmanska reviewed gene: MMP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 34407464, 36035187; Phenotypes: Metaphyseal anadysplasia 2, OMIM:613073, metaphyseal anadysplasia 2, MONDO:0013113; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v10.3 MMP9 Ida Ertmanska Phenotypes for gene: MMP9 were changed from Metaphyseal anadysplasia 2 613073 to Metaphyseal anadysplasia 2, OMIM:613073; metaphyseal anadysplasia 2, MONDO:0013113
Skeletal dysplasia v10.2 MMP9 Ida Ertmanska Publications for gene: MMP9 were set to 28342220; 19615667
Skeletal dysplasia v10.1 MMP9 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: MMP9.
Skeletal dysplasia v10.1 MMP9 Ida Ertmanska reviewed gene: MMP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 34407464, 36035187; Phenotypes: Metaphyseal anadysplasia 2, OMIM:613073, metaphyseal anadysplasia 2, MONDO:0013113; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v11.7 LMAN2L Ida Ertmanska Tag watchlist was removed from gene: LMAN2L.
Tag Q3_26_promote_green tag was added to gene: LMAN2L.
Intellectual disability v11.7 LMAN2L Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th Aug 2026.
Intellectual disability v11.7 LMAN2L Ida Ertmanska Phenotypes for gene: LMAN2L were changed from Intellectual disability; epilepsy to ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863; ?Intellectual developmental disorder, autosomal recessive 52, OMIM:61688; intellectual disability, autosomal recessive 52, MONDO:0014815; intellectual developmental disorder, autosomal dominant 69, MONDO:0029465
Early onset or syndromic epilepsy v9.60 LMAN2L Ida Ertmanska edited their review of gene: LMAN2L: Changed phenotypes to: ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863, ?Intellectual developmental disorder, autosomal recessive 52, OMIM:61688, intellectual disability, autosomal recessive 52, MONDO:0014815, intellectual developmental disorder, autosomal dominant 69, MONDO:0029465
Early onset or syndromic epilepsy v9.60 LMAN2L Ida Ertmanska edited their review of gene: LMAN2L: Changed phenotypes to: ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863, ?Intellectual developmental disorder, autosomal recessive 52, OMIM:61688, intellectual disability, autosomal recessive 52, MONDO:0014815
Intellectual disability v11.6 LMAN2L Ida Ertmanska Publications for gene: LMAN2L were set to 31020005; 26566883
Intellectual disability v11.5 LMAN2L Ida Ertmanska Mode of inheritance for gene: LMAN2L was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v11.4 LMAN2L Ida Ertmanska commented on gene: LMAN2L: There are now 3 unrelated probands reported in literature with biallelic LMAN2L variants and severe GDD/ID. There is also one pedigree reported with a heterozygous LMAN2L variant segregating with ID. Hence, this gene can be promoted to Green at the next update, with MOI set to 'BIALLELIC, autosomal or pseudoautosomal', until more evidence emerges for the dominant association.
Early onset or syndromic epilepsy v9.60 LMAN2L Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated probands reported in literature with biallelic LMAN2L variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated probands reported in literature with biallelic LMAN2L variants and early-onset epilepsy. There is also one pedigree reported with a heterozygous LMAN2L variant segregating with tonic clonic seizures. Hence, this gene can be promoted to Green at the next update, with MOI set to 'BIALLELIC, autosomal or pseudoautosomal', until more evidence emerges for the dominant association.
Early onset or syndromic epilepsy v9.60 ELAVL2 Achchuthan Shanmugasundram gene: ELAVL2 was added
gene: ELAVL2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: ELAVL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELAVL2 were set to 42556336
Phenotypes for gene: ELAVL2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: ELAVL2 was set to GREEN
Added comment: PMID:42556336 (2026) reported 13 previously unpublished individuals, plus three previously reported cases, with de novo heterozygous ELAVL2 variants presenting with a neurodevelopmental disorder in which epilepsy was a recurrent, though not universal, feature—seizures were reported in 4 of 13 newly described individuals (1/7 with truncating/structural variants and 3/6 with missense variants), comprising absence, febrile, tonic-clonic, and spasms (West syndrome in one individual with a missense variant). All affected individuals additionally presented with developmental delay, intellectual disability of varying severity, motor and speech delay, autism spectrum diagnoses, sleep disturbance, sensory processing abnormalities (hyper- or hyposensitivity to sound, texture, and light), and behavioural/emotional dysregulation.

Drosophila loss-of-function models of the ELAVL2 ortholog fne (null mutant and pan-neuronal RNAi knockdown) showed significantly increased seizure-like behaviour (both duration and frequency) following mechanical induction, establishing a causal functional link between ELAVL2 loss-of-function and seizure susceptibility.

This gene has not yet been associated with relevant phenotypes either in OMIM, ClinGen or Gene2Phenotype (last accessed 13 August 2026).
Sources: Literature
Intellectual disability v11.4 LMAN2L Ida Ertmanska reviewed gene: LMAN2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 37667433, 40221759; Phenotypes: ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863, ?Intellectual developmental disorder, autosomal recessive 52, OMIM:616887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.59 LMAN2L Ida Ertmanska commented on gene: LMAN2L: Comment on list classification: There are now 3 unrelated probands reported in literature with biallelic LMAN2L variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.59 LMAN2L Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th Aug 2026.
Early onset or syndromic epilepsy v9.59 LMAN2L Ida Ertmanska Phenotypes for gene: LMAN2L were changed from Intellectual disability; Epilepsy to ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863; ?Intellectual developmental disorder, autosomal recessive 52, OMIM:616887; intellectual developmental disorder, autosomal dominant 69, MONDO:0029465; intellectual disability, autosomal recessive 52, MONDO:0014815
Early onset or syndromic epilepsy v9.58 LMAN2L Ida Ertmanska Publications for gene: LMAN2L were set to 31020005; 26566883
Early onset or syndromic epilepsy v9.57 LMAN2L Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: LMAN2L.
Early onset or syndromic epilepsy v9.57 LMAN2L Ida Ertmanska reviewed gene: LMAN2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 37667433, 40221759; Phenotypes: ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863, ?Intellectual developmental disorder, autosomal recessive 52, OMIM:616887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v11.4 ELAVL2 Achchuthan Shanmugasundram Classified gene: ELAVL2 as Amber List (moderate evidence)
Intellectual disability v11.4 ELAVL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with a neurodevelopmental disorder with intellectual disability as the primary feature of the disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v11.4 ELAVL2 Achchuthan Shanmugasundram Gene: elavl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v11.3 ELAVL2 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: ELAVL2.
Monogenic hearing loss v6.41 DIAPH3 Ida Ertmanska Mode of pathogenicity for gene: DIAPH3 was changed from Other - please provide details in the comments to None
Monogenic hearing loss v6.40 DIAPH3 Ida Ertmanska changed review comment from: Comment on list classification: There are now more than 3 unrelated families reported where monoallelic DIAPH3 variants have been reported to co-segregate with dominant hearing loss. There is only one pedigree reported where some affected individuals were homozygous. Hence, this gene can be promoted to Green on Monogenic hearing loss, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.; to: Comment on list classification: There are now more than 3 unrelated families reported where monoallelic DIAPH3 variants have been reported to co-segregate with dominant hearing loss. There is only one pedigree reported where some affected individuals were heterozygous and some homozygous (no difference in phenotype). Hence, this gene can be promoted to Green on Monogenic hearing loss, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, until more evidence emerges for biallelic cases.
Monogenic hearing loss v6.40 DIAPH3 Ida Ertmanska commented on gene: DIAPH3: Comment on list classification: There are now more than 3 unrelated families reported where monoallelic DIAPH3 variants have been reported to co-segregate with dominant hearing loss. There is only one pedigree reported where some affected individuals were homozygous. Hence, this gene can be promoted to Green on Monogenic hearing loss, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Monogenic hearing loss v6.40 DIAPH3 Ida Ertmanska Phenotypes for gene: DIAPH3 were changed from Auditory neuropathy, autosomal dominant, 1, 609129 to Auditory neuropathy, autosomal dominant 1, OMIM:609129; autosomal dominant auditory neuropathy 1, MONDO:0012196
Monogenic hearing loss v6.39 DIAPH3 Ida Ertmanska Publications for gene: DIAPH3 were set to 14767582; 15520414; 18755006; 19457867; 20624953; 20624953; 27658576
Monogenic hearing loss v6.38 DIAPH3 Ida Ertmanska Mode of inheritance for gene: DIAPH3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v6.37 DIAPH3 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: DIAPH3.
Monogenic hearing loss v6.37 DIAPH3 Ida Ertmanska reviewed gene: DIAPH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38860500, 39767564, 40040362, 41511813; Phenotypes: Auditory neuropathy, autosomal dominant 1, OMIM:609129, autosomal dominant auditory neuropathy 1, MONDO:0012196; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.57 DHX16 Ida Ertmanska commented on gene: DHX16: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). 3 unrelated individuals presented with infantile spasms / epilepsy. Hence, this gene should be promoted to Green on Early onset or syndromic epilepsy at the next update.
Early onset or syndromic epilepsy v9.57 DHX16 Ida Ertmanska Tag watchlist was removed from gene: DHX16.
Tag Q3_26_promote_green tag was added to gene: DHX16.
Early onset or syndromic epilepsy v9.57 DHX16 Ida Ertmanska edited their review of gene: DHX16: Changed rating: GREEN
Early onset or syndromic epilepsy v9.57 DHX16 Ida Ertmanska reviewed gene: DHX16: Rating: RED; Mode of pathogenicity: None; Publications: 31256877, 36212160, 36211162, 37574199, 37664979, 40141454, 41555919; Phenotypes: 31256877, 36212160, 36211162, 37574199, 37664979, 40141454, 41555919; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v6.37 DHX16 Ida Ertmanska Classified gene: DHX16 as Amber List (moderate evidence)
Monogenic hearing loss v6.37 DHX16 Ida Ertmanska Added comment: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). Moreover, severe hearing loss was the main / presenting finding in some patients. Hence, this gene should be promoted to Green for Monogenic hearing loss at the next update.
Monogenic hearing loss v6.37 DHX16 Ida Ertmanska Gene: dhx16 has been classified as Amber List (Moderate Evidence).
Retinal disorders v9.17 DHX16 Ida Ertmanska Classified gene: DHX16 as Amber List (moderate evidence)
Retinal disorders v9.17 DHX16 Ida Ertmanska Added comment: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). Moreover, retinitis pigmentosa was the main / presenting finding in some patients. Hence, this gene should be promoted to Green for Retinal disorders at the next update.
Retinal disorders v9.17 DHX16 Ida Ertmanska Gene: dhx16 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.36 DHX16 Ida Ertmanska gene: DHX16 was added
gene: DHX16 was added to Monogenic hearing loss. Sources: Literature
Q3_26_promote_green tags were added to gene: DHX16.
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX16 were set to 31256877; 36212160; 36211162; 37574199; 37664979; 40141454; 41555919
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890
Review for gene: DHX16 was set to GREEN
Added comment: PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40326698 Clay et al., 2025
3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy.

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).

PMID: 36212160 Park et al., 2022
Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported.

PMID: 31256877 Paine et al., 2019
Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome.
P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC.
P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His.
P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL.
P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; Tapetoretinal degeneration and total vision loss; SNHL; contractures.
Sources: Literature
Retinal disorders v9.16 DHX16 Ida Ertmanska gene: DHX16 was added
gene: DHX16 was added to Retinal disorders. Sources: Literature
Q3_26_promote_green tags were added to gene: DHX16.
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX16 were set to 31256877; 36212160; 36211162; 37574199; 37664979; 40141454; 41555919
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890
Review for gene: DHX16 was set to GREEN
Added comment: PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40326698 Clay et al., 2025
3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy.

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).

PMID: 36212160 Park et al., 2022
Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported.

PMID: 31256877 Paine et al., 2019
Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome.
P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC.
P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His.
P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL.
P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; Tapetoretinal degeneration and total vision loss; SNHL; contractures.
Sources: Literature
Congenital myopathy v7.80 DHX16 Ida Ertmanska Phenotypes for gene: DHX16 were changed from Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733 to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890
Congenital myopathy v7.79 DHX16 Ida Ertmanska Publications for gene: DHX16 were set to 31256877
Congenital myopathy v7.78 DHX16 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: DHX16.
Congenital myopathy v7.78 DHX16 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinal disease (9/12). Hence, this gene should be promoted to Green for Congenital myopathy at the next update.; to: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). 5 probands presented with congenital myopathy / severe congenital hypotonia. Hence, this gene should be promoted to Green for Congenital myopathy at the next update.
Congenital myopathy v7.78 DHX16 Ida Ertmanska changed review comment from: PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40326698 Clay et al., 2025
3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy.

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).

PMID: 36212160 Park et al., 2022
Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported.

PMID: 31256877 Paine et al., 2019
Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome.
P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC.
P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His.
P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL.
P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; total vision loss; SNHL; contractures.; to: PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40326698 Clay et al., 2025
3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy.

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).

PMID: 36212160 Park et al., 2022
Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported.

PMID: 31256877 Paine et al., 2019
Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome.
P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC.
P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His.
P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL.
P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; Tapetoretinal degeneration and total vision loss; SNHL; contractures.
Congenital myopathy v7.78 DHX16 Ida Ertmanska commented on gene: DHX16: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinal disease (9/12). Hence, this gene should be promoted to Green for Congenital myopathy at the next update.
Congenital myopathy v7.78 DHX16 Ida Ertmanska edited their review of gene: DHX16: Changed phenotypes to: Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733, neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890
Congenital myopathy v7.78 DHX16 Ida Ertmanska edited their review of gene: DHX16: Changed publications to: 31256877, 36212160, 36211162, 37574199, 37664979, 40141454, 41555919
Congenital myopathy v7.78 DHX16 Ida Ertmanska changed review comment from: PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy.

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).; to: PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40326698 Clay et al., 2025
3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy.

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).

PMID: 36212160 Park et al., 2022
Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported.

PMID: 31256877 Paine et al., 2019
Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome.
P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC.
P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His.
P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL.
P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; total vision loss; SNHL; contractures.
Intellectual disability v11.3 ELAVL2 Achchuthan Shanmugasundram gene: ELAVL2 was added
gene: ELAVL2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ELAVL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELAVL2 were set to 42556336
Phenotypes for gene: ELAVL2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: ELAVL2 was set to GREEN
Added comment: PMID:42556336 (2026) reported 13 previously unpublished individuals, plus three previously reported cases, presenting with developmental delay, intellectual disability of varying severity, autism spectrum disorder, seizures (absence, febrile, tonic-clonic), sleep disturbances (insomnia, sleep apnea), sensory processing abnormalities (hyper- and hyposensitivity to sound, texture, light), and behavioral/emotional dysregulation with attention deficits. Among the 13 newly described individuals, ID severity was mild in 4, moderate in 1, severe in 2, borderline in 2, and unspecified learning difficulties in 2; one individual had no ID, and one was not formally assessed.

These individuals were identified with de novo heterozygous variants in ELAVL2, including two structural variants (a pericentric inversion and a reciprocal translocation disrupting the gene), five truncating variants (c.142C>T/p.Gln48*, c.166_167del/p.Lys56Glufs8, c.189dup/p.Glu64, c.380dupT/p.Leu127Phefs48, c.657C>G/p.Tyr219), and six missense variants (c.154C>A/p.Gln52Lys, c.159G>C/p.Glu53Asp, c.475G>A/p.Asp159Asn, c.527G>A/p.Arg176Gln, c.695A>C/p.Gln232Pro, c.913G>A/p.Val305Met).

ID was present in 3/7 individuals with truncating/structural variants versus 6/6 individuals with missense variants, with the most severely affected individual (severe ID, walking at 6 years, first words at 6 years) also carrying a pathogenic NF1 variant that may have contributed to disease severity. Motor delay was seen in 6/7 individuals with truncating/structural variants and 5/6 with missense variants, while speech delay occurred in 5/7 and 6/6, respectively; one adult female with a structural variant additionally presented with premature ovarian insufficiency.

This gene has not yet been associated with relevant phenotypes either in OMIM, ClinGen or Gene2Phenotype (last accessed 13 August 2026).
Sources: Literature
Congenital myopathy v7.78 DHX16 Ida Ertmanska edited their review of gene: DHX16: Changed publications to: 36211162, 37574199, 37664979, 40141454, 41555919
Congenital myopathy v7.78 DHX16 Ida Ertmanska changed review comment from: PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss, retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).; to: PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy.

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).
Congenital myopathy v7.78 DHX16 Ida Ertmanska reviewed gene: DHX16: Rating: GREEN; Mode of pathogenicity: None; Publications: 36211162, 37574199, 37664979, 41555919; Phenotypes: Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v11.2 COPB1 Ida Ertmanska Publications for gene: COPB1 were set to 33632302
Intellectual disability v11.1 COPB1 Ida Ertmanska Tag watchlist was removed from gene: COPB1.
Tag Q3_26_promote_green tag was added to gene: COPB1.
Severe microcephaly v9.15 COPB1 Ida Ertmanska Publications for gene: COPB1 were set to 33632302
Intellectual disability v11.1 COPB1 Ida Ertmanska reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v9.14 COPB1 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Luke Stuart, there are now 8 individuals from 3 unrelated families reported in literature with biallelic COPB1 variants and Baralle-Macken syndrome. 3 unrelated probands reported had severe microcephaly (over 3SD below average, or below the 1st percentile). There is also a Xenopus model, supportive of the gene-disease association. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: As reviewed by Luke Stuart, there are now 8 individuals from 3 unrelated families reported in literature with biallelic COPB1 variants and Baralle-Macken syndrome. 3 unrelated probands reported had severe microcephaly (over 3SD below average, or OFC below the 1st percentile). There is also a Xenopus model, supportive of the gene-disease association. Hence, this gene should be promoted to Green at the next update.
Severe microcephaly v9.14 COPB1 Ida Ertmanska reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v9.14 COPB1 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: COPB1.
Bilateral congenital or childhood onset cataracts v8.7 COPB1 Ida Ertmanska edited their review of gene: COPB1: Changed rating: GREEN
Bilateral congenital or childhood onset cataracts v8.7 COPB1 Ida Ertmanska commented on gene: COPB1
Bilateral congenital or childhood onset cataracts v8.7 COPB1 Ida Ertmanska Publications for gene: COPB1 were set to 33632302
Bilateral congenital or childhood onset cataracts v8.6 COPB1 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: COPB1.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 NFATC1 Achchuthan Shanmugasundram Classified gene: NFATC1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 NFATC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case and functional evidence available in support of the association of NFATC1 with immunodeficiency. Hence, this gene should be rated amber with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 NFATC1 Achchuthan Shanmugasundram Gene: nfatc1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.96 NFATC1 Achchuthan Shanmugasundram Phenotypes for gene: NFATC1 were changed from recurrent infections; hypogammaglobulinemia; decreased antibody responses to inborn error of immunity, MONDO:0003778
Primary immunodeficiency or monogenic inflammatory bowel disease v9.95 NFATC1 Achchuthan Shanmugasundram reviewed gene: NFATC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37249233; Phenotypes: inborn error of immunity, MONDO:0003778; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.95 NFATC2 Achchuthan Shanmugasundram Classified gene: NFATC2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.95 NFATC2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two unrelated cases published with biallelic NFATC2 variants and with a relevant phenotype. They displayed phenotypic variability with both displaying lymphoproliferative disorder, but only one with skeletal phenotype. Hence, this gene should be rated amber with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.95 NFATC2 Achchuthan Shanmugasundram Gene: nfatc2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.94 NFATC2 Achchuthan Shanmugasundram Publications for gene: NFATC2 were set to 35789258
Primary immunodeficiency or monogenic inflammatory bowel disease v9.93 NFATC2 Achchuthan Shanmugasundram Phenotypes for gene: NFATC2 were changed from progressive joint contractures; osteochondromas; B cell malignancy; diarrhea; chronic lung disease; hypogammaglobulinemia to ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369; lymphoproliferative syndrome, MONDO:0016537
Primary immunodeficiency or monogenic inflammatory bowel disease v9.92 NFATC2 Achchuthan Shanmugasundram reviewed gene: NFATC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35789258, 38427060; Phenotypes: ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232, joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369, lymphoproliferative syndrome, MONDO:0016537; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v9.11 ATP1A3 Achchuthan Shanmugasundram Classified gene: ATP1A3 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v9.11 ATP1A3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are nine unrelated cases reported with the same recurrent heterozygous variant and functional evidence available in support of the association of this gene with a novel disorder with spasticity and ID/ DD. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary spastic paraplegia, childhood onset v9.11 ATP1A3 Achchuthan Shanmugasundram Gene: atp1a3 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v9.10 ATP1A3 Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: ATP1A3.
Tag Q3_26_promote_green tag was added to gene: ATP1A3.
Hereditary spastic paraplegia, childhood onset v9.10 ATP1A3 Achchuthan Shanmugasundram Phenotypes for gene: ATP1A3 were changed from spasticity; developmental delay; intellectual disability to Alternating hemiplegia of childhood 2, OMIM:614820; alternating hemiplegia of childhood 2, MONDO:0013900; Developmental and epileptic encephalopathy 99, OMIM:619606; developmental and epileptic encephalopathy 99, MONDO:0030473; Spasticity, HP:0001257; intellectual disability, MONDO:0001071
Hereditary spastic paraplegia, childhood onset v9.9 ATP1A3 Achchuthan Shanmugasundram Publications for gene: ATP1A3 were set to PMID: 37043503
Hereditary spastic paraplegia, childhood onset v9.8 ATP1A3 Achchuthan Shanmugasundram reviewed gene: ATP1A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37043503; Phenotypes: Alternating hemiplegia of childhood 2, OMIM:614820, alternating hemiplegia of childhood 2, MONDO:0013900, Developmental and epileptic encephalopathy 99, OMIM:619606, developmental and epileptic encephalopathy 99, MONDO:0030473, Spasticity, HP:0001257, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v13.35 Achchuthan Shanmugasundram Panel version 13.34 has been signed off on 2026-08-12
Cystic renal disease v13.6 Achchuthan Shanmugasundram Panel version 13.5 has been signed off on 2026-08-12
Cerebral malformation v16.12 Ida Ertmanska Panel version 16.11 has been signed off on 2026-08-12
Adult-onset neurological disorders v9.20 Ida Ertmanska Panel version 9.19 has been signed off on 2026-08-12
Other rare neuromuscular disorders v31.136 Achchuthan Shanmugasundram Panel version 31.135 has been signed off on 2026-08-12
Rare multisystem ciliopathy Super panel v22.3 Ida Ertmanska Panel version 22.2 has been signed off on 2026-08-12
Hypotonic infant v47.2 Arina Puzriakova Panel version 47.1 has been signed off on 2026-08-12
Paediatric disorders v76.2 Ida Ertmanska Panel version 76.1 has been signed off on 2026-08-12
Unexplained death in infancy and sudden unexplained death in childhood v23.106 Arina Puzriakova Panel version 23.105 has been signed off on 2026-08-12
Hereditary ataxia and cerebellar anomalies, childhood onset v23.33 Achchuthan Shanmugasundram Panel version 23.32 has been signed off on 2026-08-12
Sudden unexplained death or survivors of a cardiac event v23.19 Arina Puzriakova Panel version 23.18 has been signed off on 2026-08-12
Leukodystrophy, childhood onset v32.3 Achchuthan Shanmugasundram Panel version 32.2 has been signed off on 2026-08-12
Cardiac arrhythmias v14.32 Arina Puzriakova Panel version 14.31 has been signed off on 2026-08-12
Intellectual disability v11.1 Arina Puzriakova Panel version 11.0 has been signed off on 2026-08-12
Intellectual disability v11.0 Arina Puzriakova promoted panel to version 11.0
Childhood interstitial lung disease v1.10 Arina Puzriakova Panel version 1.9 has been signed off on 2026-08-12
Sarcoma of possible germline origin v1.3 Arina Puzriakova Panel version 1.2 has been signed off on 2026-08-12
Embryonal tumour of possible germline origin v1.3 Arina Puzriakova Panel version 1.2 has been signed off on 2026-08-12
NICE approved PARP inhibitor treatment v1.4 Arina Puzriakova Panel version 1.3 has been signed off on 2026-08-12
Unexplained young onset end-stage renal disease - additional genes v2.2 Arina Puzriakova Panel version 2.1 has been signed off on 2026-08-12
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Diagnostic v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Glutaric acidaemia type 1 - Diagnostic v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Isovaleric acidaemia - Diagnostic v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Monogenic short stature v2.9 Arina Puzriakova Panel version 2.8 has been signed off on 2026-08-12
Wiskott-Aldrich syndrome v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Wilson disease v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
von Willebrand disease v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Von Hippel Lindau syndrome v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Variegate porphyria v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Tuberous sclerosis v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Thiamine metabolism dysfunction syndrome 2 v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Thanatophoric dysplasia v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Sickle cell, thalassaemia and other haemoglobinopathies v2.12 Arina Puzriakova Panel version 2.11 has been signed off on 2026-08-12
Tay-Sachs disease v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Syndromic and non syndromic craniosynostosis involving midline sutures v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Spinal muscular atrophy - Diagnostic v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Smith-Lemli-Opitz syndrome v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Sitosterolaemia v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Short stature - SHOX deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Severe combined immunodeficiency with PNP deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Severe combined immunodeficiency with adenosine deaminase deficiency v1.7 Arina Puzriakova Panel version 1.6 has been signed off on 2026-08-12
Segmental or atypical neurofibromatosis type 1 testing v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
SCID with features of gamma chain deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Sandhoff disease v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Retinoblastoma v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Pulmonary alveolar microlithiasis v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
PTEN Hamartoma Tumor Syndrome v1.8 Arina Puzriakova Panel version 1.7 has been signed off on 2026-08-12
Pseudoxanthoma elasticum v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Primary hyperaldosteronism v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
POLG-related disorder v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Phenylketonuria v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Peutz Jeghers Syndrome v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Nijmegen breakage syndrome v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Niemann-Pick disease type A or B v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Niemann Pick disease type C v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Neutropaenia consistent with ELANE variants v1.7 Arina Puzriakova Panel version 1.6 has been signed off on 2026-08-12
Neuronal ceroid lipofuscinosis type 2 v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Neurofibromatosis type 1 (GMS) v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Neonatal diabetes - small panel v1.8 Arina Puzriakova Panel version 1.7 has been signed off on 2026-08-12
NARP syndrome or maternally inherited Leigh syndrome v2.4 Arina Puzriakova Panel version 2.3 has been signed off on 2026-08-12
Multiple exostoses v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Multiple endocrine neoplasia type 2 v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Mucopolysaccharidosis type VI v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Mucopolysaccharidosis type IVA v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Mucopolysaccharidosis type IIIB v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Mucopolysaccharidosis type IIIA v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Mucopolysaccharidosis type II v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Mucopolysaccharidosis type IH or S v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Mucolipidosis II and III Alpha or Beta v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Monitoring for G(M)CSF escape variants v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Mitochondrial neurogastrointestinal encephalopathy v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Mitochondrial Complex V deficiency, TMEM70 type v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Lysosomal acid lipase deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Lymphoproliferative syndrome with absent SAP expression v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Krabbe disease - Saposin A deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Krabbe disease - GALC deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Inherited parathyroid cancer v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Incontinentia pigmenti v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Hereditary angioedema types I and II v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Haemophagocytic syndrome with absent XIAP expression v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Haemophagocytic syndrome with absent perforin expression v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Glycogen storage disease V v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Glucokinase-related fasting hyperglycaemia v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Generalised arterial calcification in infancy v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Gaucher disease v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Fumarate hydratase-related tumour syndromes v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Familial tumours of the nervous system v3.3 Arina Puzriakova Panel version 3.2 has been signed off on 2026-08-12
Familial dysalbuminaemic hyperthyroxinaemia v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Factor XIII deficiency v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Factor XI deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Factor X deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Factor VIII deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Factor VII deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Factor V deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Factor IX deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Factor II deficiency v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Facioscapulohumeral muscular dystrophy - extended testing v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Fabry disease v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Elastin-related phenotypes v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Duchenne or Becker muscular dystrophy v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
DICER1-related cancer predisposition v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Cystinosis v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Cystic fibrosis - Diagnostic v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Congenital adrenal hyperplasia v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Combined vitamin K-dependent clotting factor deficiency v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Central congenital hypoventilation v1.9 Arina Puzriakova Panel version 1.8 has been signed off on 2026-08-12
Carney complex v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Calcium-sensing receptor phenotypes v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
CADASIL v1.9 Arina Puzriakova Panel version 1.8 has been signed off on 2026-08-12
Blepharophimosis ptosis and epicanthus inversus v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Beckwith-Wiedemann syndrome v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Barth syndrome v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Hereditary isolated diabetes insipidus v2.4 Arina Puzriakova Panel version 2.3 has been signed off on 2026-08-12
Inherited prostate cancer v1.8 Arina Puzriakova Panel version 1.7 has been signed off on 2026-08-12
Li Fraumeni Syndrome v1.8 Arina Puzriakova Panel version 1.7 has been signed off on 2026-08-12
Hereditary diffuse gastric cancer v2.7 Arina Puzriakova Panel version 2.6 has been signed off on 2026-08-12
Paediatric pseudo-obstruction syndrome v2.8 Arina Puzriakova Panel version 2.7 has been signed off on 2026-08-12
BAP1 associated tumour predisposition syndrome v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Autoimmune Polyendocrine Syndrome v1.6 Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12
Autoimmune lymphoproliferative syndrome with defective apoptosis v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Ataxia telangiectasia - mutation testing v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
APC associated Polyposis v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.10 Arina Puzriakova Panel version 1.9 has been signed off on 2026-08-12
Alstrom syndrome v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2026-08-12
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v2.0 Arina Puzriakova promoted panel to version 2.0
Agammaglobulinaemia with absent BTK expression v1.5 Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12
Acute intermittent porphyria v2.3 Arina Puzriakova Panel version 2.2 has been signed off on 2026-08-12
Pulmonary Fibrosis, Familial v1.18 Arina Puzriakova Panel version 1.17 has been signed off on 2026-08-12
Acute rhabdomyolysis v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2026-08-12
Acute rhabdomyolysis v3.0 Arina Puzriakova promoted panel to version 3.0
Multi Locus Imprinting Disorder (MLID) v2.5 Arina Puzriakova Panel version 2.4 has been signed off on 2026-08-12
Malignant hyperthermia v1.7 Arina Puzriakova Panel version 1.6 has been signed off on 2026-08-12
Autoinflammatory disorders v3.17 Arina Puzriakova Panel version 3.16 has been signed off on 2026-08-12
Thrombocythaemia v2.3 Arina Puzriakova Panel version 2.2 has been signed off on 2026-08-12
Osteopetrosis v2.3 Arina Puzriakova Panel version 2.2 has been signed off on 2026-08-12
Dystonia, chorea or related movement disorder, childhood onset v8.14 Arina Puzriakova Panel version 8.13 has been signed off on 2026-08-12
Hereditary neuropathy or pain disorder v8.31 Arina Puzriakova Panel version 8.30 has been signed off on 2026-08-12
Cardiac arrhythmias - additional genes v3.13 Arina Puzriakova Panel version 3.12 has been signed off on 2026-08-12
Familial hypercholesterolaemia (GMS) v2.7 Arina Puzriakova Panel version 2.6 has been signed off on 2026-08-12
Paediatric or syndromic cardiomyopathy v8.5 Arina Puzriakova Panel version 8.4 has been signed off on 2026-08-12
Neurological segmental overgrowth v3.6 Arina Puzriakova Panel version 3.5 has been signed off on 2026-08-12
Skeletal ciliopathies v7.2 Arina Puzriakova Panel version 7.1 has been signed off on 2026-08-12
Renal ciliopathies v5.2 Arina Puzriakova Panel version 5.1 has been signed off on 2026-08-12
Neurological ciliopathies v7.2 Arina Puzriakova Panel version 7.1 has been signed off on 2026-08-12
Ophthalmological ciliopathies v6.2 Arina Puzriakova Panel version 6.1 has been signed off on 2026-08-12
Thoracic aortic aneurysm or dissection (GMS) v5.8 Arina Puzriakova Panel version 5.7 has been signed off on 2026-08-12
Corneal dystrophy v4.12 Arina Puzriakova Panel version 4.11 has been signed off on 2026-08-12
Polycystic liver disease v1.34 Arina Puzriakova Panel version 1.33 has been signed off on 2026-08-12
Dilated and arrhythmogenic cardiomyopathy v4.4 Arina Puzriakova Panel version 4.3 has been signed off on 2026-08-12
Hypogonadotropic hypogonadism (GMS) v5.4 Arina Puzriakova Panel version 5.3 has been signed off on 2026-08-12
Inherited phaeochromocytoma and paraganglioma excluding NF1 v5.1 Arina Puzriakova Panel version 5.0 has been signed off on 2026-08-12
Inherited phaeochromocytoma and paraganglioma excluding NF1 v5.0 Arina Puzriakova promoted panel to version 5.0
Endocrine neoplasia v3.9 Arina Puzriakova Panel version 3.8 has been signed off on 2026-08-12
Inherited breast cancer and ovarian cancer v3.3 Arina Puzriakova Panel version 3.2 has been signed off on 2026-08-12
Leukodystrophy, adult onset v7.9 Arina Puzriakova Panel version 7.8 has been signed off on 2026-08-12
Hereditary spastic paraplegia, childhood onset v9.8 Arina Puzriakova Panel version 9.7 has been signed off on 2026-08-12
Hereditary spastic paraplegia, adult onset v6.14 Arina Puzriakova Panel version 6.13 has been signed off on 2026-08-12
Primary pigmented nodular adrenocortical disease v1.13 Arina Puzriakova Panel version 1.12 has been signed off on 2026-08-12
Rare genetic inflammatory skin disorders v4.26 Arina Puzriakova Panel version 4.25 has been signed off on 2026-08-12
Mosaic skin disorders - Deep sequencing v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2026-08-12
Mosaic skin disorders - Deep sequencing v4.0 Arina Puzriakova promoted panel to version 4.0
Vascular skin disorders v2.8 Arina Puzriakova Panel version 2.7 has been signed off on 2026-08-12
Epidermodysplasia verruciformis v1.9 Arina Puzriakova Panel version 1.8 has been signed off on 2026-08-12
Cutaneous photosensitivity with a likely genetic cause v3.18 Arina Puzriakova Panel version 3.17 has been signed off on 2026-08-12
Pigmentary skin disorders v5.13 Arina Puzriakova Panel version 5.12 has been signed off on 2026-08-12
Multiple monogenic benign skin tumours v2.8 Arina Puzriakova Panel version 2.7 has been signed off on 2026-08-12
Autosomal recessive primary hypertrophic osteoarthropathy v2.3 Arina Puzriakova Panel version 2.2 has been signed off on 2026-08-12
Palmoplantar keratodermas v4.17 Arina Puzriakova Panel version 4.16 has been signed off on 2026-08-12
Ichthyosis and erythrokeratoderma v4.17 Arina Puzriakova Panel version 4.16 has been signed off on 2026-08-12
Epidermolysis bullosa and congenital skin fragility v2.17 Arina Puzriakova Panel version 2.16 has been signed off on 2026-08-12
Ectodermal dysplasia v5.5 Arina Puzriakova Panel version 5.4 has been signed off on 2026-08-12
Familial tumoral calcinosis v1.13 Arina Puzriakova Panel version 1.12 has been signed off on 2026-08-12
Respiratory ciliopathies including non-CF bronchiectasis v5.4 Arina Puzriakova Panel version 5.3 has been signed off on 2026-08-12
Laterality disorders and isomerism v5.3 Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12
Tubulointerstitial kidney disease v3.35 Arina Puzriakova Panel version 3.34 has been signed off on 2026-08-12
Severe insulin resistance and lipodystrophy syndromes v5.3 Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12
Bleeding and platelet disorders v4.17 Arina Puzriakova Panel version 4.16 has been signed off on 2026-08-12
Cholestasis v4.18 Arina Puzriakova Panel version 4.17 has been signed off on 2026-08-12
Bardet Biedl syndrome v2.19 Arina Puzriakova Panel version 2.18 has been signed off on 2026-08-12
Skeletal muscle channelopathy v3.10 Arina Puzriakova Panel version 3.9 has been signed off on 2026-08-12
Paroxysmal central nervous system disorders v4.7 Arina Puzriakova Panel version 4.6 has been signed off on 2026-08-12
Dystonia, chorea or related movement disorder, adult onset v6.8 Arina Puzriakova Panel version 6.7 has been signed off on 2026-08-12
Possible mitochondrial disorder, nuclear genes v5.18 Arina Puzriakova Panel version 5.17 has been signed off on 2026-08-12
Mitochondrial disorder with complex V deficiency v3.7 Arina Puzriakova Panel version 3.6 has been signed off on 2026-08-12
Mitochondrial disorder with complex IV deficiency v5.5 Arina Puzriakova Panel version 5.4 has been signed off on 2026-08-12
Mitochondrial disorder with complex III deficiency v2.9 Arina Puzriakova Panel version 2.8 has been signed off on 2026-08-12
Mitochondrial disorder with complex II deficiency v2.13 Arina Puzriakova Panel version 2.12 has been signed off on 2026-08-12
Mitochondrial disorder with complex I deficiency v4.3 Arina Puzriakova Panel version 4.2 has been signed off on 2026-08-12
Mitochondrial DNA maintenance disorder v3.11 Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12
Mitochondrial liver disease v1.17 Arina Puzriakova Panel version 1.16 has been signed off on 2026-08-12
Pyruvate dehydrogenase (PDH) deficiency v1.42 Arina Puzriakova Panel version 1.41 has been signed off on 2026-08-12
Lysosomal storage disorder v3.11 Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12
Glycogen storage disease v2.9 Arina Puzriakova Panel version 2.8 has been signed off on 2026-08-12
Familial Chylomicronaemia Syndrome v3.7 Arina Puzriakova Panel version 3.6 has been signed off on 2026-08-12
Neuronal ceroid lipofuscinosis v3.5 Arina Puzriakova Panel version 3.4 has been signed off on 2026-08-12
Inherited predisposition to acute myeloid leukaemia (AML) v3.11 Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12
Inherited pancreatic cancer v3.5 Arina Puzriakova Panel version 3.4 has been signed off on 2026-08-12
Inherited predisposition to GIST v1.18 Arina Puzriakova Panel version 1.17 has been signed off on 2026-08-12
Familial melanoma v2.16 Arina Puzriakova Panel version 2.15 has been signed off on 2026-08-12
Inherited renal cancer v1.31 Arina Puzriakova Panel version 1.30 has been signed off on 2026-08-12
Cytopenia - NOT Fanconi anaemia v5.8 Arina Puzriakova Panel version 5.7 has been signed off on 2026-08-12
Rare anaemia v4.8 Arina Puzriakova Panel version 4.7 has been signed off on 2026-08-12
Combined factor V and VIII deficiency v1.13 Arina Puzriakova Panel version 1.12 has been signed off on 2026-08-12
Thrombophilia with a likely monogenic cause v3.3 Arina Puzriakova Panel version 3.2 has been signed off on 2026-08-12
Iron metabolism disorders - NOT common HFE mutations v4.4 Arina Puzriakova Panel version 4.3 has been signed off on 2026-08-12
Intestinal failure or congenital diarrhoea v3.18 Arina Puzriakova Panel version 3.17 has been signed off on 2026-08-12
Non-acute porphyrias v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2026-08-12
Non-acute porphyrias v2.0 Arina Puzriakova promoted panel to version 2.0
Congenital fibrosis of the extraocular muscles v2.8 Arina Puzriakova Panel version 2.7 has been signed off on 2026-08-12
Albinism or congenital nystagmus v4.13 Arina Puzriakova Panel version 4.12 has been signed off on 2026-08-12
Sporadic aniridia v3.8 Arina Puzriakova Panel version 3.7 has been signed off on 2026-08-12
Structural eye disease v5.8 Arina Puzriakova Panel version 5.7 has been signed off on 2026-08-12
Fanconi anaemia or Bloom syndrome v2.18 Arina Puzriakova Panel version 2.17 has been signed off on 2026-08-12
Common craniosynostosis syndromes v1.19 Arina Puzriakova Panel version 1.18 has been signed off on 2026-08-12
Progressive cardiac conduction disease v2.18 Arina Puzriakova Panel version 2.17 has been signed off on 2026-08-12
Inherited polyposis and early onset colorectal cancer - germline testing v4.3 Arina Puzriakova Panel version 4.2 has been signed off on 2026-08-12
Inherited MMR deficiency (Lynch syndrome) v1.16 Arina Puzriakova Panel version 1.15 has been signed off on 2026-08-12
Hereditary systemic amyloidosis v1.31 Arina Puzriakova Panel version 1.30 has been signed off on 2026-08-12
DDG2P v8.1 Arina Puzriakova Panel version 8.0 has been signed off on 2026-08-12
DDG2P v8.0 Arina Puzriakova promoted panel to version 8.0
Pituitary hormone deficiency v4.11 Arina Puzriakova Panel version 4.10 has been signed off on 2026-08-12
Hypophosphataemia or rickets v4.5 Arina Puzriakova Panel version 4.4 has been signed off on 2026-08-12
Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v3.11 Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12
Paediatric disorders - additional genes v8.9 Arina Puzriakova Panel version 8.8 has been signed off on 2026-08-12
Fetal anomalies v8.1 Arina Puzriakova Panel version 8.0 has been signed off on 2026-08-12
Fetal anomalies v8.0 Arina Puzriakova promoted panel to version 8.0
Ataxia and cerebellar anomalies - childhood onset v9.23 Arina Puzriakova Panel version 9.22 has been signed off on 2026-08-12
White matter disorders and cerebral calcification - childhood onset v8.7 Arina Puzriakova Panel version 8.6 has been signed off on 2026-08-12
Neurodegenerative disorders, adult onset v9.5 Arina Puzriakova Panel version 9.4 has been signed off on 2026-08-12
Monogenic diabetes v3.27 Arina Puzriakova Panel version 3.26 has been signed off on 2026-08-12
Likely inborn error of metabolism v9.30 Arina Puzriakova Panel version 9.29 has been signed off on 2026-08-12
Hereditary ataxia, adult onset v9.5 Arina Puzriakova Panel version 9.4 has been signed off on 2026-08-12
Early onset or syndromic epilepsy v9.57 Arina Puzriakova Panel version 9.56 has been signed off on 2026-08-12
Primary immunodeficiency or monogenic inflammatory bowel disease v9.92 Arina Puzriakova Panel version 9.91 has been signed off on 2026-08-12
Pancreatitis v3.7 Arina Puzriakova Panel version 3.6 has been signed off on 2026-08-12
Limb disorders v9.1 Arina Puzriakova Panel version 9.0 has been signed off on 2026-08-12
Limb disorders v9.0 Arina Puzriakova promoted panel to version 9.0
Familial hypoparathyroidism v3.7 Arina Puzriakova Panel version 3.6 has been signed off on 2026-08-12
Skeletal dysplasia v10.1 Arina Puzriakova Panel version 10.0 has been signed off on 2026-08-12
Skeletal dysplasia v10.0 Arina Puzriakova promoted panel to version 10.0
Congenital hyperinsulinism v3.10 Arina Puzriakova Panel version 3.9 has been signed off on 2026-08-12
Retinal disorders v9.15 Arina Puzriakova Panel version 9.14 has been signed off on 2026-08-12
Neonatal diabetes v6.3 Arina Puzriakova Panel version 6.2 has been signed off on 2026-08-12
Renal tubulopathies v6.10 Arina Puzriakova Panel version 6.9 has been signed off on 2026-08-12
Cystic kidney disease v9.2 Arina Puzriakova Panel version 9.1 has been signed off on 2026-08-12
Amelogenesis imperfecta v4.38 Arina Puzriakova Panel version 4.37 has been signed off on 2026-08-12
Arthrogryposis v10.17 Arina Puzriakova Panel version 10.16 has been signed off on 2026-08-12
Hyperthyroidism v3.8 Arina Puzriakova Panel version 3.7 has been signed off on 2026-08-12
Distal myopathies v7.6 Arina Puzriakova Panel version 7.5 has been signed off on 2026-08-12
Congenital myaesthenic syndrome v6.3 Arina Puzriakova Panel version 6.2 has been signed off on 2026-08-12
Bilateral congenital or childhood onset cataracts v8.6 Arina Puzriakova Panel version 8.5 has been signed off on 2026-08-12
Congenital myopathy v7.78 Arina Puzriakova Panel version 7.77 has been signed off on 2026-08-12
Short QT syndrome v3.24 Arina Puzriakova Panel version 3.23 has been signed off on 2026-08-12
Catecholaminergic polymorphic VT v5.6 Arina Puzriakova Panel version 5.5 has been signed off on 2026-08-12
Congenital muscular dystrophy v7.27 Arina Puzriakova Panel version 7.26 has been signed off on 2026-08-12
Osteogenesis imperfecta v6.8 Arina Puzriakova Panel version 6.7 has been signed off on 2026-08-12
Pulmonary arterial hypertension v4.15 Arina Puzriakova Panel version 4.14 has been signed off on 2026-08-12
Optic neuropathy v6.47 Arina Puzriakova Panel version 6.46 has been signed off on 2026-08-12
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 Arina Puzriakova Panel version 6.17 has been signed off on 2026-08-12
Hydrocephalus v5.15 Arina Puzriakova Panel version 5.14 has been signed off on 2026-08-12
Rare syndromic craniosynostosis or isolated multisuture synostosis v7.1 Arina Puzriakova Panel version 7.0 has been signed off on 2026-08-12
Rare syndromic craniosynostosis or isolated multisuture synostosis v7.0 Arina Puzriakova promoted panel to version 7.0
Severe microcephaly v9.14 Arina Puzriakova Panel version 9.13 has been signed off on 2026-08-12
Hereditary Erythrocytosis v3.3 Arina Puzriakova Panel version 3.2 has been signed off on 2026-08-12
Nephrocalcinosis or nephrolithiasis v6.3 Arina Puzriakova Panel version 6.2 has been signed off on 2026-08-12
Cerebral vascular malformations v5.3 Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12
Congenital adrenal hypoplasia v5.6 Arina Puzriakova Panel version 5.5 has been signed off on 2026-08-12
Inherited ovarian cancer (without breast cancer) v5.3 Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12
Atypical haemolytic uraemic syndrome v3.11 Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12
Arrhythmogenic right ventricular cardiomyopathy v3.18 Arina Puzriakova Panel version 3.17 has been signed off on 2026-08-12
Severe early-onset obesity v7.1 Arina Puzriakova Panel version 7.0 has been signed off on 2026-08-12
Severe early-onset obesity v7.0 Arina Puzriakova promoted panel to version 7.0
Monogenic hearing loss v6.35 Arina Puzriakova Panel version 6.34 has been signed off on 2026-08-12
Hereditary haemorrhagic telangiectasia v3.9 Arina Puzriakova Panel version 3.8 has been signed off on 2026-08-12
Mitochondrial disorders v10.19 Arina Puzriakova Panel version 10.18 has been signed off on 2026-08-12
Proteinuric renal disease v6.14 Arina Puzriakova Panel version 6.13 has been signed off on 2026-08-12
Pneumothorax - familial v3.8 Arina Puzriakova Panel version 3.7 has been signed off on 2026-08-12
Haematuria v2.20 Arina Puzriakova Panel version 2.19 has been signed off on 2026-08-12
Segmental overgrowth disorders - Deep sequencing v5.3 Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12
Malformations of cortical development v8.7 Arina Puzriakova Panel version 8.6 has been signed off on 2026-08-12
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.15 Arina Puzriakova Panel version 3.14 has been signed off on 2026-08-12
Clefting v7.9 Arina Puzriakova Panel version 7.8 has been signed off on 2026-08-12
Paediatric motor neuronopathies v3.17 Arina Puzriakova Panel version 3.16 has been signed off on 2026-08-12
Holoprosencephaly v6.4 Arina Puzriakova Panel version 6.3 has been signed off on 2026-08-12
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.9 Arina Puzriakova Panel version 3.8 has been signed off on 2026-08-12
Long QT syndrome v3.15 Arina Puzriakova Panel version 3.14 has been signed off on 2026-08-12
Rhabdomyolysis and metabolic muscle disorders v6.9 Arina Puzriakova Panel version 6.8 has been signed off on 2026-08-12
Primary lymphoedema v5.3 Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12
Ehlers Danlos syndrome with a likely monogenic cause v4.17 Arina Puzriakova Panel version 4.16 has been signed off on 2026-08-12
Hypertrophic cardiomyopathy v6.4 Arina Puzriakova Panel version 6.3 has been signed off on 2026-08-12
Congenital hypothyroidism v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2026-08-12
Congenital hypothyroidism v4.0 Arina Puzriakova promoted panel to version 4.0
Congenital disorders of glycosylation v8.8 Arina Puzriakova Panel version 8.7 has been signed off on 2026-08-12
Brugada syndrome and cardiac sodium channel disease v3.18 Arina Puzriakova Panel version 3.17 has been signed off on 2026-08-12
Differences in sex development v4.23 Arina Puzriakova Panel version 4.22 has been signed off on 2026-08-12
Stickler syndrome v4.12 Arina Puzriakova Panel version 4.11 has been signed off on 2026-08-12
Intellectual disability v10.98 Arina Puzriakova List of related panels changed from Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; Intellectual disability - microarray and sequencing; R29 to Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; Intellectual disability - microarray and sequencing
Mosaic skin disorders - Deep sequencing v3.35 Arina Puzriakova Panel name changed from Mosaic skin disorders - deep sequencing to Mosaic skin disorders - Deep sequencing
Monitoring for G(M)CSF escape variants v1.5 Arina Puzriakova Panel name changed from Monitoring for G(M)CSF escape mutations to Monitoring for G(M)CSF escape variants
List of related panels changed from R338; GT188; TP539 to Monitoring for G(M)CSF escape mutations; R338; GT188; TP539
Mitochondrial liver disease v1.16 Arina Puzriakova Panel name changed from Mitochondrial liver disease, including transient infantile liver failure to Mitochondrial liver disease
List of related panels changed from Mitochondrial liver disease; R317; GT766; TP167 to Mitochondrial liver disease; including transient infantile liver failure; R317; GT766; TP167
Cystic fibrosis - Diagnostic v1.5 Achchuthan Shanmugasundram Panel name changed from Cystic fibrosis diagnostic test to Cystic fibrosis - Diagnostic
List of related panels changed from R184; GT219; TP46 to Cystic fibrosis diagnostic test; R184; GT219; TP46
Congenital adrenal hyperplasia v1.5 Achchuthan Shanmugasundram Panel name changed from Congenital adrenal hyperplasia diagnostic test to Congenital adrenal hyperplasia
List of related panels changed from R180; GT724; TP41 to Congenital adrenal hyperplasia diagnostic test; R180; GT724; TP41
Fanconi anaemia or Bloom syndrome v2.17 Achchuthan Shanmugasundram Panel name changed from Confirmed Fanconi anaemia or Bloom syndrome to Fanconi anaemia or Bloom syndrome
List of related panels changed from R229; R258; Confirmed Fanconi anaemia or Bloom syndrome - mutation testing; Cytopenia - Fanconi breakage testing indicated; GT566; TP191 to Confirmed Fanconi anaemia or Bloom syndrome - mutation testing; Cytopenia - Fanconi breakage testing indicated; Confirmed Fanconi anaemia or Bloom syndrome; R229; R258; GT566; TP191
Leukodystrophy, childhood onset v31.151 Achchuthan Shanmugasundram Panel name changed from Childhood onset leukodystrophy to Leukodystrophy, childhood onset
List of related panels changed from White matter disorders - childhood onset; R109; GT207; TP419 to White matter disorders - childhood onset; Childhood onset leukodystrophy; R109; GT207; TP419
Hereditary ataxia, adult onset v9.4 Arina Puzriakova Panel name changed from Hereditary ataxia with onset in adulthood to Hereditary ataxia, adult onset
List of related panels changed from Hereditary ataxia - adult onset to Hereditary ataxia with onset in adulthood; Hereditary ataxia - adult onset
Hereditary spastic paraplegia, childhood onset v9.7 Achchuthan Shanmugasundram Panel name changed from Childhood onset hereditary spastic paraplegia to Hereditary spastic paraplegia, childhood onset
List of related panels changed from Hereditary spastic paraplegia - childhood onset; R61; GT34; TP579 to Hereditary spastic paraplegia - childhood onset; Childhood onset hereditary spastic paraplegia; R61; GT34; TP579
Hereditary ataxia and cerebellar anomalies, childhood onset v23.31 Arina Puzriakova Panel name changed from Hereditary ataxia and cerebellar anomalies - childhood onset to Hereditary ataxia and cerebellar anomalies, childhood onset
List of related panels changed from Hereditary ataxia with onset in childhood; Cerebellar anomalies; R55; R84; GT936; TP356; TP411 to Hereditary ataxia and cerebellar anomalies - childhood onset; Hereditary ataxia with onset in childhood; Cerebellar anomalies; R55; R84; GT936; TP356; TP411
Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v3.10 Arina Puzriakova Panel name changed from Familial hyperparathyroidism or hypocalciuric hypercalcaemia to Familial hyperparathyroidism or Hypocalciuric hypercalcaemia
White matter disorders and cerebral calcification - childhood onset v8.6 Ida Ertmanska Panel name changed from White matter disorders and cerebral calcification - narrow panel to White matter disorders and cerebral calcification - childhood onset
List of related panels changed from to White matter disorders and cerebral calcification - narrow panel
Dystonia, chorea or related movement disorder, childhood onset v8.13 Achchuthan Shanmugasundram Panel name changed from Childhood onset dystonia, chorea or related movement disorder to Dystonia, chorea or related movement disorder, childhood onset
List of related panels changed from Childhood onset dystonia or chorea or related movement disorder; R57; GT25; TP173 to Childhood onset dystonia or chorea or related movement disorder; Childhood onset dystonia; chorea or related movement disorder; R57; GT25; TP173
Familial Chylomicronaemia Syndrome v3.6 Arina Puzriakova Panel name changed from Familial chylomicronaemia syndrome (FCS) to Familial Chylomicronaemia Syndrome
List of related panels changed from Lipoprotein lipase deficiency; R324; GT850; TP33 to Familial chylomicronaemia syndrome (FCS); Lipoprotein lipase deficiency; R324; GT850; TP33
Spinal muscular atrophy - Diagnostic v1.5 Ida Ertmanska Panel name changed from Spinal muscular atrophy type 1 rare mutation testing to Spinal muscular atrophy - Diagnostic
List of related panels changed from R71; GT571; TP137 to Spinal muscular atrophy type 1 rare mutation testing; R71; GT571; TP137
Ataxia and cerebellar anomalies - childhood onset v9.22 Achchuthan Shanmugasundram Panel name changed from Ataxia and cerebellar anomalies - narrow panel to Ataxia and cerebellar anomalies - childhood onset
List of related panels changed from to Ataxia and cerebellar anomalies - narrow panel
Leukodystrophy, adult onset v7.8 Achchuthan Shanmugasundram Panel name changed from Adult onset leukodystrophy to Leukodystrophy, adult onset
List of related panels changed from White matter disorders - adult onset; R62; GT117; TP85 to White matter disorders - adult onset; Adult onset leukodystrophy; R62; GT117; TP85
Neurodegenerative disorders, adult onset v9.4 Achchuthan Shanmugasundram Panel name changed from Adult onset neurodegenerative disorder to Neurodegenerative disorders, adult onset
List of related panels changed from Neurodegenerative disorders - adult onset; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy; R58 to Neurodegenerative disorders - adult onset; Adult onset neurodegenerative disorder; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy
Early onset or syndromic epilepsy v9.56 Arina Puzriakova List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy; Genetic epilepsy syndromes; R59 to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy; Genetic epilepsy syndromes
Sickle cell, thalassaemia and other haemoglobinopathies v2.11 Ida Ertmanska List of related panels changed from R93; Thalassaemia and other haemoglobinopathies; GT713; TP199; TP473 to Sickle cell; thalassaemia and other haemoglobinopathies; R93; Sickle cell; thalassaemia and other haemoglobinopathies trait or carrier testing; R361; GT713; TP199; TP473
Pulmonary Fibrosis, Familial v1.17 Ida Ertmanska Panel name changed from Pulmonary fibrosis familial to Pulmonary Fibrosis, Familial
List of related panels changed from R421; GT1047; TP235 to Pulmonary fibrosis familial; R421; GT1047; TP235
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Diagnostic v1.4 Arina Puzriakova Panel name changed from Diagnostic testing for MCADD - Medium-chain acyl-CoA dehydrogenase deficiency - full ACADM sequencing to Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Diagnostic
List of related panels changed from R451; GT1105; TP378 to Diagnostic testing for MCADD - Medium-chain acyl-CoA dehydrogenase deficiency - full ACADM sequencing; R451; GT1105; TP378
PTEN Hamartoma Tumor Syndrome v1.7 Ida Ertmanska Panel name changed from PTEN Hamartoma Tumour Syndrome to PTEN Hamartoma Tumor Syndrome
List of related panels changed from PTEN Hamartoma Tumor Syndrome; R213; GT1202; TP66 to PTEN Hamartoma Tumour Syndrome; R213; GT1202; TP66
Primary hyperaldosteronism v1.5 Ida Ertmanska Panel name changed from Primary hyperaldosteronism - KCNJ5 to Primary hyperaldosteronism
List of related panels changed from R344; GT176; TP410 to Primary hyperaldosteronism - KCNJ5; R344; GT176; TP410
Isovaleric acidaemia - Diagnostic v1.4 Arina Puzriakova Panel name changed from Diagnostic testing for Isovaleric acidaemia to Isovaleric acidaemia - Diagnostic
List of related panels changed from R450; GT1229; TP67 to Diagnostic testing for Isovaleric acidaemia; R450; GT1229; TP67
Multi Locus Imprinting Disorder (MLID) v2.4 Ida Ertmanska List of related panels changed from R417.2; GT377; TP270; Multi locus imprinting disorders to Multi locus imprinting disorders; R417.2; GT377; TP270
Neutropaenia consistent with ELANE variants v1.6 Ida Ertmanska List of related panels changed from R313; GT502; TP76; Neutropaenia consistent with ELANE mutations to Neutropaenia consistent with ELANE mutations; R313; GT502; TP76
Glutaric acidaemia type 1 - Diagnostic v1.5 Arina Puzriakova Panel name changed from Diagnostic testing for Glutaric acidaemia I to Glutaric acidaemia type 1 - Diagnostic
List of related panels changed from R449; GT374; TP407 to Diagnostic testing for Glutaric acidaemia I; R449; GT374; TP407
Possible mitochondrial disorder, nuclear genes v5.17 Ida Ertmanska Panel name changed from Possible mitochondrial disorder - nuclear genes to Possible mitochondrial disorder, nuclear genes
Hereditary spastic paraplegia, adult onset v6.13 Achchuthan Shanmugasundram Panel name changed from Adult onset hereditary spastic paraplegia to Hereditary spastic paraplegia, adult onset
List of related panels changed from Hereditary spastic paraplegia - adult onset to Hereditary spastic paraplegia - adult onset; Adult onset hereditary spastic paraplegia
Possible mitochondrial disorder, nuclear genes v5.16 Ida Ertmanska List of related panels changed from R63; GT759; TP627 to Possible mitochondrial disorder - nuclear genes; R63; GT759; TP627
Neutropaenia consistent with ELANE variants v1.5 Ida Ertmanska Panel name changed from Neutropaenia consistent with ELANE mutations to Neutropaenia consistent with ELANE variants
List of related panels changed from R313; GT502; TP76 to R313; GT502; TP76; Neutropaenia consistent with ELANE mutations
Dystonia, chorea or related movement disorder, adult onset v6.7 Achchuthan Shanmugasundram Panel name changed from Adult onset dystonia, chorea or related movement disorder to Dystonia, chorea or related movement disorder, adult onset
List of related panels changed from Adult onset movement disorder to Adult onset movement disorder; Adult onset dystonia; chorea or related movement disorder
Multi Locus Imprinting Disorder (MLID) v2.3 Ida Ertmanska Panel name changed from Multi locus imprinting disorders to Multi Locus Imprinting Disorder (MLID)
List of related panels changed from R417.2; GT377; TP270 to R417.2; GT377; TP270; Multi locus imprinting disorders
Mitochondrial disorders v10.18 UQCC1 Hannah Robinson reviewed gene: UQCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39504961; Phenotypes: lactic acidosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v5.15 UQCC1 Hannah Robinson reviewed gene: UQCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39504961; Phenotypes: lactic acidosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex III deficiency v2.8 UQCC1 Hannah Robinson reviewed gene: UQCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39504961; Phenotypes: lactic acidosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v9.6 ATP1A3 Katherine Schon gene: ATP1A3 was added
gene: ATP1A3 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: ATP1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP1A3 were set to PMID: 37043503
Phenotypes for gene: ATP1A3 were set to spasticity; developmental delay; intellectual disability
Penetrance for gene: ATP1A3 were set to Complete
Review for gene: ATP1A3 was set to GREEN
Added comment: Recurrent de novo pathogenic variant reported in nine individuals with childhood onset of phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy.
Sources: Literature
Paediatric pseudo-obstruction syndrome v2.7 MT-TL1 Katherine Schon gene: MT-TL1 was added
gene: MT-TL1 was added to Paediatric pseudo-obstruction syndrome. Sources: Literature
Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL
Publications for gene: MT-TL1 were set to PMID: 27453452; 42024134; 28458318
Phenotypes for gene: MT-TL1 were set to Intestinal pseudo-obstruction HP:0004389
Penetrance for gene: MT-TL1 were set to Incomplete
Mode of pathogenicity for gene: MT-TL1 was set to Other
Review for gene: MT-TL1 was set to GREEN
Added comment: Intestinal pseudo-obstruction is observed as one of the phenotypes of the multi-system mitochondrial disease associated with the m.3243A>G pathogenic variant.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.91 PTPN6 Achchuthan Shanmugasundram Classified gene: PTPN6 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.91 PTPN6 Achchuthan Shanmugasundram Gene: ptpn6 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.90 PTPN6 Achchuthan Shanmugasundram Publications for gene: PTPN6 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 PTPN6 Achchuthan Shanmugasundram edited their review of gene: PTPN6: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 PTPN6 Achchuthan Shanmugasundram edited their review of gene: PTPN6: Changed publications to: 21406173
Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 PTPN6 Achchuthan Shanmugasundram reviewed gene: PTPN6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 GPR15 Achchuthan Shanmugasundram Classified gene: GPR15 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 GPR15 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with GPR15 variants and with early-onset inflammatory bowel disease. Patients were reported with both biallelic and monoallelic inheritance in at least two families each - biallelic in families 1-3 and monoallelic carriers in families 2 and 4. However, the phenotype is milder in monoallelic carriers. There is also functional evidence available from both homozygous and heterozygous varaiants and from GPR15 knockout model.

Hence, this gene should be promoted to green rating with 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' MOI in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 GPR15 Achchuthan Shanmugasundram Gene: gpr15 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.88 GPR15 Achchuthan Shanmugasundram Phenotypes for gene: GPR15 were changed from Inflammatory bowel disease; IBD; VEOIBD to inflammatory bowel disease, MONDO:0005265
Primary immunodeficiency or monogenic inflammatory bowel disease v9.87 GPR15 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: GPR15.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.87 GPR15 Achchuthan Shanmugasundram reviewed gene: GPR15: Rating: GREEN; Mode of pathogenicity: None; Publications: 42259915; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v10.97 ZBTB7B Achchuthan Shanmugasundram changed review comment from: Comment on list classification: The global developmental delay is reported only as a clinical feature of the broader syndrome, without formal cognitive/IQ assessment in the single reported case. No functional or mechanistic evidence specifically supports a causal role for ZBTB7B in intellectual disability. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: Global developmental delay is reported only as a clinical feature of the broader syndrome, without formal cognitive/IQ assessment in the single reported case. No functional or mechanistic evidence specifically supports a causal role for ZBTB7B in intellectual disability. Hence, this gene should be rated red with the current evidence.
Intellectual disability v10.97 ZBTB7B Achchuthan Shanmugasundram Classified gene: ZBTB7B as Red List (low evidence)
Intellectual disability v10.97 ZBTB7B Achchuthan Shanmugasundram Added comment: Comment on list classification: The global developmental delay is reported only as a clinical feature of the broader syndrome, without formal cognitive/IQ assessment in the single reported case. No functional or mechanistic evidence specifically supports a causal role for ZBTB7B in intellectual disability. Hence, this gene should be rated amber with the current evidence.
Intellectual disability v10.97 ZBTB7B Achchuthan Shanmugasundram Gene: zbtb7b has been classified as Red List (Low Evidence).
Childhood interstitial lung disease v1.9 ZBTB7B Achchuthan Shanmugasundram Phenotypes for gene: ZBTB7B were changed from inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925 to inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925; Global developmental delay, HP:0001263
Childhood interstitial lung disease v1.8 ZBTB7B Achchuthan Shanmugasundram edited their review of gene: ZBTB7B: Changed phenotypes to: inborn error of immunity, MONDO:0003778, interstitial lung disease, MONDO:0015925, Global developmental delay, HP:0001263
Primary immunodeficiency or monogenic inflammatory bowel disease v9.87 ZBTB7B Achchuthan Shanmugasundram Phenotypes for gene: ZBTB7B were changed from inborn error of immunity, MONDO:0003778 to inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925; Global developmental delay, HP:0001263
Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 ZBTB7B Achchuthan Shanmugasundram edited their review of gene: ZBTB7B: Changed phenotypes to: inborn error of immunity, MONDO:0003778, interstitial lung disease, MONDO:0015925, Global developmental delay, HP:0001263
Childhood interstitial lung disease v1.8 ZBTB7B Achchuthan Shanmugasundram changed review comment from: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay.

Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype.
Sources: Literature; to: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay.

Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 07 August 2026).
Sources: Literature
Intellectual disability v10.96 ZBTB7B Achchuthan Shanmugasundram gene: ZBTB7B was added
gene: ZBTB7B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZBTB7B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB7B were set to 40392549
Phenotypes for gene: ZBTB7B were set to inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925; Global developmental delay, HP:0001263
Review for gene: ZBTB7B was set to RED
Added comment: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with global developmental delay and growth failure, alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, fibroinflammatory interstitial lung disease, corneal defects, and sensorineural hearing loss.

Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets; however, all functional validation (lentiviral gene-transfer in healthy-donor T cells and pulmonary fibroblasts, luciferase, EMSA, HT-SELEX, ChIP-seq) was directed at immune and fibrotic mechanisms, with no neuronal/CNS cell model or evidence directly linking K360N to a neurodevelopmental mechanism.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 07 August 2026).
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v9.21 GPN2 Ida Ertmanska Classified gene: GPN2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v9.21 GPN2 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there are now 2 pedigrees reported where individuals harbouring biallelic GPN2 variants presented with ataxia (2 sibs, age of onset not specified), and cerebellar atrophy (both families). Based on available evidence, this gene can only be rated Amber.
Ataxia and cerebellar anomalies - childhood onset v9.21 GPN2 Ida Ertmanska Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.95 COPB1 Luke Stuart reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33632302, 40396222; Phenotypes: Baralle-Macken syndrome (OMIM #619255), accessed 08/2026; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v6.34 GPN2 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: GPN2.
Monogenic hearing loss v6.34 GPN2 Ida Ertmanska Classified gene: GPN2 as Amber List (moderate evidence)
Monogenic hearing loss v6.34 GPN2 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there are now 3 families (2 with shared ancestry) where individuals harbouring biallelic GPN2 variants presented with hearing loss. In addition, there is some supportive functional evidence. Hence, this gene can be promoted to Green on Monogenic hearing loss.
Monogenic hearing loss v6.34 GPN2 Ida Ertmanska Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v9.13 COPB1 Luke Stuart reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33632302, 40396222; Phenotypes: Baralle-Macken syndrome (OMIM #619255), accessed 08/2026; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.95 GPN2 Ida Ertmanska Classified gene: GPN2 as Red List (low evidence)
Intellectual disability v10.95 GPN2 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there is only 1 individual reported with biallelic GPN2 variants and mild intellectual disability. Hence, this gene can only be rated Red with the current level of evidence.
Intellectual disability v10.95 GPN2 Ida Ertmanska Gene: gpn2 has been classified as Red List (Low Evidence).
Bilateral congenital or childhood onset cataracts v8.5 COPB1 Luke Stuart reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33632302, 40396222; Phenotypes: Baralle-Macken syndrome (OMIM #619255, accessed 08/2026); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v1.8 ZBTB7B Achchuthan Shanmugasundram Classified gene: ZBTB7B as Amber List (moderate evidence)
Childhood interstitial lung disease v1.8 ZBTB7B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one case with a syndromic phenotype including fibroinflammatory interstitial lung disease and functional evidence reported in support of the association of ZBTB7B gene with this panel. Hence, this gene can be rated amber with the current evidence.
Childhood interstitial lung disease v1.8 ZBTB7B Achchuthan Shanmugasundram Gene: zbtb7b has been classified as Amber List (Moderate Evidence).
Childhood interstitial lung disease v1.7 ZBTB7B Achchuthan Shanmugasundram changed review comment from: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay.

Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype. This is currently a single reported case, and ILD occurs as one component of a broader multisystem syndrome rather than an isolated pulmonary phenotype, which should be considered when applying this gene to an ILD-specific panel.
Sources: Literature; to: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay.

Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype.
Sources: Literature
Childhood interstitial lung disease v1.7 ZBTB7B Achchuthan Shanmugasundram edited their review of gene: ZBTB7B: Changed rating: AMBER
Childhood interstitial lung disease v1.7 ZBTB7B Achchuthan Shanmugasundram gene: ZBTB7B was added
gene: ZBTB7B was added to Childhood interstitial lung disease. Sources: Literature
Mode of inheritance for gene: ZBTB7B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB7B were set to 40392549
Phenotypes for gene: ZBTB7B were set to inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925
Review for gene: ZBTB7B was set to RED
Added comment: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay.

Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype. This is currently a single reported case, and ILD occurs as one component of a broader multisystem syndrome rather than an isolated pulmonary phenotype, which should be considered when applying this gene to an ILD-specific panel.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 KARS Ida Ertmanska commented on gene: KARS
Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 KARS Ida Ertmanska Tag new-gene-name tag was added to gene: KARS.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 ZBTB7B Achchuthan Shanmugasundram Classified gene: ZBTB7B as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 ZBTB7B Achchuthan Shanmugasundram Added comment: Comment on list classification: A single patient case and functional evidence available in support of the association of ZBTB7B gene with inborn error of immunity. Hence, this gene should be rated amber with the current evidence on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 ZBTB7B Achchuthan Shanmugasundram Gene: zbtb7b has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.85 ZBTB7B Achchuthan Shanmugasundram Phenotypes for gene: ZBTB7B were changed from CD4+ T-cell deficiency; Allergic disease; Interstitial lung disease; Corneal neovascularization; Corneal scarring; Global developmental delay; Growth failure to inborn error of immunity, MONDO:0003778
Primary immunodeficiency or monogenic inflammatory bowel disease v9.84 ZBTB7B Achchuthan Shanmugasundram Mode of inheritance for gene: ZBTB7B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 ZBTB7B Achchuthan Shanmugasundram edited their review of gene: ZBTB7B: Changed phenotypes to: inborn error of immunity, MONDO:0003778
Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 ZBTB7B Achchuthan Shanmugasundram reviewed gene: ZBTB7B: Rating: AMBER; Mode of pathogenicity: None; Publications: 40392549; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 SIT1 Achchuthan Shanmugasundram Classified gene: SIT1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 SIT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case and functional evidence reported in support of the association of SIT1 gene with combined immunodeficiency. Hence, this gene should be rated amber with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 SIT1 Achchuthan Shanmugasundram Gene: sit1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.82 SIT1 Achchuthan Shanmugasundram Phenotypes for gene: SIT1 were changed from Combined immunodeficiency; Hodgkin lymphoma; Abnormal T cell physiology; Impaired CD8+ T cell cytotoxicity to combined immunodeficiency, MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 SIT1 Achchuthan Shanmugasundram reviewed gene: SIT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 42128181; Phenotypes: combined immunodeficiency, MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 SH2B3 Achchuthan Shanmugasundram Classified gene: SH2B3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 SH2B3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are over 10 unrelated patients with biallelic SH2B3 germline variants and with myeloproliferation and autoimmunity. Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 SH2B3 Achchuthan Shanmugasundram Gene: sh2b3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.80 SH2B3 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SH2B3.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.80 SH2B3 Achchuthan Shanmugasundram changed review comment from: PMID:23908464 (2013) reported two siblings from a consanguineous family of Eastern European Ashkenazi Jewish descent presenting with growth retardation, mild developmental delay, chronic hepatitis, and Hashimoto autoimmune thyroiditis. One of them (sister) developed B-precursor acute lymphoblastic leukemia (ALL). They were identified with germline homozygous frameshift variant in SH2B3 gene (c.671insGGCCCCG/ p. Asp231Gly fs*38).

PMID:37206266 (2023) reported two further unrelated families with biallelic loss-of-function variants in SH2B3 gene (c.441_468del/ p.Arg148Profs*40 in patient 1 and c.1204G>A/ p.Val402Met in patient 2). These patients showed striking phenotypic similarity to each other as well as to the previous family from PMID:23908464 (2013) - presenting with myeloproliferation and multi-organ autoimmunity. One of these probands also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifested significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype.

PMID:40481232 (2025) reported ten patients with Germline SH2B3 variants, which included biallelic variants in eight patients (homozygous in seven and compound heterozygous in one) and monoallelic variants in two. However, both patients with germline heterozygous variants had homozygous variants in hematopoietic cells. Of the ten patients, eight (six with biallelic and two with monoallelic germline variants) presented with a myeloproliferative disease characterized by leukocytosis with a leukoerythoblastic picture, low blast percentage in BM and splenomegaly, at birth or in the first months of life.

Biallelic variants in this gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 07 August 2026). This gene has been associated with Semidominant inheritance for SH2B3-related immune system disorder (MONDO:1060195) by Childhood, Adolescent and Young Adult Cancer Predisposition GCEP on ClinGen with 'Definitive' rating (https://search.clinicalgenome.org/CCID:009335).; to: PMID:23908464 (2013) reported two siblings from a consanguineous family of Eastern European Ashkenazi Jewish descent presenting with growth retardation, mild developmental delay, chronic hepatitis, and Hashimoto autoimmune thyroiditis. One of them (sister) developed B-precursor acute lymphoblastic leukemia (ALL). They were identified with germline homozygous frameshift variant in SH2B3 gene (c.671insGGCCCCG/ p. Asp231Gly fs*38).

PMID:37206266 (2023) reported two further unrelated families with biallelic loss-of-function variants in SH2B3 gene (c.441_468del/ p.Arg148Profs*40 in patient 1 and c.1204G>A/ p.Val402Met in patient 2). These patients showed striking phenotypic similarity to each other as well as to the previous family from PMID:23908464 (2013) - presenting with myeloproliferation and multi-organ autoimmunity. One of these probands also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifested significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype.

PMID:40481232 (2025) reported ten patients with germline SH2B3 variants, which included biallelic variants in eight patients (homozygous in seven and compound heterozygous in one) and monoallelic variants in two. However, both patients with germline heterozygous variants had homozygous variants in hematopoietic cells. Of the ten patients, eight (six with biallelic and two with monoallelic germline variants) presented with a myeloproliferative disease characterized by leukocytosis with a leukoerythoblastic picture, low blast percentage in BM and splenomegaly, at birth or in the first months of life.

Biallelic variants in this gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 07 August 2026). This gene has been associated with Semidominant inheritance for SH2B3-related immune system disorder (MONDO:1060195) by Childhood, Adolescent and Young Adult Cancer Predisposition GCEP on ClinGen with 'Definitive' rating (https://search.clinicalgenome.org/CCID:009335).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.80 SH2B3 Achchuthan Shanmugasundram Publications for gene: SH2B3 were set to 37206266
Primary immunodeficiency or monogenic inflammatory bowel disease v9.79 SH2B3 Achchuthan Shanmugasundram Phenotypes for gene: SH2B3 were changed from Myeloproliferative disorder; Autoimmunity; Hepatosplenomegaly; Thrombosis; Autoimmune thyroiditis; Autoimmune hepatitis; Global developmental delay to SH2B3-related immune system disorder, MONDO:1060195
Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 SH2B3 Achchuthan Shanmugasundram reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23908464, 37206266, 40481232; Phenotypes: SH2B3-related immune system disorder, MONDO:1060195; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory disorders v3.16 SHARPIN Achchuthan Shanmugasundram Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v9.78
Autoinflammatory disorders v3.16 SHARPIN Achchuthan Shanmugasundram gene: SHARPIN was added
gene: SHARPIN was added to Autoinflammatory disorders. Sources: Expert Review Amber,Expert list,Literature
Q3_26_promote_green tags were added to gene: SHARPIN.
Mode of inheritance for gene: SHARPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHARPIN were set to 17538631; 38609546
Phenotypes for gene: SHARPIN were set to Autoinflammation with episodic fever and immune dysregulation, OMIM:620795; autoinflammation with episodic fever and immune dysregulation, MONDO:0968982
Penetrance for gene: SHARPIN were set to unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 SHARPIN Achchuthan Shanmugasundram Classified gene: SHARPIN as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 SHARPIN Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients and functional evidence including mouse model available in support of the association of SHARPIN gene with autoinflammatory disease. Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 SHARPIN Achchuthan Shanmugasundram Gene: sharpin has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.77 SHARPIN Achchuthan Shanmugasundram Phenotypes for gene: SHARPIN were changed from Autoinflammation; Immunodeficiency; Recurrent fever; Dermatitis; Recurrent infections to Autoinflammation with episodic fever and immune dysregulation, OMIM:620795; autoinflammation with episodic fever and immune dysregulation, MONDO:0968982
Primary immunodeficiency or monogenic inflammatory bowel disease v9.76 SHARPIN Achchuthan Shanmugasundram Publications for gene: SHARPIN were set to 38609546
Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 SHARPIN Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SHARPIN.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 SHARPIN Achchuthan Shanmugasundram reviewed gene: SHARPIN: Rating: GREEN; Mode of pathogenicity: None; Publications: 17538631, 38609546; Phenotypes: Autoinflammation with episodic fever and immune dysregulation, OMIM:620795, autoinflammation with episodic fever and immune dysregulation, MONDO:0968982; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.33 FBN2 Ida Ertmanska changed review comment from: Comment on list classification: Heterozygous variants in FBN2 are known to cause congenital contractural arachnodactyly. These patients do not tend to have skeletal defects beyond mild digit anomalies (camptodactyly, arachnodactyly). Tall stature was found to be associated with FBN1, but I did not find evidence of association with FBN2 variants. Hence, this gene should be downgraded to Red on the Skeletal dysplasia panel. An expert-review tag was added as this is a proposed demotion from Green rating.; to: Comment on list classification: Heterozygous variants in FBN2 are known to cause congenital contractural arachnodactyly. These patients do not tend to have skeletal defects beyond mild digit anomalies (camptodactyly, arachnodactyly). Tall stature was found to be associated with FBN1, but I did not find evidence of association with FBN2 variants. There are also 4 cases reported with biallelic FBN2 variants and various presentations, none with skeletal manifestations beyond digit anomalies. Hence, this gene should be downgraded to Red on the Skeletal dysplasia panel. An expert-review tag was added as this is a proposed demotion from Green rating.
Skeletal dysplasia v9.33 FBN2 Ida Ertmanska edited their review of gene: FBN2: Changed rating: RED
Skeletal dysplasia v9.33 FBN2 Ida Ertmanska Deleted their comment
Skeletal dysplasia v9.33 FBN2 Ida Ertmanska commented on gene: FBN2: Comment on list classification: Heterozygous variants in FBN2 are known to cause congenital contractural arachnodactyly. These patients do not tend to have skeletal defects beyond mild digit anomalies (camptodactyly, arachnodactyly). Tall stature was found to be associated with FBN1, but I did not find evidence of association with FBN2 variants. Hence, this gene should be downgraded to Red on the Skeletal dysplasia panel. An expert-review tag was added as this is a proposed demotion from Green rating.
Skeletal dysplasia v9.33 FBN2 Ida Ertmanska commented on gene: FBN2: Comment on list classification: Heterozygous variants in FBN2 are known to cause congenital contractural arachnodactyly. These patients do not tend to have skeletal defects beyond mild digit anomalies (camptodactyly, arachnodactyly). Tall stature was found to be associated with FBN1, but I did not find evidence of association with FBN2 variants. Hence, this gene should be downgraded to Red on the Skeletal dysplasia panel. An expert-review tag was added as this is a proposed demotion from Green rating.
Skeletal dysplasia v9.33 FBN2 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: FBN2.
Skeletal dysplasia v9.33 FBN2 Ida Ertmanska Tag Q3_26_demote_red tag was added to gene: FBN2.
Skeletal dysplasia v9.33 FBN2 Ida Ertmanska edited their review of gene: FBN2: Added comment: MONOALLELIC CASES:
PMID: 35360850 Sun et al., 2022
Report of 27 congenital contractural arachnodactyly (CCA) patients from 10 families, harbouring heterozygous FBN2 variants (mostly missense, 2 confirmed de novo).
Arachnodactyly (27/27, 100%), crumpled ears (26/27, 96.3%), camptodactyly (26/27, 96.3%), and muscle hypoplasia (22/26, 85%) were observed in almost all recruited cases. More than half patients (16/25, 64%) presented with contracture of large joints, including elbow, wrist, knee, ankle, and shoulder. 54% patients (13/24) present with kyphosis or scoliosis; 29% patients (7/24) presented with pectus deformity, including four patients with pectus carinatum and three patients with pectus excavatum; 74% patients (17/23) presented with high arched palate and 71% patients (17/24) presented with micrognathia; 33% patients (9/27) presented with pes planus.
No wider skeletal defects noted beyond mild digit anomalies. No patient presented with dolichostenomelia (disproportionately long limbs).

PMID: 24833718 Buchan et al., 2014
Study of 852 adolescent idiopathic scoliosis cases and 669 controls.
In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house controls (2.4%) (OR = 3.5, P = 5.46 × 10(-4)) and Exome Sequencing Project controls (2.3%) (OR = 3.5, P = 1.48 × 10(-6))
FBN1 variants associated with tall stature - not noted in FBN2.; Changed publications to: 24833718, 25558065, 28383543, 33571691, 35360850, 38791509
Retinal disorders v9.14 FBN2 Ida Ertmanska commented on gene: FBN2: Comment on list classification: As there is only 1 pedigree reported in literature where a het FBN2 variant segregated with macular degeneration, this gene can only be rated Red on Retinal disorders.
Retinal disorders v9.14 FBN2 Ida Ertmanska changed review comment from: PMID: 24899048 Ratnapriya et al., 2014
Summary copied from OMIM: "Reported a family in which a father and 4 sons had early-onset macular dystrophy. Clinical features varied among the 5 affected individuals. The father was diagnosed with macular degeneration at 69 years of age, and examination at age 75 showed large areas of pigment epithelial atrophy in the macula of both eyes. The eldest son reported a history of distorted vision in his left eye from the age of 46 years; examination at age 52 confirmed pigmentary changes of the left macula. Another son had a history of choroidal neovascularization in the right eye at age 35. Two more sons exhibited clinical findings consistent with atrophic macular disease in their forties. There was no history of skeletal, joint, or muscle abnormalities in these patients."
A heterozygous FBN2 c.3430G>A, p.Glu1144Lys variant was posed to be causal. MAF in gnomAD v4 = 0.0001761. Conflicting in ClinVar (VUS/B).
Sources: Literature; to: PMID: 24899048 Ratnapriya et al., 2014
Summary copied from OMIM: "Reported a family in which a father and 4 sons had early-onset macular dystrophy. Clinical features varied among the 5 affected individuals. The father was diagnosed with macular degeneration at 69 years of age, and examination at age 75 showed large areas of pigment epithelial atrophy in the macula of both eyes. The eldest son reported a history of distorted vision in his left eye from the age of 46 years; examination at age 52 confirmed pigmentary changes of the left macula. Another son had a history of choroidal neovascularization in the right eye at age 35. Two more sons exhibited clinical findings consistent with atrophic macular disease in their forties. There was no history of skeletal, joint, or muscle abnormalities in these patients."
A heterozygous FBN2 c.3430G>A, p.Glu1144Lys variant segregated with disease and was posed to be causal. MAF in gnomAD v4 = 0.0001761. Conflicting in ClinVar (VUS/B).
Sources: Literature
Retinal disorders v9.14 FBN2 Ida Ertmanska gene: FBN2 was added
gene: FBN2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: FBN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBN2 were set to 24899048
Phenotypes for gene: FBN2 were set to Macular degeneration, early-onset, OMIM:616118; macular degeneration, early-onset, MONDO:0014501
Review for gene: FBN2 was set to RED
Added comment: PMID: 24899048 Ratnapriya et al., 2014
Summary copied from OMIM: "Reported a family in which a father and 4 sons had early-onset macular dystrophy. Clinical features varied among the 5 affected individuals. The father was diagnosed with macular degeneration at 69 years of age, and examination at age 75 showed large areas of pigment epithelial atrophy in the macula of both eyes. The eldest son reported a history of distorted vision in his left eye from the age of 46 years; examination at age 52 confirmed pigmentary changes of the left macula. Another son had a history of choroidal neovascularization in the right eye at age 35. Two more sons exhibited clinical findings consistent with atrophic macular disease in their forties. There was no history of skeletal, joint, or muscle abnormalities in these patients."
A heterozygous FBN2 c.3430G>A, p.Glu1144Lys variant was posed to be causal. MAF in gnomAD v4 = 0.0001761. Conflicting in ClinVar (VUS/B).
Sources: Literature
Arthrogryposis v10.16 FBN2 Ida Ertmanska Publications for gene: FBN2 were set to 7493032; 33571691; 25558065; 28383543
Arthrogryposis v10.15 FBN2 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: FBN2.
Arthrogryposis v10.15 FBN2 Ida Ertmanska commented on gene: FBN2: Comment on mode of inheritance: There are 4 unrelated individuals reported in literature with biallelic FBN2 variants. However, these individuals presented with a spectrum of phenotypes: one with dextro-transposition of the great arteries, one with congenital contractural arachnodactyly, one individual with a myofibrillar myopathy, and one fetal case with fetal akinesia with brain ischemia and neonatal death. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown.
Thoracic aortic aneurysm or dissection (GMS) v5.7 FBN2 Ida Ertmanska Phenotypes for gene: FBN2 were changed from Congenital Contractural Arachnodactyly; Contractural arachnodactyly, congenital, 121050 to Contractural arachnodactyly, congenital, OMIM:121050; congenital contractural arachnodactyly, MONDO:0007363
Thoracic aortic aneurysm or dissection (GMS) v5.6 FBN2 Ida Ertmanska Publications for gene: FBN2 were set to 25944730; 29907982
Thoracic aortic aneurysm or dissection (GMS) v5.5 FBN2 Ida Ertmanska commented on gene: FBN2: Comment on mode of inheritance: There are 4 unrelated individuals reported in literature with biallelic FBN2 variants. However, these individuals presented with a spectrum of phenotypes: one with dextro-transposition of the great arteries, one with congenital contractural arachnodactyly, one individual with a myofibrillar myopathy, and one fetal case with fetal akinesia with brain ischemia and neonatal death. Hence, the mode of inheritance should remain MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown, until more evidence emerges.
Thoracic aortic aneurysm or dissection (GMS) v5.5 FBN2 Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arthrogryposis v10.15 FBN2 Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v9.33 FBN2 Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v7.33 FBN2 Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ehlers Danlos syndrome with a likely monogenic cause v4.16 FBN2 Ida Ertmanska commented on gene: FBN2: Comment on mode of inheritance: There are 4 unrelated individuals reported in literature with biallelic FBN2 variants. However, these individuals presented with a spectrum of phenotypes: one with dextro-transposition of the great arteries, one with congenital contractural arachnodactyly, one individual with a myofibrillar myopathy, and one fetal case with fetal akinesia with brain ischemia and neonatal death. Hence, the mode of inheritance should remain MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown, until more evidence emerges.
Ehlers Danlos syndrome with a likely monogenic cause v4.16 FBN2 Ida Ertmanska Phenotypes for gene: FBN2 were changed from Contractural arachnodactyly, congenital, OMIM:121050 to Contractural arachnodactyly, congenital, OMIM:121050; congenital contractural arachnodactyly, MONDO:0007363
Ehlers Danlos syndrome with a likely monogenic cause v4.15 FBN2 Ida Ertmanska Publications for gene: FBN2 were set to 9737771; 10797416; 20799338
Ehlers Danlos syndrome with a likely monogenic cause v4.14 FBN2 Ida Ertmanska changed review comment from: BIALLELIC CASES:
PMID: 38791509 Zodanu et al., 2024
Proband B was prenatally diagnosed with dextro-transposition of the great arteries, based on a fetal echocardiogram at 20 weeks of gestation and required cardiac surgery at 0 and 5 days after birth. WES of proband B and his parents, showed compound heterozygous missense, c.518C>T and c.8230T>G (p.Tyr2744Asp), variants in the FBN2 in proband B; unaffected parents confirmed het for one variant each.

PMID: 33571691 Kloth et al., 2021
Report of a 15-year-old girl with a severe form of congenital contractural arachnodactyly and novel biallelic variants in FBN2: the missense variant c.3563G > T/p.(Gly1188Val) from her unaffected father and the nonsense variant c.6831C > A/p.(Cys2277*) from her healthy mother.

PMID: 28383543 Monies et al., 2017
Family 16DG0107 - male proband homozygous for FBN2 variant NM_001999.3:c.41T>G:p.(Leu14Arg) - het in unaffected parents and sibs. Variant not found in gnomAD v4. Proband presented at birth with clubfoot. At 13 yrs he had fatigue, mild to severe muscle weakness (severe in hip extensors), camptodactyly. The CK value was normal, but muscle biopsy showed myofibrillar disorganization.

PMID: 25558065 Alazami et al., 2015
Large cohort of consanguineous families. Method: WES.
Individual 12DG0104 had a FBN2 variant NM_001999:c.1064G>A, p.G355D, and presented with fetal akinesia with brain ischemia and neonatal death.; to: BIALLELIC CASES:
PMID: 38791509 Zodanu et al., 2024
Proband B was prenatally diagnosed with dextro-transposition of the great arteries, based on a fetal echocardiogram at 20 weeks of gestation and required cardiac surgery at 0 and 5 days after birth. WES of proband B and his parents, showed compound heterozygous missense, c.518C>T and c.8230T>G (p.Tyr2744Asp), variants in the FBN2 in proband B; unaffected parents confirmed het for one variant each.

PMID: 33571691 Kloth et al., 2021
Report of a 15-year-old girl with a severe form of congenital contractural arachnodactyly and novel biallelic variants in FBN2: the missense variant c.3563G > T/p.(Gly1188Val) from her unaffected father and the nonsense variant c.6831C > A/p.(Cys2277*) from her healthy mother.

PMID: 28383543 Monies et al., 2017
Family 16DG0107 - male proband homozygous for FBN2 variant NM_001999.3:c.41T>G:p.(Leu14Arg) - het in unaffected parents and sibs. Variant not found in gnomAD v4. Proband presented at birth with clubfoot. At 13 yrs he had fatigue, mild to severe muscle weakness (severe in hip extensors), camptodactyly. The CK value was normal, but muscle biopsy showed myofibrillar disorganization.

PMID: 25558065 Alazami et al., 2015
Large cohort of consanguineous families. Method: WES.
Individual 12DG0104 had a FBN2 variant NM_001999:c.1064G>A, p.G355D, and presented with fetal akinesia with brain ischemia and neonatal death.

FBN2 is associated with AD Contractural arachnodactyly, congenital, OMIM:121050 in OMIM. The association between FBN2 and AD congenital contractural arachnodactyly is classified as Definitive in ClinGen (Nov 2025, Hereditary Cardiovascular Disease GCEP). Resources accessed 6th Aug 2026.
Ehlers Danlos syndrome with a likely monogenic cause v4.14 FBN2 Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 LY96 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is only one family and functional evidence available in support of the disease association. The phenotype is variable across the two siblings from the same family. Hence, this gene can only be rated red with the current evidence.; to: Comment on list classification: There is only one family and functional evidence available in support of the disease association. The phenotype is variable across the two siblings from the same family. Hence, this gene can only be rated red with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 LY96 Achchuthan Shanmugasundram edited their review of gene: LY96: Changed rating: RED
Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 LY96 Achchuthan Shanmugasundram Classified gene: LY96 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 LY96 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one family and functional evidence available in support of the disease association. The phenotype is variable across the two siblings from the same family. Hence, this gene can only be rated red with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 LY96 Achchuthan Shanmugasundram Gene: ly96 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.74 LY96 Achchuthan Shanmugasundram Phenotypes for gene: LY96 were changed from Inflammatory bowel disease; Pneumonia; Otitis media; Abnormal inflammatory response; Recurrent bacterial infections to inflammatory bowel disease, MONDO:0005265; pneumonia, MONDO:0005249; otitis media, MONDO:0005441
Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 LY96 Achchuthan Shanmugasundram edited their review of gene: LY96: Changed phenotypes to: inflammatory bowel disease, MONDO:0005265, pneumonia, MONDO:0005249, otitis media, MONDO:0005441
Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 LY96 Achchuthan Shanmugasundram reviewed gene: LY96: Rating: AMBER; Mode of pathogenicity: None; Publications: 36462957; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.17 CAV3 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: CAV3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.17 CAV3 Ida Ertmanska commented on gene: CAV3: Comment on mode of inheritance: There are more than 3 unrelated individuals reported in literature with biallelic CAV3 variants and a caveolinopathy, which primarily manifests in exercise intolerance and elevated CK. Proximal weakness and hypertrophy of limbs are also often reported, though the disease is often mild and slow progressing. The severity of disease does not clearly correlate with the mode of inheritance. Based on available evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Rhabdomyolysis and metabolic muscle disorders v6.8 CAV3 Ida Ertmanska commented on gene: CAV3: Comment on mode of inheritance: There are more than 3 unrelated individuals reported in literature with biallelic CAV3 variants and a caveolinopathy, which primarily manifests in exercise intolerance and elevated CK. Proximal weakness and hypertrophy of limbs are also often reported, though the disease is often mild and slow progressing. The severity of disease does not clearly correlate with the mode of inheritance. Based on available evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Rhabdomyolysis and metabolic muscle disorders v6.8 CAV3 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: CAV3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.17 CAV3 Ida Ertmanska Publications for gene: CAV3 were set to http://www.ncbi.nlm.nih.gov/books/NBK1408/
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.16 CAV3 Ida Ertmanska Phenotypes for gene: CAV3 were changed from Rippling muscle disease 2, OMIM:606072; Myopathy, distal, Tateyama type, OMIM:614321 to caveolinopathy MONDO:0016146; Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease 2, OMIM:606072; rippling muscle disease 2, MONDO:0019947; distal myopathy, Tateyama type, MONDO:0013686
Rhabdomyolysis and metabolic muscle disorders v6.8 CAV3 Ida Ertmanska Publications for gene: CAV3 were set to 15668980; 12666119; 9536092; 11251997; 16730439
Rhabdomyolysis and metabolic muscle disorders v6.7 CAV3 Ida Ertmanska Phenotypes for gene: CAV3 were changed from Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease, OMIM:606072 to caveolinopathy MONDO:0016146; Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease 2, OMIM:606072; rippling muscle disease 2, MONDO:0019947; distal myopathy, Tateyama type, MONDO:0013686
Acute rhabdomyolysis v2.18 CAV3 Ida Ertmanska Phenotypes for gene: CAV3 were changed from Rippling muscle disease, OMIM:606072; Myopathy, distal, Tateyama type, OMIM:614321 to caveolinopathy MONDO:0016146; Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease 2, OMIM:606072; rippling muscle disease 2, MONDO:0019947; distal myopathy, Tateyama type, MONDO:0013686
Acute rhabdomyolysis v2.17 CAV3 Ida Ertmanska Publications for gene: CAV3 were set to 12666119; 15668980; 11251997; 27312022; 16730439; 9536092
Acute rhabdomyolysis v2.16 CAV3 Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).; to: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 PAX5 Achchuthan Shanmugasundram Classified gene: PAX5 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 PAX5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only patient and functional evidence available in support of the disease association. Hence, this gene is rated amber on this panel with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 PAX5 Achchuthan Shanmugasundram Gene: pax5 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v6.6 CAV3 Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.
---------------------
CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGe; to: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.
---------------------
CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGe
Acute rhabdomyolysis v2.16 CAV3 Ida Ertmanska edited their review of gene: CAV3: Changed publications to: 9536092, 12666119, 15668980, 16730439, 18253147, 37166430
Primary immunodeficiency or monogenic inflammatory bowel disease v9.72 PAX5 Achchuthan Shanmugasundram Phenotypes for gene: PAX5 were changed from hypogammaglobulinemia; reduced B cells; sensorimotor deficits; autism spectrum disorder to PAX5-related B lymphopenia and autism spectrum disorder, MONDO:0100299; Hypogammaglobulinaemia
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 CAV3 Ida Ertmanska edited their review of gene: CAV3: Changed publications to: 9536092, 12666119, 15668980, 16730439, 18253147, 37166430
Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 PAX5 Achchuthan Shanmugasundram edited their review of gene: PAX5: Changed phenotypes to: PAX5-related B lymphopenia and autism spectrum disorder, MONDO:0100299, Hypogammaglobulinaemia
Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 PAX5 Achchuthan Shanmugasundram reviewed gene: PAX5: Rating: AMBER; Mode of pathogenicity: None; Publications: 35947077; Phenotypes: Hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 CAV3 Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.
---------------------
CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).; to: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.
---------------------
BIALLELIC CASES - review by Ivone Leong, copied from Rhabdomyolysis and metabolic muscle disorders panel

PMID: 9536092, reported one patient with homozygous G56S. The patient was the only member of the family to be affected by disease (proximal muscle weakness in the first decade of life). The variant was not found in 200 controls. The patient's skeletal muscle biopsy looked normal and expression of dystrophin, sarcoglycans and caveolin-3 was normal. This variant was later reclassified as a VUS as PMID:11251997 identified 2 Brazilian patients with LGMD with heterozygous G55S. Both patients had onset in adulthood, calf hypertrophy, elevated creatine kinase, and difficulty walking. Muscle protein analyses from both patients were normal. Screening 200 normal controls showed 4 controls also had this variant.
In OMIM: "Hamosh (2018) found that the G55S variant was present in heterozygous state in 3,142 of 277,064 alleles and in 184 homozygotes in the gnomAD database (January 24, 2018), calling into question the pathogenicity of the variant."

PMID: 12666119, reported an Italian patient with severe rippling muscle disease (A92T) who was AR. Actually A93T.

PMID: 15668980, the same authors of PMID: 12666119 reported 1 family with 2 affected sibs who have AR rippling muscle disease (same variant as above A92T). Unaffected parents were both heterozygous for the variant. The authors note that the parents were not known to be consanguineous but they are from the same small village in Germany. The authors also did a haplotype analysis and showed that this variant arose separately from the Italian case, suggesting that A92 might be a mutation hot spot. According to ClinVar, this variant has conflicting interpretations of pathogenicity (https://www.ncbi.nlm.nih.gov/clinvar/variation/8285/)

PMID: 16730439, reports on 1 patient (AR) with mild proximal muscle weakness of the lower limbs. No other family members were available for further analysis. Patient is homozygous for a splice variant (IVS1+2T>C).
---------------------
CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).
Rhabdomyolysis and metabolic muscle disorders v6.6 CAV3 Ida Ertmanska edited their review of gene: CAV3: Changed publications to: 18253147, 37166430
Rhabdomyolysis and metabolic muscle disorders v6.6 CAV3 Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).
---------------------
CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).; to: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.
---------------------
CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGe
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 CAV3 Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).
---------------------
CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).; to: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.
---------------------
CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 CAV3 Ida Ertmanska edited their review of gene: CAV3: Changed rating: GREEN; Changed publications to: 37166430; Changed phenotypes to: caveolinopathy MONDO:0016146, Myopathy, distal, Tateyama type, OMIM:614321, Rippling muscle disease 2, OMIM:606072, rippling muscle disease 2, MONDO:0019947, distal myopathy, Tateyama type, MONDO:0013686; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 CAV3 Ida Ertmanska commented on gene: CAV3
Rhabdomyolysis and metabolic muscle disorders v6.6 CAV3 Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).; to: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).
---------------------
CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).
Rhabdomyolysis and metabolic muscle disorders v6.6 CAV3 Ida Ertmanska reviewed gene: CAV3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37166430; Phenotypes: caveolinopathy MONDO:0016146, Myopathy, distal, Tateyama type, OMIM:614321, Rippling muscle disease 2, OMIM:606072, rippling muscle disease 2, MONDO:0019947, distal myopathy, Tateyama type, MONDO:0013686; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Acute rhabdomyolysis v2.16 CAV3 Ida Ertmanska edited their review of gene: CAV3: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Acute rhabdomyolysis v2.16 CAV3 Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).; to: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).
Acute rhabdomyolysis v2.16 CAV3 Ida Ertmanska commented on gene: CAV3: PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).
Acute rhabdomyolysis v2.16 CAV3 Ida Ertmanska reviewed gene: CAV3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9536092, 12666119, 15668980, 16730439; Phenotypes: caveolinopathy MONDO:0016146, Myopathy, distal, Tateyama type, OMIM:614321, Rippling muscle disease 2, OMIM:606072, rippling muscle disease 2, MONDO:0019947, distal myopathy, Tateyama type, MONDO:0013686; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v3.15 IKBKE Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases identified with monoallelic IKBKE variants and functional evidence is also available for these variants. However, different phenotypes were reported in these two patients (HSV-2 meningitis vs autoinflammatory disease). Hence, this gene can only be rated amber with the current evidence.; to: Comment on list classification: There are two unrelated cases identified with monoallelic IKBKE variants and functional evidence is also available for these variants. However, different phenotypes were reported in these two patients and only one of them have autoinflammatory disease (other with HSV-2 meningitis). Hence, this gene can only be rated amber with the current evidence.
Autoinflammatory disorders v3.15 IKBKE Achchuthan Shanmugasundram Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v9.71
Autoinflammatory disorders v3.15 IKBKE Achchuthan Shanmugasundram gene: IKBKE was added
gene: IKBKE was added to Autoinflammatory disorders. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: IKBKE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKBKE were set to 37937644; 39524436
Phenotypes for gene: IKBKE were set to Herpes Simplex Virus type 2 (HSV-2) meningitis; autoinflammatory syndrome, MONDO:0019751
Penetrance for gene: IKBKE were set to unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 GINS4 Achchuthan Shanmugasundram edited their review of gene: GINS4: Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 GINS4 Achchuthan Shanmugasundram Classified gene: GINS4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 GINS4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with biallelic GINS4 variants and with NK cell deficiency and neutropenia. This includes three unrelated patients with the same recurrent potentially founder variant (p.Val171Met) and two additional families reported with compound heterozygous variants (and one variant in both these families is p.Val171Leu). There is also extensive functional evidence available.

Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 GINS4 Achchuthan Shanmugasundram Gene: gins4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 GINS4 Achchuthan Shanmugasundram Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 GINS4 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: GINS4.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 GINS4 Achchuthan Shanmugasundram Tag watchlist was removed from gene: GINS4.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 IKBKE Achchuthan Shanmugasundram Classified gene: IKBKE as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 IKBKE Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases identified with monoallelic IKBKE variants and functional evidence is also available for these variants. However, different phenotypes were reported in these two patients (HSV-2 meningitis vs autoinflammatory disease). Hence, this gene can only be rated amber with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 IKBKE Achchuthan Shanmugasundram Gene: ikbke has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.69 IKBKE Achchuthan Shanmugasundram Phenotypes for gene: IKBKE were changed from Herpes Simplex Virus type 2 (HSV-2) meningitis; Mollaret meningitis to Herpes Simplex Virus type 2 (HSV-2) meningitis; autoinflammatory syndrome, MONDO:0019751
Primary immunodeficiency or monogenic inflammatory bowel disease v9.68 IKBKE Achchuthan Shanmugasundram Publications for gene: IKBKE were set to 37937644
Primary immunodeficiency or monogenic inflammatory bowel disease v9.67 IKBKE Achchuthan Shanmugasundram Mode of inheritance for gene: IKBKE was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 IKBKE Achchuthan Shanmugasundram edited their review of gene: IKBKE: Changed phenotypes to: Herpes Simplex Virus type 2 (HSV-2) meningitis, autoinflammatory syndrome, MONDO:0019751
Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 IKBKE Achchuthan Shanmugasundram reviewed gene: IKBKE: Rating: AMBER; Mode of pathogenicity: None; Publications: 37937644, 39524436; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 GINS4 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: GINS4.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 GINS4 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: GINS4.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 GINS4 Achchuthan Shanmugasundram Classified gene: GINS4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 GINS4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with the same recurrent potential founder variant (p.Val171Met) that is also found in homozygous state in one individual in gnomAD4.1.1. There are two additional families reported with compound heterozygous variants and one of these variants in both these cases are the same (p.Val171Leu).

Hence, this gene is rated amber with the current evidence. However, 'watchlist' tag has been added to review the gene with any new evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 GINS4 Achchuthan Shanmugasundram Gene: gins4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.65 GINS4 Achchuthan Shanmugasundram Phenotypes for gene: GINS4 were changed from NK cell deficiency; neutropenia; viral infections to combined immunodeficiency, MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v9.64 GINS4 Achchuthan Shanmugasundram Publications for gene: GINS4 were set to 36345943
Primary immunodeficiency or monogenic inflammatory bowel disease v9.63 GINS4 Achchuthan Shanmugasundram reviewed gene: GINS4: Rating: AMBER; Mode of pathogenicity: None; Publications: 36345943, 40510848, 40768335; Phenotypes: combined immunodeficiency, MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.94 EIF1AX Achchuthan Shanmugasundram Classified gene: EIF1AX as Amber List (moderate evidence)
Intellectual disability v10.94 EIF1AX Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Julia Baptista, there is sufficient evidence available (four unrelated cases) for the association of EIF1AX with intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v10.94 EIF1AX Achchuthan Shanmugasundram Gene: eif1ax has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.93 EIF1AX Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: EIF1AX.
Tag Q3_26_promote_green tag was added to gene: EIF1AX.
Intellectual disability v10.93 EIF1AX Achchuthan Shanmugasundram Publications for gene: EIF1AX were set to PMID: 42337333
Intellectual disability v10.92 EIF1AX Achchuthan Shanmugasundram Phenotypes for gene: EIF1AX were changed from intellectual disability to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v10.91 EIF1AX Achchuthan Shanmugasundram Mode of inheritance for gene: EIF1AX was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v10.90 EIF1AX Achchuthan Shanmugasundram reviewed gene: EIF1AX: Rating: GREEN; Mode of pathogenicity: None; Publications: 42337333; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Optic neuropathy v6.46 PHB Eleanor Williams commented on gene: PHB
Intellectual disability v10.90 ZSCAN10 Eleanor Williams Phenotypes for gene: ZSCAN10 were changed from Otofacial neurodevelopmental syndrome, OMIM:620910 to Otofacial neurodevelopmental syndrome, OMIM:620910; otofacial neurodevelopmental syndrome, MONDO:0975705
Primary immunodeficiency or monogenic inflammatory bowel disease v9.63 NOX1 Achchuthan Shanmugasundram Classified gene: NOX1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.63 NOX1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are over 10 patients reported with inflammatory bowel disease (IBD) and with NOX1 variants, large cohort analyses suggest that NOX1 loss-of-function variants may not always present as a fully penetrant Mendelian disorder and that other genetic modifiers or environmental factors may contribute to disease pathogenesis. Hence, this gene should be rated amber with the current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.63 NOX1 Achchuthan Shanmugasundram Gene: nox1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.62 NOX1 Achchuthan Shanmugasundram changed review comment from: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1.

PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier.

PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 05 August 2026).; to: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser in one patient; c.967G>A, p.Asp360Asn in two patients). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1.

PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 inflammatory bowel disease (IBD) patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier.

PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 05 August 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.62 NOX1 Achchuthan Shanmugasundram changed review comment from: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1.

PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier.

PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen.

; to: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1.

PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier.

PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 05 August 2026).
Cerebral vascular malformations v5.2 PDCD10 Alexandra Njegic reviewed gene: PDCD10: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 15543491, 31114296, 39173099; Phenotypes: Cerebral cavernous malformations-3; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hypothyroidism v3.11 DUOX2 Arina Puzriakova Phenotypes for gene: DUOX2 were changed from Congenital hypothyroidism; Thryoid dyshormonogenesis 6, 607200; permanent congenital hypothyroidism; transient congenital hypothyroidism; eutopic gland-in-situ; goitre; borderline congenital hypothyroidism; iodide organification defect to Thyroid dyshormonogenesis 6, OMIM:607200
Primary immunodeficiency or monogenic inflammatory bowel disease v9.62 DUOX2 Arina Puzriakova Phenotypes for gene: DUOX2 were changed from inflammatory bowel disease; MONDO:0005265; IBD; VEOIBD to inflammatory bowel disease, MONDO:0005265
Rare genetic inflammatory skin disorders v4.25 OSMR Arina Puzriakova Phenotypes for gene: OSMR were changed from AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1, OMIM:105250; atopic eczema, MONDO:0004980 to Amyloidosis, primary localized cutaneous, 1, OMIM:105250; atopic eczema, MONDO:0004980
Pigmentary skin disorders v5.12 OSMR Arina Puzriakova Phenotypes for gene: OSMR were changed from Amyloidosis cutis; PLCA1; AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1 to Amyloidosis, primary localized cutaneous, 1, OMIM:105250
Optic neuropathy v6.46 PHB Ida Ertmanska Phenotypes for gene: PHB were changed from to optic atrophy, MONDO:0003608
Optic neuropathy v6.45 PHB Ida Ertmanska Classified gene: PHB as Red List (low evidence)
Optic neuropathy v6.45 PHB Ida Ertmanska Added comment: Comment on list classification: As reviewed by Cassandra Smith, there is one pedigree reported in literature where a heterozygous missense variant in PHB1 segregated with optic atrophy. Hence, this gene can only be rated Red until more evidence emerges for the association.
Optic neuropathy v6.45 PHB Ida Ertmanska Gene: phb has been classified as Red List (Low Evidence).
Optic neuropathy v6.44 PHB Ida Ertmanska commented on gene: PHB
Optic neuropathy v6.44 PHB Ida Ertmanska Tag new-gene-name tag was added to gene: PHB.
Intellectual disability v10.89 USP34 Ida Ertmanska Tag Q3_26_NHS_review tag was added to gene: USP34.
Intellectual disability v10.89 USP34 Ida Ertmanska edited their review of gene: USP34: Changed rating: GREEN; Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092
Intellectual disability v10.89 USP34 Ida Ertmanska Phenotypes for gene: USP34 were changed from to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v10.88 USP34 Ida Ertmanska Classified gene: USP34 as Amber List (moderate evidence)
Intellectual disability v10.88 USP34 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Benito Banos Pinero, there are 6 individuals reported in the literature with heterozygous USP34 variants (5 confirmed de novo) and a neurodevelopmental phenotype. Hence, this gene can be promoted to Green on Intellectual disability, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Intellectual disability v10.88 USP34 Ida Ertmanska Gene: usp34 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.87 USP34 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: USP34.
Intellectual disability v10.87 ZSCAN10 Ida Ertmanska Classified gene: ZSCAN10 as Amber List (moderate evidence)
Intellectual disability v10.87 ZSCAN10 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic ZSCAN10 variants and syndromic intellectual disability with motor developmental delay. Hence, this gene should be promoted to Green on Intellectual disability with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Intellectual disability v10.87 ZSCAN10 Ida Ertmanska Gene: zscan10 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.86 ZSCAN10 Ida Ertmanska gene: ZSCAN10 was added
gene: ZSCAN10 was added to Intellectual disability. Sources: Literature
Q3_26_promote_green tags were added to gene: ZSCAN10.
Mode of inheritance for gene: ZSCAN10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZSCAN10 were set to 38386308; 40605417
Phenotypes for gene: ZSCAN10 were set to Otofacial neurodevelopmental syndrome, OMIM:620910
Review for gene: ZSCAN10 was set to GREEN
Added comment: PMID: 38386308 Laugwitz et al., 2024
Report of 7 individuals from 5 unrelated families (3 consanguineous) with biallelic ZSCAN10 variants and a neurodevelopmental disorder with facial dysmorphism. All 7 probands harboured biallelic nonsense variants. Cognitive impairment was mild (1), moderate (3) or severe (3) in these patients, with moderate to profound delay of motor development. 4/7 probands also had a hearing impairment (1 with unilateral deafness only).
Other less consistent features included microgenitalia (2/7), heart defects (1/7) and cleft palate (1/7). 3 individuals had unspecified vision impairment.

PMID: 40605417 Alfalah et al., 2025
Research letter describing a male patient from a consanguineous Saudi family with mild cognitive impairment, moderate motor delay, ADHD, left SNHL, and vision impairment (myopia the vision is 20/40 bilateral ptosis). He had a clinical diagnosis of Goldenhar syndrome. He harboured a homozygous ZSCAN10 variant NM_032805.3: c.598_602del, p.Pro200Lysfs*48. Het parents unaffected.
Sources: Literature
Intellectual disability v10.85 EIF1AX Julia Baptista gene: EIF1AX was added
gene: EIF1AX was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF1AX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: EIF1AX were set to PMID: 42337333
Phenotypes for gene: EIF1AX were set to intellectual disability
Review for gene: EIF1AX was set to GREEN
Added comment: PMID: 42337333- describes four de novo hemizygous EIF1AX variants (comprising three missense and one splice variant) in four male individuals exhibiting variable neurodevelopmental disorders, including developmental and language delays, autistic behavioral problems, and facial dysmorphisms.
Functional studies using Drosophila models supported a LOF effect for (Lys64Glu) and p.(Asp90Gly) whilst no significant effect was seen for p.(Asn17Asp). Minigene analysis for the c.204 G > C showed aberrant mRNA splicing and a LOF allele.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.61 NOX1 Achchuthan Shanmugasundram Phenotypes for gene: NOX1 were changed from Inflammatory bowel disease; IBD; VEOIBD to inflammatory bowel disease, MONDO:0005265
Primary immunodeficiency or monogenic inflammatory bowel disease v9.60 NOX1 Achchuthan Shanmugasundram Publications for gene: NOX1 were set to 32064493; 26301257; 29091079
Primary immunodeficiency or monogenic inflammatory bowel disease v9.59 NOX1 Achchuthan Shanmugasundram Mode of inheritance for gene: NOX1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.58 NOX1 Achchuthan Shanmugasundram changed review comment from: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1.

PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier.

PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in patients with pediatric-onset IBD.; to: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1.

PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier.

PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.58 HCK Arina Puzriakova Publications for gene: HCK were set to 34536415
Retinal disorders v9.13 XXYLT1 Achchuthan Shanmugasundram Classified gene: XXYLT1 as Amber List (moderate evidence)
Retinal disorders v9.13 XXYLT1 Achchuthan Shanmugasundram Gene: xxylt1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v9.12 XXYLT1 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: XXYLT1.
Retinal disorders v9.12 XXYLT1 Achchuthan Shanmugasundram Phenotypes for gene: XXYLT1 were changed from Retinal dystrophy to Cone-rod dystrophy, MONDO:0015993; Inherited retinal dystrophy, MONDO:0019118
Retinal disorders v9.11 XXYLT1 Achchuthan Shanmugasundram Publications for gene: XXYLT1 were set to PMID: 42530953
Primary immunodeficiency or monogenic inflammatory bowel disease v9.57 KARS Achchuthan Shanmugasundram Classified gene: KARS as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.57 KARS Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer & Luke Stuart, this gene should be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.57 KARS Achchuthan Shanmugasundram Gene: kars has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.56 KARS Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: KARS.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.56 KARS Achchuthan Shanmugasundram Phenotypes for gene: KARS were changed from progressive leukoencephalopathy; peripheral neuropathy; deafness; antibody deficiency; hypogammaglobulinemia to Hypogammaglobulinemia; antibody deficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v9.55 KARS Achchuthan Shanmugasundram Publications for gene: KARS were set to 37770806
Retinal disorders v9.10 XXYLT1 Luke Stuart reviewed gene: XXYLT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 42530953; Phenotypes: Cone-rod dystrophy (MONDO:0015993), Inherited retinal dystrophy (MONDO:0019118); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 KARS Luke Stuart reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 33942428, 37770806; Phenotypes: Hypogammaglobulinemia, antibody deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v9.10 XXYLT1 Siying Lin gene: XXYLT1 was added
gene: XXYLT1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: XXYLT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XXYLT1 were set to PMID: 42530953
Phenotypes for gene: XXYLT1 were set to Retinal dystrophy
Mode of pathogenicity for gene: XXYLT1 was set to Other
Review for gene: XXYLT1 was set to GREEN
Added comment: Biallelic XXYLT1 variants were identified in 7 affected individuals from 5 unrelated families (4 Finnish and 1 UK) with autosomal recessive inherited retinal disease. The recurrent splice variant was supported by RNA studies demonstrating aberrant splicing and loss of function, while the independent UK family harboured a distinct homozygous missense variant. These findings support XXYLT1 is a novel cause of autosomal recessive inherited retinal disease.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 NOX1 Achchuthan Shanmugasundram reviewed gene: NOX1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26301257, 29091079, 32064493; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 CD48 Achchuthan Shanmugasundram Classified gene: CD48 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 CD48 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients with two different variants affecting the same residue and functional evidence available in support of the association of CD48 gene with immune dysregulation. Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 CD48 Achchuthan Shanmugasundram Gene: cd48 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.53 CD48 Achchuthan Shanmugasundram Phenotypes for gene: CD48 were changed from Hemophagocytic lymphohistiocytosis; Urticaria; Hives; Inflammation; Fever; Hepatosplenomegaly to inborn error of immunity, MONDO:0003778
Primary immunodeficiency or monogenic inflammatory bowel disease v9.52 CD48 Achchuthan Shanmugasundram Publications for gene: CD48 were set to 31419545
Primary immunodeficiency or monogenic inflammatory bowel disease v9.51 CD48 Achchuthan Shanmugasundram Mode of inheritance for gene: CD48 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 CD48 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: CD48.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 CD48 Achchuthan Shanmugasundram reviewed gene: CD48: Rating: GREEN; Mode of pathogenicity: None; Publications: 31419545, 41984595; Phenotypes: inborn error of immunity, MONDO:0003778; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v3.14 FGR Achchuthan Shanmugasundram Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v9.50
Autoinflammatory disorders v3.14 FGR Achchuthan Shanmugasundram gene: FGR was added
gene: FGR was added to Autoinflammatory disorders. Sources: Expert Review Amber,Literature
Q3_26_promote_green tags were added to gene: FGR.
Mode of inheritance for gene: FGR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGR were set to 31138708; 41920357
Phenotypes for gene: FGR were set to chronic recurrent multifocal osteomyelitis, MONDO:0009813; vasculitis, MONDO:0018882
Penetrance for gene: FGR were set to unknown
Mode of pathogenicity for gene: FGR was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 FGR Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants.
1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants, and functional evidence for these two variants and from mouse model available.
2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below)

Based on these evidence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants.
1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants, and functional evidence for these two variants and from mouse model available.
2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below)

Based on this evidence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 FGR Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants.
1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants and functional evidence for these two variants and from mouse model available.
2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below)

Based on these evidence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants.
1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants, and functional evidence for these two variants and from mouse model available.
2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below)

Based on these evidence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 FGR Achchuthan Shanmugasundram Classified gene: FGR as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 FGR Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants.
1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants and functional evidence for these two variants and from mouse model available.
2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below)

Based on these evidence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 FGR Achchuthan Shanmugasundram Gene: fgr has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.49 FGR Achchuthan Shanmugasundram changed review comment from: PMID:31138708 (2019) reported whole-exome sequencing of 99 Chronic recurrent multifocal osteomyelitis (CRMO) patients including 88 trios and 11 dyads, of which 11 different rare exonic heterozygous variants in FGR gene were identified in 13 probands. These include two missense variants, p.Arg118Trp found in SH3 domain and and p.Pro525Ser variant found in C-terminal tail. Functional analysis showed p.Arg118Trp variant decreased kinase activity, while p.Pro525Ser showed increased kinase activity (gain-of-function). Studies on Ali18 mice carrying a gain‑of‑function missense mutation in the C‑terminal regulatory region of Fgr shiwed that it reduces its negative regulatory phosphorylation, and this aberrant Fgr activity is necessary and sufficient to drive the spontaneous sterile osteomyelitis and systemic low bone mineral density inflammatory phenotype.

PMID:41920357 (2026) reported three unrelated kindreds with sarcoma (Src) family of non-receptor tyrosine kinase (SFK)-associated vasculitis, of which one large family of 13 affected members across four generations was identified with a novel missense variant in FGR (p.Tyr523His). All clinically affected individuals (10) were heterozygous, while four unaffected members did not carry the variant. Two self-reported healthy members were also heterozygous, suggesting AD inheritance with incomplete penetrance or variable expressivity, although these two carriers have not undergone investigations for subclinical disease.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 31 July 2026).; to: PMID:31138708 (2019) reported whole-exome sequencing of 99 Chronic recurrent multifocal osteomyelitis (CRMO) patients including 88 trios and 11 dyads, of which 11 different rare exonic heterozygous variants in FGR gene were identified in 13 probands. These include two missense variants, p.Arg118Trp found in SH3 domain and and p.Pro525Ser variant found in C-terminal tail. Functional analysis showed p.Arg118Trp variant decreased kinase activity, while p.Pro525Ser showed increased kinase activity (gain-of-function). Studies on Ali18 mice carrying a gain‑of‑function missense mutation in the C‑terminal regulatory region of Fgr shiwed that it reduces its negative regulatory phosphorylation, and this aberrant Fgr activity is necessary and sufficient to drive the spontaneous sterile osteomyelitis and systemic low bone mineral density inflammatory phenotype.

PMID:41920357 (2026) reported three unrelated kindreds with sarcoma (Src) family of non-receptor tyrosine kinase (SFK)-associated vasculitis, of which one large family of 13 affected members across four generations was identified with a novel missense variant in FGR (p.Tyr523His). All clinically affected individuals (10) were heterozygous, while four unaffected members did not carry the variant. Two self-reported healthy members were also heterozygous, suggesting AD inheritance with incomplete penetrance or variable expressivity, although these two carriers have not undergone investigations for subclinical disease. Functional studies on p.Tyr523His variant showed ~50% reduced Fgr protein, enhanced STAT1/STAT5 signaling and increased CD11b/CD18 integrin expression.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 31 July 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.49 FGR Achchuthan Shanmugasundram changed review comment from: PMID:31138708 (2019) reported whole-exome sequencing of 99 Chronic recurrent multifocal osteomyelitis (CRMO) patients including 88 trios and 11 dyads, of which 11 different rare exonic heterozygous variants in FGR gene were identified in 13 probands. These include two missense variants, p.Arg118Trp found in SH3 domain and and p.Pro525Ser variant found in C-terminal tail. Functional analysis showed p.Arg118Trp variant decreased kinase activity, while p.Pro525Ser showed increased kinase activity (gain-of-function). Studies on Ali18 mice carrying a gain‑of‑function missense mutation in the C‑terminal regulatory region of Fgr shiwed that it reduces its negative regulatory phosphorylation, and this aberrant Fgr activity is necessary and sufficient to drive the spontaneous sterile osteomyelitis and systemic low bone mineral density inflammatory phenotype.

PMID:41920357 (2026) reported three unrelated kindreds with sarcoma (Src) family of non-receptor tyrosine kinase (SFK)-associated vasculitis, of which one large family of 13 affected members across four generations was identified with a novel missense variant in FGR (p.Tyr523His). All clinically affected individuals (10) were heterozygous, while four unaffected members did not carry the variant. Two self-reported healthy members were also heterozygous, suggesting AD inheritance with incomplete penetrance or variable expressivity, although these two carriers have not undergone investigations for subclinical disease.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:31138708 (2019) reported whole-exome sequencing of 99 Chronic recurrent multifocal osteomyelitis (CRMO) patients including 88 trios and 11 dyads, of which 11 different rare exonic heterozygous variants in FGR gene were identified in 13 probands. These include two missense variants, p.Arg118Trp found in SH3 domain and and p.Pro525Ser variant found in C-terminal tail. Functional analysis showed p.Arg118Trp variant decreased kinase activity, while p.Pro525Ser showed increased kinase activity (gain-of-function). Studies on Ali18 mice carrying a gain‑of‑function missense mutation in the C‑terminal regulatory region of Fgr shiwed that it reduces its negative regulatory phosphorylation, and this aberrant Fgr activity is necessary and sufficient to drive the spontaneous sterile osteomyelitis and systemic low bone mineral density inflammatory phenotype.

PMID:41920357 (2026) reported three unrelated kindreds with sarcoma (Src) family of non-receptor tyrosine kinase (SFK)-associated vasculitis, of which one large family of 13 affected members across four generations was identified with a novel missense variant in FGR (p.Tyr523His). All clinically affected individuals (10) were heterozygous, while four unaffected members did not carry the variant. Two self-reported healthy members were also heterozygous, suggesting AD inheritance with incomplete penetrance or variable expressivity, although these two carriers have not undergone investigations for subclinical disease.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 31 July 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.49 FGR Achchuthan Shanmugasundram Phenotypes for gene: FGR were changed from Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease to chronic recurrent multifocal osteomyelitis, MONDO:0009813; vasculitis, MONDO:0018882
Primary immunodeficiency or monogenic inflammatory bowel disease v9.48 FGR Achchuthan Shanmugasundram edited their review of gene: FGR: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v9.48 FGR Achchuthan Shanmugasundram Publications for gene: FGR were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v9.47 FGR Achchuthan Shanmugasundram Mode of inheritance for gene: FGR was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 FGR Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: FGR.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 FGR Achchuthan Shanmugasundram reviewed gene: FGR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31138708, 41920357; Phenotypes: chronic recurrent multifocal osteomyelitis, MONDO:0009813, vasculitis, MONDO:0018882; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 LY9 Achchuthan Shanmugasundram Classified gene: LY9 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 LY9 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there is sufficient evidence available (three unrelated cases and functional evidence) for the association of LY9 gene with this panel. Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 LY9 Achchuthan Shanmugasundram Gene: ly9 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.45 LY9 Achchuthan Shanmugasundram edited their review of gene: LY9: Changed phenotypes to: inborn error of immunity, MONDO:0003778, Mycobacterium tuberculosis, susceptibility, MONDO:0000070
Primary immunodeficiency or monogenic inflammatory bowel disease v9.45 LY9 Achchuthan Shanmugasundram Phenotypes for gene: LY9 were changed from Tubercolosis to inborn error of immunity, MONDO:0003778; Mycobacterium tuberculosis, susceptibility, MONDO:0000070
Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 LY9 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: LY9.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 LY9 Achchuthan Shanmugasundram reviewed gene: LY9: Rating: GREEN; Mode of pathogenicity: None; Publications: 40446017; Phenotypes: inborn error of immunity, MONDO:0003778; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 BIRC3 Achchuthan Shanmugasundram changed review comment from: PMID:42335979 (2026) reported the identification of rare and damaging BIRC3 variants in 14 patients from 10 unrelated families with Crohn's disease (CD) diagnosed between infancy and adulthood. They carried 8 distinct BIRC3 variants — 5 heterozygous missense/ nonsense variants (p.H312Y - recurrent in 2 families, p.T35A, p.P266R, p.C557X, p.D530H) causing pediatric- to adult-onset CD (age range <1 to 31 years), and 3 homozygous nonsense/ frameshift variants (p.Y522X, p.C588Y, p.X605Rext*10) in sibling pairs from consanguineous families, causing infantile-onset CD.

Functional studies showed that BIRC3 (cIAP2) deficiency impairs RIPK1 ubiquitylation, causing RIPK1 autophosphorylation, resulting in increased epithelial cell death. Knock‑in cIAP2 (H312Y/+) mice and ciap1‑deficient zebrafish developed or exacerbated colitis, transcriptome analysis of mice organoids and zebrafish showed that BIRC3 deficiency led to inappropriate sustained activation of TNF‑responsive genes even without stimuli, and intestinal inflammation in BIRC3‑deficient models was attenuated by small‑molecule inhibition of RIPK1 or caspases.

This gene has not yet been associated with relevant phenotypes in OMIM or ClinGen (last accessed 30 July 2026).; to: PMID:42335979 (2026) reported the identification of rare and damaging BIRC3 variants in 14 patients from 10 unrelated families with Crohn's disease (CD) diagnosed between infancy and adulthood. They carried 8 distinct BIRC3 variants — 5 heterozygous missense/ nonsense variants (p.H312Y - recurrent in 2 families and de novo in the index patient), p.T35A, p.P266R, p.C557X, p.D530H) causing pediatric- to adult-onset CD (age range <1 to 31 years), and 3 homozygous nonsense/ frameshift variants (p.Y522X, p.C588Y, p.X605Rext*10) in sibling pairs from consanguineous families, causing infantile-onset CD.

Functional studies showed that BIRC3 (cIAP2) deficiency impairs RIPK1 ubiquitylation, causing RIPK1 autophosphorylation, resulting in increased epithelial cell death. Knock‑in cIAP2 (H312Y/+) mice and ciap1‑deficient zebrafish developed or exacerbated colitis, transcriptome analysis of mice organoids and zebrafish showed that BIRC3 deficiency led to inappropriate sustained activation of TNF‑responsive genes even without stimuli, and intestinal inflammation in BIRC3‑deficient models was attenuated by small‑molecule inhibition of RIPK1 or caspases.

This gene has not yet been associated with relevant phenotypes in OMIM or ClinGen (last accessed 30 July 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 BIRC3 Achchuthan Shanmugasundram Classified gene: BIRC3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 BIRC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there is sufficient evidence available (seven unrelated families with monoallelic variants and three unrelated families with biallelic variants) for the association of of BIRC3 with inflammatory bowel disease. Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 BIRC3 Achchuthan Shanmugasundram Gene: birc3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.43 BIRC3 Achchuthan Shanmugasundram Phenotypes for gene: BIRC3 were changed from Inflammatory bowel disease; IBD; Crohn's disease to inborn error of immunity, MONDO:0003778; Crohn disease, MONDO:0005011
Primary immunodeficiency or monogenic inflammatory bowel disease v9.42 BIRC3 Achchuthan Shanmugasundram Publications for gene: BIRC3 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 BIRC3 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: BIRC3.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 BIRC3 Achchuthan Shanmugasundram reviewed gene: BIRC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 42335979; Phenotypes: inborn error of immunity, MONDO:0003778, Crohn disease, MONDO:0005011; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 MYB Achchuthan Shanmugasundram Classified gene: MYB as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 MYB Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients with heterozygous SNVs in Myb gene and functional evidence including mouse models available from peer-reviewed published scientific literature in support of the association of Myb with combined immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 MYB Achchuthan Shanmugasundram Gene: myb has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.40 MYB Achchuthan Shanmugasundram Phenotypes for gene: MYB were changed from Evans syndrome; Neutropenia; Autoimmune cytopenias; B cell lymphopenia to combined immunodeficiency, MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v9.39 MYB Achchuthan Shanmugasundram Mode of inheritance for gene: MYB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.38 MYB Achchuthan Shanmugasundram Publications for gene: MYB were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 MYB Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: MYB.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 MYB Achchuthan Shanmugasundram reviewed gene: MYB: Rating: GREEN; Mode of pathogenicity: None; Publications: 20130238, 27577878, 29654210, 36168523; Phenotypes: combined immunodeficiency, MONDO:0015131; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v5.7 TBK1 Luke Stuart reviewed gene: TBK1: Rating: RED; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 21447600, 33892047, 28984711; Phenotypes: low tension glaucoma (MONDO:0006837), juvenile open angle glaucoma (MONDO:0020367); Mode of inheritance: Other
Early onset or syndromic epilepsy v9.55 SP9 Achchuthan Shanmugasundram Classified gene: SP9 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.55 SP9 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available (three unrelated cases) for the association of SP9 to epilepsy, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v9.55 SP9 Achchuthan Shanmugasundram Gene: sp9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.85 SP9 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v10.85 SP9 Achchuthan Shanmugasundram Classified gene: SP9 as Amber List (moderate evidence)
Intellectual disability v10.85 SP9 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available (four unrelated cases) for the association of SP9 to developmental delay/ intellectual disability, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v10.85 SP9 Achchuthan Shanmugasundram Gene: sp9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.85 SP9 Achchuthan Shanmugasundram Classified gene: SP9 as Amber List (moderate evidence)
Intellectual disability v10.85 SP9 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available (four unrelated cases) for the association of SP9 to developmental delay/ intellectual disability, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v10.85 SP9 Achchuthan Shanmugasundram Gene: sp9 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.54 SP9 Achchuthan Shanmugasundram gene: SP9 was added
gene: SP9 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_26_promote_green tags were added to gene: SP9.
Mode of inheritance for gene: SP9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SP9 were set to 38288683
Phenotypes for gene: SP9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: SP9 was set to GREEN
Added comment: PMID:38288683 (2024) reported the identification of four different de novo heterozygous variants in SP9 as a cause of a novel form of interneuronopathy in five unrelated cases.

Individual 1 is a male fetus with moderate ventriculomegaly and multiple periventricular and deep gray matter cystic/ischemic lesions (choroid plexus and periventricular cysts, bilateral GE and caudate signal abnormalities with restricted diffusion) identified on late third‑trimester MRI, leading to termination of pregnancy at 35 weeks’ gestation. This individual was identified with c.1133A>C (p.Glu378Ala) variant in SP9 gene.

The age of other four individuals ranged from six months to six years and all had neurodevelopmental disorder of variable severity. A first clinical phenotype consisting of moderate intellectual disability (ID) associated with an ASD with or without epilepsy was present in individuals 2 and 5 who carried frameshift SP9 variants, p.c.1216del (p.His406ThrfsTer2) and c.1192_1207dup (p.Arg403Glnfs∗15), respectively. A second, more severe clinical phenotype consisting of epileptic encephalopathy was present in individuals 3 and 4, who both carried a missense variant c.1133A>G (p.Glu378Gly) involving the same glutamate residue in position 378 as individual 1.

In summary, (global) developmental delay and/or intellectual disability was reported in four patients, while epilepsy was reported in three.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet reported in OMIM (last accessed 30 July 2026).
Sources: Literature
Intellectual disability v10.84 SP9 Achchuthan Shanmugasundram gene: SP9 was added
gene: SP9 was added to Intellectual disability. Sources: Literature
Q3_26_promote_green tags were added to gene: SP9.
Mode of inheritance for gene: SP9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SP9 were set to 38288683
Phenotypes for gene: SP9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: SP9 was set to GREEN
Added comment: PMID:38288683 (2024) reported the identification of four different de novo heterozygous variants in SP9 as a cause of a novel form of interneuronopathy in five unrelated cases.

Individual 1 is a male fetus with moderate ventriculomegaly and multiple periventricular and deep gray matter cystic/ischemic lesions (choroid plexus and periventricular cysts, bilateral GE and caudate signal abnormalities with restricted diffusion) identified on late third‑trimester MRI, leading to termination of pregnancy at 35 weeks’ gestation. This individual was identified with c.1133A>C (p.Glu378Ala) variant in SP9 gene.

The age of other four individuals ranged from six months to six years and all had neurodevelopmental disorder of variable severity. A first clinical phenotype consisting of moderate intellectual disability (ID) associated with an ASD with or without epilepsy was present in individuals 2 and 5 who carried frameshift SP9 variants, p.c.1216del (p.His406ThrfsTer2) and c.1192_1207dup (p.Arg403Glnfs∗15), respectively. A second, more severe clinical phenotype consisting of epileptic encephalopathy was present in individuals 3 and 4, who both carried a missense variant c.1133A>G (p.Glu378Gly) involving the same glutamate residue in position 378 as individual 1.

In summary, (global) developmental delay and/or intellectual disability was reported in four patients, while epilepsy was reported in three.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet reported in OMIM (last accessed 30 July 2026).
Sources: Literature
Structural eye disease v5.7 OPTN Luke Stuart reviewed gene: OPTN: Rating: RED; Mode of pathogenicity: None; Publications: 34536459, 16043855, 33892047, 15326130, 38872230, 37530275; Phenotypes: Glaucoma 1, open angle, E, OMIM:137760, {Glaucoma, normal tension, susceptibility to}, OMIM:606657; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dystonia, chorea or related movement disorder, childhood onset v8.12 OGDH Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (five unrelated families) for the association of biallelic OGDH variants with global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (four unrelated families) for the association of biallelic OGDH variants with childhood-onset dystonia. Hence, this gene can be promoted to green rating in the next GMS update.
Dystonia, chorea or related movement disorder, childhood onset v8.12 OGDH Achchuthan Shanmugasundram Entity copied from Intellectual disability v10.83
Dystonia, chorea or related movement disorder, childhood onset v8.12 OGDH Achchuthan Shanmugasundram gene: OGDH was added
gene: OGDH was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Expert Review Amber,Literature
Q3_26_promote_green tags were added to gene: OGDH.
Mode of inheritance for gene: OGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDH were set to 32383294; 36520152
Phenotypes for gene: OGDH were set to Oxoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759
Intellectual disability v10.83 OGDH Achchuthan Shanmugasundram Classified gene: OGDH as Amber List (moderate evidence)
Intellectual disability v10.83 OGDH Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (five unrelated families) for the association of biallelic OGDH variants with global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v10.83 OGDH Achchuthan Shanmugasundram Gene: ogdh has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.82 OGDH Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: OGDH.
Intellectual disability v10.82 OGDH Achchuthan Shanmugasundram gene: OGDH was added
gene: OGDH was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDH were set to 32383294; 36520152
Phenotypes for gene: OGDH were set to Oxoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759
Review for gene: OGDH was set to GREEN
Added comment: PMID:32383294 (2021) reported two siblings identified with a homozygous missense variant c.959A>G (p.Asn320Ser) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure.

PMID:36520152 (2023) reported four unrelated individuals with 3 different homozygous OGDH variants and presenting with a neurodevelopmental disorder characterised by global developmental delay, movement disorder, and metabolic abnormalities.

There are six patients from five families reported in total with four different homozygous variants in OGDH gene and with a neurodevelopmental disorder with metabolic and movement abnormalities. Age of onset of the disease ranged from 6 weeks of age to 3 years old. All described individuals shared the clinical features of global developmental delay, hypotonia, metabolic acidosis and increased serum lactate. Additional shared clinical features included dystonia (5/6), microcephaly (3/4), abnormal nasal bridge morphology (3/6), hyperammonemia (3/6), hyperglutaminemia (3/3 who were tested), and elevated alpha-ketoglutarate in the urine (2/4 who were tested).

This gene has been associated with relevant phenotype in OMIM (MIM #203740, last accessed 29 July 2026) and in Gene2Phenotype (with 'moderate' rating on the DD panel). This gene has also been associated with mitochondrial disease (MONDO:0044970) with 'Definitive' rating by the Mitochondrial Diseases GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009318).
Sources: Literature
Mitochondrial disorders v10.18 OGDH Achchuthan Shanmugasundram Classified gene: OGDH as Amber List (moderate evidence)
Mitochondrial disorders v10.18 OGDH Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with biallelic OGDH variants and functional evidence available in support of the association. OGDH is part of a multicomplex enzyme involved in the Kreb cycle and this gene is associated with mitochondrial disease with 'Definitive' rating by Mitochondrial Diseases GCEP in ClinGen.

However, expert review has been requested from NHSE as the recommendation for promotion to green rating has previously been disagreed by the NHSE suggesting that this gene is not associated with primary mitochondrial disease.
Mitochondrial disorders v10.18 OGDH Achchuthan Shanmugasundram Gene: ogdh has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v10.17 OGDH Achchuthan Shanmugasundram Tag Q3_26_expert_review tag was added to gene: OGDH.
Tag Q3_26_promote_green tag was added to gene: OGDH.
Mitochondrial disorders v10.17 OGDH Achchuthan Shanmugasundram Phenotypes for gene: OGDH were changed from Alpha-ketoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759 to Oxoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759
Mitochondrial disorders v10.16 OGDH Achchuthan Shanmugasundram reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 32383294, 36520152; Phenotypes: Oxoglutarate dehydrogenase deficiency, OMIM:203740, oxoglutaricaciduria, MONDO:0008759; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.81 NPTN Achchuthan Shanmugasundram Classified gene: NPTN as Amber List (moderate evidence)
Intellectual disability v10.81 NPTN Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (8 unrelated patients) for the association of monoallelic NPTN variants with mild-severe intellectual disability/ developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v10.81 NPTN Achchuthan Shanmugasundram Gene: nptn has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.80 NPTN Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: NPTN.
Intellectual disability v10.80 NPTN Achchuthan Shanmugasundram gene: NPTN was added
gene: NPTN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NPTN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTN were set to 42387534
Phenotypes for gene: NPTN were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: NPTN was set to GREEN
Added comment: PMID:42387534 (2026) reported a cohort of eight individuals with seven different heterozygous variants in NPTN, seven of which are of de novo origin. The patients presented with an overlapping, but unspecific phenotype, All eight individuals presented with developmental delay (DD) and/or intellectual disability (ID) ranging from mild to severe (severe in four, moderate in two and mild in two). Seven individuals were diagnosed with autism spectrum disorder and six were reported with subtle dysmorphic facial features.

Four individuals had variants (three variants) affecting the two hNp isoforms, hNp55 and hNp65 and other four variants affect only the neuron-specific hNp65 isoform. It was observed that the severity of ID/DD and other clinical findings correlate with the impact on both hNp isoforms (severe) or only on the hNp65 isoform (mild/moderate).

Functional evidence from human cell line, cultured primary rodent neurons, and in vivo in Drosophila melanogaster showed that the missense variants are inefficiently expressed and inefficiently support PMCA levels, resulting in failed cytosolic Ca(2+) regulation. Haploinsuffient Nptn+/− mice expressed reduced amounts of both Np and PMCA. In a social behavior test, Nptn+/− mice displayed loss of preference for a novel mouse representing an endophenotype analog to social deficits that characterize autism.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 29 July 2026).
Sources: Literature
Retinal disorders v9.10 PRDM13 Eleanor Williams commented on gene: PRDM13
Intellectual disability v10.79 GTPBP1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: GTPBP1.
Tag Q3_26_promote_green tag was added to gene: GTPBP1.
Differences in sex development v4.22 TBX6 Luke Stuart gene: TBX6 was added
gene: TBX6 was added to Differences in sex development. Sources: Literature
Mode of inheritance for gene: TBX6 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TBX6 were set to 36049007; 23954021
Phenotypes for gene: TBX6 were set to Mullerian aplasia (MONDO:0019128); Mayer-Rokitansky-Kuster-Hauser syndrome (MONDO:0017771)
Review for gene: TBX6 was set to AMBER
Added comment: Ma et al. 2022 (PMID 36049007): 622 Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) probands, 16 rare heterozygous TBX6 variants, all single alleles with no biallelic or in-trans genotypes. Several variants were supported by in vitro functional evidence (splice/frameshift c.423G>A p.Leu141Leu, c.839+5G>A; reduced protein c.422T>C p.Leu141Pro, c.745G>A Val249Met; reduced transactivation c.10C>T, c.400G>A; mislocalisation c.356G>A p.Arg119His plus one prior canonical splice variant c.621+1G>A. Against diagnostic-grade rating: segregation studies showed multiple non manifesting female carriers suggesting incomplete penetrance (unaffected carrier mother, c.10C>T p.Pro4Ser; two of three carrier sisters with normal uterus, c.356G>A p.Arg119His), penetrance of the Müllerian phenotype is low among TBX6 LoF and 16p11.2-deletion carriers generally, and no second in-trans allele was found. The authors propose an digenic/oligogenic model in which TBX6 confers risk of urogenital phenotypes. No family showed penetrant monogenic segregation.

Sandbacka et al. 2013 (PMID 23954021): ascertained series of 112 mullerain aplasia (MA) patients vs 200 controls. Heterozygous whole-gene TBX6/16p11.2 deletion in 5/112, three of whom also had skeletal/vertebral findings; this recurrent deletion is found in unaffected and non-reproductive-phenotype carriers elsewhere, indicating low penetrance of this phenotype. Splice variant c.622-2A>T in two patients was predicted LoF but RT-PCR was inconclusive. Two recurrent missense variants (p.Gly162Ser, p.Arg272Gln) were enriched in affecteds but also frequent in controls. No segregation data was shown. Two patients were homozygous for both recurrent TBX6 missense variants (p.Gly162Ser, p.Arg272Gln): one also carried a heterozygous missense variant in LHX1 (p.Pro312His), another a candidate gene for MRKHS, the other an 11q13.4 deletion. A third patient, heterozygous for both TBX6 recurrent missense variants, also carried LHX1 p.Pro312His.

Overall: both studies support risk association and complex/oligogenic inheritance, but neither provides segregation, completed functional validation of a penetrant effect, or convincing evidence free of confounding co-occurring variants. The evidence does not meet criteria for penetrant monogenic disease reportable in a diagnostic setting; amber rating is appropriate. This phenotype regarding TBX6 is not cited in OMIM.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v8.11 GTPBP1 Achchuthan Shanmugasundram Classified gene: GTPBP1 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v8.11 GTPBP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated families reported with biallelic GTPBP1 variants and with movement disorder. Hence, this gene should be rated amber with the current evidence.
Dystonia, chorea or related movement disorder, childhood onset v8.11 GTPBP1 Achchuthan Shanmugasundram Gene: gtpbp1 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v8.10 GTPBP1 Achchuthan Shanmugasundram gene: GTPBP1 was added
gene: GTPBP1 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP1 were set to 38118446
Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MONDO:0975745
Review for gene: GTPBP1 was set to AMBER
Added comment: PMID:38118446 (2024) reported a cohort of 20 individuals from 16 families with distinct neurodevelopmental disorders (NDDs) and syndromic facial features and identified with biallelic variants in either GTPBP1 or GTPBP2 genes. Of these, four patients from three unrelated families were identified with homozygous variants in GTPBP1 gene. Two families have different NMD-predicted nonsense variants and the third has a missense variant, and all are absent from gnomad v4.1.1.

The shared clinical features of the syndrome include microcephaly, severe/ profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. In addition, abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome.

Abnormal hand movements and tremor of hands and jaws were reported in 2 patients from 2 families with GTPBP1 variants.

This gene has been associated with relevant phenotypes in OMIM (MIM #620888, last accessed 29 July 2026) and in Gene2Phenotype ('moderate' rating on the DD panel).
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v9.20 GTPBP1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated families reported with biallelic GTPBP1 variants and with cerebellar atrophy. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are two unrelated families reported with biallelic GTPBP1 variants and with cerebellar atrophy. Hence, this gene should be rated amber with the current evidence.
Ataxia and cerebellar anomalies - childhood onset v9.20 GTPBP1 Achchuthan Shanmugasundram Classified gene: GTPBP1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v9.20 GTPBP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated families reported with biallelic GTPBP1 variants and with cerebellar atrophy. Hence, this gene should be rated amber with the current evidence.
Ataxia and cerebellar anomalies - childhood onset v9.20 GTPBP1 Achchuthan Shanmugasundram Gene: gtpbp1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v9.19 GTPBP1 Achchuthan Shanmugasundram gene: GTPBP1 was added
gene: GTPBP1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP1 were set to 38118446
Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MONDO:0975745
Review for gene: GTPBP1 was set to AMBER
Added comment: PMID:38118446 (2024) reported a cohort of 20 individuals from 16 families with distinct neurodevelopmental disorders (NDDs) and syndromic facial features and identified with biallelic variants in either GTPBP1 or GTPBP2 genes. Of these, four patients from three unrelated families were identified with homozygous variants in GTPBP1 gene. Two families have different NMD-predicted nonsense variants and the third has a missense variant, and all are absent from gnomad v4.1.1.

The shared clinical features of the syndrome include microcephaly, severe/ profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. In addition, abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome.

Cerebellar atrophy was reported in 3 patients from 2 families with GTPBP1 variants.

This gene has been associated with relevant phenotypes in OMIM (MIM #620888, last accessed 29 July 2026) and in Gene2Phenotype ('moderate' rating on the DD panel).
Sources: Literature
Early onset or syndromic epilepsy v9.53 GTPBP1 Achchuthan Shanmugasundram Classified gene: GTPBP1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.53 GTPBP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients reported with biallelic GTPBP1 variants and with epilepsy. Hence, this gene should be rated amber with the current evidence.
Early onset or syndromic epilepsy v9.53 GTPBP1 Achchuthan Shanmugasundram Gene: gtpbp1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.52 GTPBP1 Achchuthan Shanmugasundram gene: GTPBP1 was added
gene: GTPBP1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP1 were set to 38118446
Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MONDO:0975745
Review for gene: GTPBP1 was set to AMBER
Added comment: PMID:38118446 (2024) reported a cohort of 20 individuals from 16 families with distinct neurodevelopmental disorders (NDDs) and syndromic facial features and identified with biallelic variants in either GTPBP1 or GTPBP2 genes. Of these, four patients from three unrelated families were identified with homozygous variants in GTPBP1 gene. Two families have different NMD-predicted nonsense variants and the third has a missense variant, and all are absent from gnomad v4.1.1.

The shared clinical features of the syndrome include microcephaly, severe/ profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. In addition, abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome.

Epilepsy was reported in 2 patients from 2 families with GTPBP1 variants.

This gene has been associated with relevant phenotypes in OMIM (MIM #620888, last accessed 29 July 2026) and in Gene2Phenotype ('moderate' rating on the DD panel).
Sources: Literature
Intellectual disability v10.79 GTPBP1 Achchuthan Shanmugasundram Classified gene: GTPBP1 as Amber List (moderate evidence)
Intellectual disability v10.79 GTPBP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with biallelic GTPBP1 variants and with neurodevelopmental impairment. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v10.79 GTPBP1 Achchuthan Shanmugasundram Gene: gtpbp1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.78 GTPBP1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: GTPBP1.
Intellectual disability v10.78 GTPBP1 Achchuthan Shanmugasundram gene: GTPBP1 was added
gene: GTPBP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP1 were set to 38118446
Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MONDO:0975745
Review for gene: GTPBP1 was set to GREEN
Added comment: PMID:38118446 (2024) reported a cohort of 20 individuals from 16 families with distinct neurodevelopmental disorders (NDDs) and syndromic facial features and identified with biallelic variants in either GTPBP1 or GTPBP2 genes. Of these, four patients from three unrelated families were identified with homozygous variants in GTPBP1 gene. Two families have different NMD-predicted nonsense variants and the third has a missense variant, and all are absent from gnomad v4.1.1.

The shared clinical features of the syndrome include microcephaly, severe/ profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. In addition, abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome.

Severe/ profound neurodevelopmental impairment was present in 3 patients from 3 families with GTPBP1 variants.

This gene has been associated with relevant phenotypes in OMIM (MIM #620888, last accessed 29 July 2026) and in Gene2Phenotype ('moderate' rating on the DD panel).
Sources: Literature
Intestinal failure or congenital diarrhoea v3.17 DUOX2 Ida Ertmanska edited their review of gene: DUOX2: Changed phenotypes to: inflammatory bowel disease, MONDO:0005265
Intestinal failure or congenital diarrhoea v3.17 DUOX2 Ida Ertmanska Phenotypes for gene: DUOX2 were changed from inflammatory bowel disease; MONDO:0005265 to inflammatory bowel disease, MONDO:0005265
Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 DUOX2 Ida Ertmanska Tag watchlist_moi tag was added to gene: DUOX2.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 DUOX2 Ida Ertmanska commented on gene: DUOX2: MONOALLELIC CASES:
PMID: 26301257 Hayes et al., 2015
2 male probands, diagnosed with IBD / ulcerative colitis at 4.7 and 4.3 yrs. Het for DUOX2 missense variants.

Adding watchlist_moi tag to monitor for heterozygous case reports.
Intestinal failure or congenital diarrhoea v3.16 DUOX2 Ida Ertmanska Tag Q3_26_promote_green was removed from gene: DUOX2.
Intestinal failure or congenital diarrhoea v3.16 DUOX2 Ida Ertmanska Classified gene: DUOX2 as Red List (low evidence)
Intestinal failure or congenital diarrhoea v3.16 DUOX2 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic DUOX2 variants and very early onset IBD, including bloody diarrhea. However, these cases do not meet the Test Directory criterion of neonatal onset (first 28 days of life). Hence, the gene should remain Red on this panel.
Intestinal failure or congenital diarrhoea v3.16 DUOX2 Ida Ertmanska Gene: duox2 has been classified as Red List (Low Evidence).
Intestinal failure or congenital diarrhoea v3.15 DUOX2 Ida Ertmanska edited their review of gene: DUOX2: Added comment: PMID: 26301257 - 2 male probands, diagnosed with IBD / ulcerative colitis at 4.7 and 4.3 yrs. Het for DUOX2 missense variants.
PMID: 28683258 - Male proband comp het for NM_014080.4:c.1825G>A; p.P609S and NM_014080.4:c.857G>A; R286H in DUOX2. He developed pancolitis with bloody diarrhea at the age of 3.
PMID: 35429653 - report of a 1-year-old boy diagnosed with VEO-IBD after presenting with bloody diarrhea. He had pancolitis and an extensive small intestinal ulcerative lesion at age 4 years.
PMID: 38075699 - Female proband diagnosed with IBD at 1 month. The infant was asymptomatic with no intestinal symptoms such as abdominal pain, rectal bleeding, perianal disease, diarrhea, or intestinal obstruction. The only sign of intestinal involvement was increased inflammatory markers.; Changed rating: RED
Intestinal failure or congenital diarrhoea v3.15 DUOX2 Ida Ertmanska Classified gene: DUOX2 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v3.15 DUOX2 Ida Ertmanska Gene: duox2 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v3.14 DUOX2 Ida Ertmanska gene: DUOX2 was added
gene: DUOX2 was added to Intestinal failure or congenital diarrhoea. Sources: Literature
Q3_26_promote_green tags were added to gene: DUOX2.
Mode of inheritance for gene: DUOX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DUOX2 were set to 26301257; 28683258; 35429653; 38075699
Phenotypes for gene: DUOX2 were set to inflammatory bowel disease; MONDO:0005265
Review for gene: DUOX2 was set to GREEN
Added comment: Literature review by Boaz Palterer (University of Florence), copied from Primary immunodeficiency or monogenic inflammatory bowel disease:
DUOX2 encodes Dual Oxidase 2, an H2O2-producing NADPH oxidase primarily expressed at the apical membranes of enterocytes, where it plays a critical role in maintaining intestinal microbial homeostasis and innate immune defense. While biallelic variants in DUOX2 are classically associated with congenital hypothyroidism (Thyroid dyshormonogenesis 6; OMIM 607200), a distinct phenotype linking DUOX2 deficiency to Inborn Errors of Immunity (IEI) and very early-onset inflammatory bowel disease (VEO-IBD) has been reported in several case reports.

The initial association was reported when inactivating missense variants in DUOX2 were identified in VEO-IBD patients, resulting in significantly reduced reactive oxygen species (ROS) production by intestinal epithelial cells and defective host resistance to enteric pathogens like Campylobacter jejuni (Hayes et al., 2015). More recently, the phenotypic spectrum has been expanded to include monogenic neonatal-onset IBD. Patients with compound heterozygous DUOX2 variants have presented with severe intestinal inflammation and colon stenosis shortly after birth, displaying significantly decreased catalytic activity without concurrent clinical hypothyroidism (Finocchi et al, Kyodo et al. Crawford et al. ).

Hayes described 2 patient with heterozgous DUOX2 VUS and VEOIBD
https://pmc.ncbi.nlm.nih.gov/articles/PMC4539615/

Finocchi et al described 1 month old with VEOIBD with compound heterozygous VUS in DUOX2
https://pubmed.ncbi.nlm.nih.gov/38075699/

Kyodo et al. described 1 year old with VEOIBD with compound heterozygous VUS in DUOX2
https://pubmed.ncbi.nlm.nih.gov/35429653/

Crawford et al, additional case report: 5-year-old male with compound heterozygous VUS in DUOX2
https://rupress.org/jhi/article/1/CIS2025/CIS2025abstract.49/277486/Biallelic-DUOX2-Variants-and-the-Link-to-Very
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 DUOX2 Ida Ertmanska Phenotypes for gene: DUOX2 were changed from Inflammatory bowel disease; IBD; VEOIBD to inflammatory bowel disease; MONDO:0005265; IBD; VEOIBD
Primary immunodeficiency or monogenic inflammatory bowel disease v9.36 DUOX2 Ida Ertmanska Publications for gene: DUOX2 were set to 38075699; 26301257; 35429653
Primary immunodeficiency or monogenic inflammatory bowel disease v9.35 DUOX2 Ida Ertmanska Mode of inheritance for gene: DUOX2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.34 DUOX2 Ida Ertmanska Classified gene: DUOX2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.34 DUOX2 Ida Ertmanska Gene: duox2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.33 DUOX2 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: DUOX2.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.33 DUOX2 Ida Ertmanska reviewed gene: DUOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26301257, 28683258, 35429653, 38075699; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v4.24 OSMR Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 8 unrelated individuals reported in literature with biallelic OSMR variants and syndromic atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. Hence, this gene can be promoted to Green at the next GMS update.; to: Comment on mode of inheritance: There are 8 unrelated individuals reported in literature with biallelic OSMR variants and syndromic atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. Hence, the mode of inheritance should be updated from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted (associated with dominant Amyloidosis) to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Rare genetic inflammatory skin disorders v4.24 OSMR Ida Ertmanska commented on gene: OSMR: Comment on mode of inheritance: There are 8 unrelated individuals reported in literature with biallelic OSMR variants and syndromic atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. Hence, this gene can be promoted to Green at the next GMS update.
Rare genetic inflammatory skin disorders v4.24 OSMR Ida Ertmanska Phenotypes for gene: OSMR were changed from AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1, OMIM:105250 to AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1, OMIM:105250; atopic eczema, MONDO:0004980
Rare genetic inflammatory skin disorders v4.23 OSMR Ida Ertmanska Publications for gene: OSMR were set to 18179886
Rare genetic inflammatory skin disorders v4.22 OSMR Ida Ertmanska Tag Q3_26_MOI tag was added to gene: OSMR.
Rare genetic inflammatory skin disorders v4.22 OSMR Ida Ertmanska reviewed gene: OSMR: Rating: GREEN; Mode of pathogenicity: None; Publications: 41783139, 42221229; Phenotypes: atopic eczema, MONDO:0004980; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.33 OSMR Ida Ertmanska edited their review of gene: OSMR: Changed phenotypes to: atopic eczema, MONDO:0004980
Primary immunodeficiency or monogenic inflammatory bowel disease v9.33 OSMR Ida Ertmanska Phenotypes for gene: OSMR were changed from Atopic dermatitis; eosinophilia; elevated IgE to Atopic dermatitis; eosinophilia; elevated IgE; atopic eczema, MONDO:0004980
Primary immunodeficiency or monogenic inflammatory bowel disease v9.32 OSMR Ida Ertmanska Publications for gene: OSMR were set to 42221229
Primary immunodeficiency or monogenic inflammatory bowel disease v9.31 OSMR Ida Ertmanska Classified gene: OSMR as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.31 OSMR Ida Ertmanska Added comment: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic OSMR variants and syndromic atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. Hence, this gene can be promoted to Green at the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.31 OSMR Ida Ertmanska Gene: osmr has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.30 OSMR Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: OSMR.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.30 OSMR Ida Ertmanska changed review comment from: PMID: 41783139 Andersen et al., 2026
Study described a patient (57-year-old man of Caucasian Danish descent) presenting with elevated IgE levels, atopic eczema, chronic pulmonary aspergillosis, frequent secondary staphylococcal skin infections and pustules, and bone fractures. Blood profiling showed elevated IgE-expressing plasmablasts and peripheral T follicular helper cells and atypical memory B cells. WGS showed that P1 was homozygous for a missense variant c.1307T>A, p.Val436Asp.
A significant reduction in OSMR surface expression on patient dermal fibroblasts compared to controls was found by flow cytometry. A skin biopsy showed perivascular inflammation with lymphocytes and eosinophils but no amyloid deposits.

PMID: 42221229 Samra et al., 2026
Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE.

OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected.
In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4.; to: PMID: 41783139 Andersen et al., 2026
Study described a patient (57-year-old man of Caucasian Danish descent) presenting with elevated IgE levels, atopic eczema, chronic pulmonary aspergillosis, frequent secondary staphylococcal skin infections and pustules, and bone fractures. Blood profiling showed elevated IgE-expressing plasmablasts and peripheral T follicular helper cells and atypical memory B cells. WGS showed that P1 was homozygous for a missense variant c.1307T>A, p.Val436Asp.
A significant reduction in OSMR surface expression on patient dermal fibroblasts compared to controls was found by flow cytometry. A skin biopsy showed perivascular inflammation with lymphocytes and eosinophils but no amyloid deposits.

PMID: 42221229 Samra et al., 2026
Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE.
OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected.
In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4.

OSMR is associated with AD Amyloidosis, primary localized cutaneous, 1, OMIM:105250; no recessive association added in OMIM, G2P, or ClinGen (accessed 29th July 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.30 OSM Ida Ertmanska gene: OSM was added
gene: OSM was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: OSM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSM were set to 39847438
Phenotypes for gene: OSM were set to bone marrow disorder, MONDO:0003225
Review for gene: OSM was set to RED
Added comment: PMID: 39847438 Garrigue et al., 2025
Report of 3 female sibs from a consanguineous family presenting with inherited severe bone marrow failure syndromes (IBMFS) characterized by profound anemia, thrombocytopenia, and neutropenia. Patients showed no susceptibility to infection, nor any bone or psychomotor defects. WES detected a homozygous OSM: c.507_508insG; Arg170AlafsTer124 variant in P1 and P2, confirmed het in unaffected parents.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 OSMR Ida Ertmanska edited their review of gene: OSMR: Changed publications to: 41783139, 42221229
Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 OSMR Ida Ertmanska changed review comment from: PMID: 42221229 Samra et al., 2026
Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE.

OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected.
In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4.; to: PMID: 41783139 Andersen et al., 2026
Study described a patient (57-year-old man of Caucasian Danish descent) presenting with elevated IgE levels, atopic eczema, chronic pulmonary aspergillosis, frequent secondary staphylococcal skin infections and pustules, and bone fractures. Blood profiling showed elevated IgE-expressing plasmablasts and peripheral T follicular helper cells and atypical memory B cells. WGS showed that P1 was homozygous for a missense variant c.1307T>A, p.Val436Asp.
A significant reduction in OSMR surface expression on patient dermal fibroblasts compared to controls was found by flow cytometry. A skin biopsy showed perivascular inflammation with lymphocytes and eosinophils but no amyloid deposits.

PMID: 42221229 Samra et al., 2026
Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE.

OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected.
In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 OSMR Ida Ertmanska changed review comment from: PMID: 42221229 Samra et al., 2026
Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE.
OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected.; to: PMID: 42221229 Samra et al., 2026
Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE.

OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected.
In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 OSMR Ida Ertmanska reviewed gene: OSMR: Rating: GREEN; Mode of pathogenicity: None; Publications: 42221229; Phenotypes: Amyloidosis, primary localized cutaneous, 1, OMIM:105250, atopic eczema, MONDO:0004980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 SEPT6 Ida Ertmanska Tag watchlist tag was added to gene: SEPT6.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 SEPT6 Ida Ertmanska Phenotypes for gene: SEPT6 were changed from Congenital neutropenia; B cell deficiency; T cell lymphopenia; Abnormal newborn screening for SCID; Hypersegmented neutrophils; Myelodysplasia; Decreased circulating B cells; Leukopenia to severe congenital neutropenia, MONDO:0018542; Immunodeficiency, HP:0002721; Congenital neutropenia; B cell deficiency; T cell lymphopenia; Abnormal newborn screening for SCID; Hypersegmented neutrophils; Myelodysplasia; Decreased circulating B cells; Leukopenia
Primary immunodeficiency or monogenic inflammatory bowel disease v9.28 SEPT6 Ida Ertmanska Classified gene: SEPT6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.28 SEPT6 Ida Ertmanska Added comment: Comment on list classification: To date, there are 2 unrelated male individuals reported in literature with hemizygous variants in SEPT6 and severe congenital neutropenia. Hence, this gene should remain Amber with the current evidence. A 'watchlist' tag was added in anticipation of more case reports.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.28 SEPT6 Ida Ertmanska Gene: sept6 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 SEPT6 Ida Ertmanska edited their review of gene: SEPT6: Added comment: PMID: 42088107 Gunderman et al., 2026
2 male sibs with severe nonsyndromic congenital neutropenia, absent circulating B cells, marrow mature myeloid, and rare plasma cell accumulation, as well as tetraploidy, with disease reversal following myeloablative HSCT. Older sibling had T-cell receptor excision circles (TRECs) of 9 copies (normal >20), while younger brother had 0 copies. No infectious symptoms were present. WGS detected a hemizygous SEPTIN6 (NM_145799.4) c.1282T>A; p.*428Kext*9 variant in both brothers (het in the unaffected mother) - diagnosed with X-linked SEPTIN6-related immunodeficiency.

PMID: 34677878 Renella et al., 2023
Report of a Caucasian male proband, presented with severe neutropenia associated with dysmyelopoiesis and tetraploidy as a newborn. The absolute neutrophil count (ANC) was 0.5 G/L at birth, subsequently 0-0.2 G/L. At age 1 year he underwent an allogeneic HLA-DQ-mismatched unrelated HSCT. WGS detected a hemizygous c.1282T>C, p.*428Glnext*9 variant in SEPT6. Second somatic SEPT6 variant was detected in cis: c.43C>T, p.Arg15* (14% of reads).

This gene is not yet associated with a disease entity in OMIM, ClinGen, or G2P (accessed 29th July 2026).; Changed rating: AMBER; Changed publications to: 42088107, 34677878; Changed phenotypes to: severe congenital neutropenia, MONDO:0018542, Immunodeficiency, HP:0002721; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v9.51 ATP2B2 Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: ATP2B2.
Tag Q3_26_promote_green tag was added to gene: ATP2B2.
Dystonia, chorea or related movement disorder, childhood onset v8.9 ATP2B2 Achchuthan Shanmugasundram Classified gene: ATP2B2 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v8.9 ATP2B2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients reported with other movement disorders including dystonia (in one patient). As this is a small subset of total patients reported with neurological/ neurodevelopmental phenotypes (14 patients from 13 unrelated families), this gene should be rated amber with current evidence. However, 'watchlist' tag has been added to review the gene in light of any new evidence.
Dystonia, chorea or related movement disorder, childhood onset v8.9 ATP2B2 Achchuthan Shanmugasundram Gene: atp2b2 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v8.8 ATP2B2 Achchuthan Shanmugasundram gene: ATP2B2 was added
gene: ATP2B2 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
watchlist tags were added to gene: ATP2B2.
Mode of inheritance for gene: ATP2B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP2B2 were set to 29655659; 37675773; 39367743
Phenotypes for gene: ATP2B2 were set to neurodevelopmental disorder, MONDO:0700092; cerebellar ataxia, MONDO:0000437; epilepsy, MONDO:0005027; intellectual disability,MONDO:0001071; inherited dystonia, MONDO:0044807
Mode of pathogenicity for gene: ATP2B2 was set to Other
Review for gene: ATP2B2 was set to AMBER
Added comment: PMID:29655659 (2018) reported a novel missense variant (p.Val1143Phe) in PMCA2/ ATP2B2 gene in a 27-year old male patient presenting with congenital cerebellar ataxia but with no overt signs of deafness. This patient presented with delayed motor development requesting clinical attention at age 5 months, had dysmetria and intentional tremor at age 3 and showed obvious gait ataxia at age 4. The patient was also reported with impaired speech and moderate intellectual disability. Brain MRI studies revealed global cerebellar atrophy without cortical and brainstem involvement.

PMID:37675773 (2023) reported seven individuals with rare, predicted deleterious heterozygous ATP2B2 variants, including 5 missense substitutions and 2 frameshift variants. De novo status was confirmed for six of these variants. All individuals displayed a spectrum of neurological abnormalities ranging from ataxia (5/7 patients) and other movement disorders including dystonic features (3 patients) to complex neurodevelopmental manifestations with intellectual disability, global developmental delay, and seizures (6 patients). Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects.

PMID:39367743 (2025) reported six previously unreported patients from five unrelated families with four different missense variants and one frameshift variant (p.Leu1089GlnfsTer60). All missense variants were confirmed de novo, while the frameshift variant is paternally inherited in one and of unknown inheritance in other. These patients shared phenotypic features with the previously described patients including developmental delay and intellectual disability (all six patients), cognitive disturbances, autistic features epilepsy (3 patients), ataxia (3 patients) and other movement disorders (one patient). Striking cerebellar atrophy was observed in one affected individual.

In total, there are 13 patients (from 12 families) with (global) developmental delay/ intellectual disability, 9 patients (from eight families) with seizures, 9 patients (from nine families) with ataxia and 4 patients (from four families) reported with other movement disorders including dystonia.

This gene has been associated with hearing loss in both OMIM (MIM #619804, last accessed 29 July 2026) and ClinGen ('Definitive' rating for autosomal dominant nonsyndromic hearing loss (MONDO:0019587) by Hearing Loss GCEP), but not with the neurological/ neurodevelopmental phenotypes in these resources.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v9.18 ATP2B2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with ataxia (nine families), this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with childhood-onset ataxia (nine families), this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - childhood onset v9.18 ATP2B2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with intellectual disability (nine families), this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with ataxia (nine families), this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v9.51 ATP2B2 Achchuthan Shanmugasundram Classified gene: ATP2B2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.51 ATP2B2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with seizures (eight families), this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v9.51 ATP2B2 Achchuthan Shanmugasundram Gene: atp2b2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.50 ATP2B2 Achchuthan Shanmugasundram Phenotypes for gene: ATP2B2 were changed from Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities to neurodevelopmental disorder, MONDO:0700092; cerebellar ataxia, MONDO:0000437; epilepsy, MONDO:0005027; intellectual disability,MONDO:0001071; inherited dystonia, MONDO:0044807
Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 SEPT6 Ida Ertmanska commented on gene: SEPT6
Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 SEPT6 Ida Ertmanska Tag new-gene-name tag was added to gene: SEPT6.
Early onset or syndromic epilepsy v9.49 ATP2B2 Achchuthan Shanmugasundram Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743
Early onset or syndromic epilepsy v9.48 ATP2B2 Achchuthan Shanmugasundram Mode of pathogenicity for gene: ATP2B2 was changed from None to Other
Intellectual disability v10.77 USP34 Benito Banos Pinero gene: USP34 was added
gene: USP34 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: USP34 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: USP34 were set to 42315110; 39050773; 28573701
Review for gene: USP34 was set to GREEN
Added comment: PMID: 42315110 described 6 patients with truncating variants, five of them confirmed de novo with a phenotype of global developmental delay, craniofacial dysmorphism, marked speech impairment, variable autism spectrum disorder, and distal limb anomalies.
USP34 is intolerant to Lof variants (pLI=1). No phenotypes associated with this gene in OMIM.
USP34 is part of the 2p15p16.1 region, copy number losses in this region cause a neurodevelopmental disorder characterised by developmental delay/intellectual disability, ASD, microcephaly, short stature, dysmorphic features and multiple congenital anomalies (HI score 3 in clingen). The authors suggest that the phenotype associated with isolated loss of USP34 overlaps substantially with that reported in 2p15p16.1 microdeletion syndrome, while suggesting that some features seen in larger deletions may reflect the contribution of additional genes within the interval.
PMID: 39050773 reports a 9 year old boy wit mild intellectual disability and dysmorphic features with a de novo 50kb 2p15 copy number loss including only USP34 and XPO1.
PMID: 28573701reports two additional cases with deletions of only USP34 and XPO1 in a prenatal case with brain anomalies and dysmorphic features. The second case with dysmorphic features, behavioural issues, rhizomelic shortening of the limbs and agenesis of the corpus callosum, deletion was de novo.
Sources: Literature
Early onset or syndromic epilepsy v9.47 ATP2B2 Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.46 ATP2B2 Achchuthan Shanmugasundram reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29655659, 37675773, 39367743; Phenotypes: neurodevelopmental disorder, MONDO:0700092, cerebellar ataxia, MONDO:0000437, epilepsy, MONDO:0005027, intellectual disability,MONDO:0001071, inherited dystonia, MONDO:0044807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 HCK Ida Ertmanska Phenotypes for gene: HCK were changed from Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease to Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296 autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204
Primary immunodeficiency or monogenic inflammatory bowel disease v9.26 HCK Ida Ertmanska Mode of inheritance for gene: HCK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v9.18 ATP2B2 Achchuthan Shanmugasundram Classified gene: ATP2B2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v9.18 ATP2B2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with intellectual disability (nine families), this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - childhood onset v9.18 ATP2B2 Achchuthan Shanmugasundram Gene: atp2b2 has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v4.22 HCK Ida Ertmanska Classified gene: HCK as Amber List (moderate evidence)
Rare genetic inflammatory skin disorders v4.22 HCK Ida Ertmanska Added comment: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Cutaneous vasculitis was the most consistent feature, present in all 5 probands. Hence, this gene can be promoted to Green at the next GMS update.
Rare genetic inflammatory skin disorders v4.22 HCK Ida Ertmanska Gene: hck has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v9.17 ATP2B2 Achchuthan Shanmugasundram Phenotypes for gene: ATP2B2 were changed from Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities to neurodevelopmental disorder, MONDO:0700092; cerebellar ataxia, MONDO:0000437; epilepsy, MONDO:0005027; intellectual disability,MONDO:0001071; inherited dystonia, MONDO:0044807
Ataxia and cerebellar anomalies - childhood onset v9.16 ATP2B2 Achchuthan Shanmugasundram Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743
Ataxia and cerebellar anomalies - childhood onset v9.15 ATP2B2 Achchuthan Shanmugasundram Mode of pathogenicity for gene: ATP2B2 was changed from None to Other
Ataxia and cerebellar anomalies - childhood onset v9.14 ATP2B2 Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - childhood onset v9.13 ATP2B2 Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: ATP2B2.
Tag Q3_26_promote_green tag was added to gene: ATP2B2.
Intellectual disability v10.77 ATP2B2 Achchuthan Shanmugasundram Classified gene: ATP2B2 as Amber List (moderate evidence)
Intellectual disability v10.77 ATP2B2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with intellectual disability (12 families), this gene can be promoted to green rating in the next GMS update.
Intellectual disability v10.77 ATP2B2 Achchuthan Shanmugasundram Gene: atp2b2 has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v4.21 HCK Ida Ertmanska gene: HCK was added
gene: HCK was added to Rare genetic inflammatory skin disorders. Sources: Literature
Q3_26_promote_green tags were added to gene: HCK.
Mode of inheritance for gene: HCK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HCK were set to 34536415; 41382121; 41920357; doi.org/10.11648/j.ajp.20190504.15
Phenotypes for gene: HCK were set to Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296; autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204
Review for gene: HCK was set to GREEN
Added comment: PMID: 41920357 Price-Kuehne et al., 2026
Family A - female proband with systemic vasculitis due to a de novo heterozygous variant in HCK c.1545 C > A, p.(Tyr515Ter) - exome seq; she was treated with allogeneic haematopoietic stem cell transplantation. She subsequently developed epistaxis, haemolacria and blood-stained stools leading to iron-deficiency anaemia requiring transfusion. From 18 months of age, she developed chronic cough and haemoptysis; chest CT scan demonstrated enlarged hilar lymph nodes and bilateral inflammatory changes and pulmonary haemorrhage.

Family B - male proband with a cutaneous-limited phenotype (purpuric rash, predominantly affecting the limbs, starting at 4hrs after birth); Skin biopsy showed leukocytoclastic vasculitis; WES identified a novel HCK missense variant c.1565A > T, (p.Tyr522Phe). Proband's father is het for the same HCK variant, and also had neonatal-onset leukocytoclastic vasculitis, now healthy.

PMID: 41382121 Berdeli, Ismayilova, & Gürbüz 2025
Report of a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and suspected recurrent lower respiratory tract infections since age 1.5 years. No cutaneous manifestations were observed, but elevated acute-phase reactants and pulmonary findings were noted. WES revealed a heterozygous splice variant c.1016-5T>C in HCK.

PMID: 34536415 Kanderova et al. 2022
Described a single patient with an autoinflammatory phenotype characterized by early-onset cutaneous vasculitis and lung inflammation leading to fibrosis.
A de novo truncating mutation (p.Tyr515*) in the HCK leading to the loss of the C-terminal inhibitory tyrosine Tyr522 was identified.
Variant pathogenicity was confirmed ex vivo in primary cells and in vitro in transduced cell lines.

doi: 10.11648/j.ajp.20190504.15 Bronz et al., 2019
Family with suspected Finkelstein-Seidlmayer disease (benign small-vessel leukocytoclastic vasculitis) - affected mother and her 3 sons. History of red-to-purpuric skin lesions with neonatal onset, no systemic involvement. WES detected a heterozygous HCK variant c.1555G>T; p.Glu519* in all 4 affected individuals. Variant not present in gnomAD v4.1.1.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v9.13 ATP2B2 Achchuthan Shanmugasundram reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29655659, 37675773, 39367743; Phenotypes: neurodevelopmental disorder, MONDO:0700092, cerebellar ataxia, MONDO:0000437, epilepsy, MONDO:0005027, intellectual disability,MONDO:0001071, inherited dystonia, MONDO:0044807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 HCK Ida Ertmanska changed review comment from: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals. Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.; to: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals (PMIDs: 34536415, 41382121) . Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.
Intellectual disability v10.76 ATP2B2 Achchuthan Shanmugasundram Phenotypes for gene: ATP2B2 were changed from Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities to neurodevelopmental disorder, MONDO:0700092; cerebellar ataxia, MONDO:0000437; epilepsy, MONDO:0005027; intellectual disability,MONDO:0001071; inherited dystonia, MONDO:0044807
Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 HCK Ida Ertmanska changed review comment from: Comment on list classification: There are now 4 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals. Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.; to: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals. Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.
Intellectual disability v10.75 ATP2B2 Achchuthan Shanmugasundram Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743
Intellectual disability v10.74 ATP2B2 Achchuthan Shanmugasundram Mode of pathogenicity for gene: ATP2B2 was changed from None to Other
Pulmonary Fibrosis, Familial v1.16 HCK Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: HCK.
Autoinflammatory disorders v3.13 HCK Ida Ertmanska Publications for gene: HCK were set to 34536415; 41382121; 41920357
Intellectual disability v10.73 ATP2B2 Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v3.12 HCK Ida Ertmanska edited their review of gene: HCK: Changed publications to: 34536415, 41382121, 41920357, doi.org/10.11648/j.ajp.20190504.15
Autoinflammatory disorders v3.12 HCK Ida Ertmanska changed review comment from: Comment on list classification: There are now 4 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Hence, this gene can be promoted to Green at the next GMS update.; to: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Hence, this gene can be promoted to Green at the next GMS update.
Intellectual disability v10.72 ATP2B2 Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v10.71 ATP2B2 Achchuthan Shanmugasundram Tag Q3_26_expert_review was removed from gene: ATP2B2.
Tag Q3_26_promote_green tag was added to gene: ATP2B2.
Intellectual disability v10.71 ATP2B2 Achchuthan Shanmugasundram Tag Q3_26_expert_review tag was added to gene: ATP2B2.
Tag Q3_26_NHS_review tag was added to gene: ATP2B2.
Pulmonary Fibrosis, Familial v1.16 HCK Ida Ertmanska Phenotypes for gene: HCK were changed from Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease to Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296; autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204
Pulmonary Fibrosis, Familial v1.15 HCK Ida Ertmanska Publications for gene: HCK were set to 34536415; 41382121; 41920357; https://doi.org/10.11648/j.ajp.20190504.15
Intellectual disability v10.71 ATP2B2 Achchuthan Shanmugasundram reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29655659, 37675773, 39367743; Phenotypes: neurodevelopmental disorder, MONDO:0700092, cerebellar ataxia, MONDO:0000437, epilepsy, MONDO:0005027, intellectual disability,MONDO:0001071, inherited dystonia, MONDO:0044807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pulmonary Fibrosis, Familial v1.14 HCK Ida Ertmanska Publications for gene: HCK were set to 34536415
Pulmonary Fibrosis, Familial v1.13 HCK Ida Ertmanska Mode of inheritance for gene: HCK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pulmonary Fibrosis, Familial v1.12 HCK Ida Ertmanska Classified gene: HCK as Amber List (moderate evidence)
Pulmonary Fibrosis, Familial v1.12 HCK Ida Ertmanska Added comment: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Pulmonary fibrosis findings were noted in 3 unrelated cases. Hence, this gene can be promoted to Green at the next GMS update.
Pulmonary Fibrosis, Familial v1.12 HCK Ida Ertmanska Gene: hck has been classified as Amber List (Moderate Evidence).
Pulmonary Fibrosis, Familial v1.11 HCK Ida Ertmanska reviewed gene: HCK: Rating: GREEN; Mode of pathogenicity: None; Publications: 41382121, 41920357; Phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296, autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v3.12 HCK Ida Ertmanska Classified gene: HCK as Amber List (moderate evidence)
Autoinflammatory disorders v3.12 HCK Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Hence, this gene can be promoted to Green at the next GMS update.
Autoinflammatory disorders v3.12 HCK Ida Ertmanska Gene: hck has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 HCK Ida Ertmanska Classified gene: HCK as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 HCK Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals. Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 HCK Ida Ertmanska Gene: hck has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v3.11 HCK Ida Ertmanska gene: HCK was added
gene: HCK was added to Autoinflammatory disorders. Sources: Literature
Q3_26_promote_green tags were added to gene: HCK.
Mode of inheritance for gene: HCK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HCK were set to 34536415; 41382121; 41920357
Phenotypes for gene: HCK were set to Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296; autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204
Review for gene: HCK was set to GREEN
Added comment: PMID: 41920357 Price-Kuehne et al., 2026
Family A - female proband with systemic vasculitis due to a de novo heterozygous variant in HCK c.1545 C > A, p.(Tyr515Ter) - exome seq; she was treated with allogeneic haematopoietic stem cell transplantation. She subsequently developed epistaxis, haemolacria and blood-stained stools leading to iron-deficiency anaemia requiring transfusion. From 18 months of age, she developed chronic cough and haemoptysis; chest CT scan demonstrated enlarged hilar lymph nodes and bilateral inflammatory changes and pulmonary haemorrhage.

Family B - male proband with a cutaneous-limited phenotype (purpuric rash, predominantly affecting the limbs, starting at 4hrs after birth); Skin biopsy showed leukocytoclastic vasculitis; WES identified a novel HCK missense variant c.1565A > T, (p.Tyr522Phe). Proband's father is het for the same HCK variant, and also had neonatal-onset leukocytoclastic vasculitis, now healthy.

PMID: 41382121 Berdeli, Ismayilova, & Gürbüz 2025
Report of a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and suspected recurrent lower respiratory tract infections since age 1.5 years. No cutaneous manifestations were observed, but elevated acute-phase reactants and pulmonary findings were noted. WES revealed a heterozygous splice variant c.1016-5T>C in HCK.

PMID: 34536415 Kanderova et al. 2022
Described a single patient with an autoinflammatory phenotype characterized by early-onset cutaneous vasculitis and lung inflammation leading to fibrosis.
A de novo truncating mutation (p.Tyr515*) in the HCK leading to the loss of the C-terminal inhibitory tyrosine Tyr522 was identified.
Variant pathogenicity was confirmed ex vivo in primary cells and in vitro in transduced cell lines.

doi: 10.11648/j.ajp.20190504.15 Bronz et al., 2019
Family with suspected Finkelstein-Seidlmayer disease (benign small-vessel leukocytoclastic vasculitis) - affected mother and her 3 sons. History of red-to-purpuric skin lesions with neonatal onset, no systemic involvement. WES detected a heterozygous HCK variant c.1555G>T; p.Glu519* in all 4 affected individuals. Variant not present in gnomAD v4.1.1.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.24 HCK Ida Ertmanska changed review comment from: PMID: 41382121 Berdeli, Ismayilova, & Gürbüz 2025
Report of a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and suspected recurrent lower respiratory tract infections since age 1.5 years. No cutaneous manifestations were observed, but elevated acute-phase reactants and pulmonary findings were noted. WES revealed a heterozygous splice variant c.1016-5T>C in HCK.

PMID: 41920357 Price-Kuehne et al., 2026
Family A - female proband with systemic vasculitis due to a de novo heterozygous variant in HCK c.1545 C > A, p.(Tyr515Ter) - exome seq; she was treated with allogeneic haematopoietic stem cell transplantation. She subsequently developed epistaxis, haemolacria and blood-stained stools leading to iron-deficiency anaemia requiring transfusion. From 18 months of age, she developed chronic cough and haemoptysis; chest CT scan demonstrated enlarged hilar lymph nodes and bilateral inflammatory changes and pulmonary haemorrhage.

Family B - male proband with a cutaneous-limited phenotype (purpuric rash, predominantly affecting the limbs, starting at 4hrs after birth); Skin biopsy showed leukocytoclastic vasculitis; WES identified a novel HCK missense variant c.1565A > T, (p.Tyr522Phe). Proband's father is het for the same HCK variant, and also had neonatal-onset leukocytoclastic vasculitis, now healthy.; to: PMID: 41920357 Price-Kuehne et al., 2026
Family A - female proband with systemic vasculitis due to a de novo heterozygous variant in HCK c.1545 C > A, p.(Tyr515Ter) - exome seq; she was treated with allogeneic haematopoietic stem cell transplantation. She subsequently developed epistaxis, haemolacria and blood-stained stools leading to iron-deficiency anaemia requiring transfusion. From 18 months of age, she developed chronic cough and haemoptysis; chest CT scan demonstrated enlarged hilar lymph nodes and bilateral inflammatory changes and pulmonary haemorrhage.

Family B - male proband with a cutaneous-limited phenotype (purpuric rash, predominantly affecting the limbs, starting at 4hrs after birth); Skin biopsy showed leukocytoclastic vasculitis; WES identified a novel HCK missense variant c.1565A > T, (p.Tyr522Phe). Proband's father is het for the same HCK variant, and also had neonatal-onset leukocytoclastic vasculitis, now healthy.

PMID: 41382121 Berdeli, Ismayilova, & Gürbüz 2025
Report of a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and suspected recurrent lower respiratory tract infections since age 1.5 years. No cutaneous manifestations were observed, but elevated acute-phase reactants and pulmonary findings were noted. WES revealed a heterozygous splice variant c.1016-5T>C in HCK.

doi: 10.11648/j.ajp.20190504.15 Bronz et al., 2019
Family with suspected Finkelstein-Seidlmayer disease (benign small-vessel leukocytoclastic vasculitis) - affected mother and her 3 sons. History of red-to-purpuric skin lesions with neonatal onset, no systemic involvement. WES detected a heterozygous HCK variant c.1555G>T; p.Glu519* in all 4 affected individuals. Variant not present in gnomAD v4.1.1.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.24 HCK Ida Ertmanska reviewed gene: HCK: Rating: AMBER; Mode of pathogenicity: None; Publications: 41382121, 41920357; Phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296, autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia, adult onset v9.3 OGDH Achchuthan Shanmugasundram Classified gene: OGDH as Amber List (moderate evidence)
Hereditary ataxia, adult onset v9.3 OGDH Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases reported with monoallelic OGDH variants and with cerebellar ataxia. There is also some functional evidence available from Drosophila showing a role for reported variants in late-onset locomotion defects.

Hence, this gene can be rated amber with 'watchlist' tag added to review gene rating in light of any new evidence.
Hereditary ataxia, adult onset v9.3 OGDH Achchuthan Shanmugasundram Gene: ogdh has been classified as Amber List (Moderate Evidence).
Hereditary ataxia, adult onset v9.2 OGDH Achchuthan Shanmugasundram Tag watchlist tag was added to gene: OGDH.
Hereditary ataxia, adult onset v9.2 OGDH Achchuthan Shanmugasundram Deleted their comment
Hereditary ataxia, adult onset v9.2 OGDH Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: AMBER
Optic neuropathy v6.44 OGDH Achchuthan Shanmugasundram Entity copied from Hereditary neuropathy or pain disorder v8.30
Optic neuropathy v6.44 OGDH Achchuthan Shanmugasundram gene: OGDH was added
gene: OGDH was added to Optic neuropathy. Sources: Expert Review Red,Expert list
Mode of inheritance for gene: OGDH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OGDH were set to 42266417
Phenotypes for gene: OGDH were set to peripheral neuropathy, MONDO:0005244; cerebellar ataxia, MONDO:0000437; hereditary optic atrophy, MONDO:0043878
Mode of pathogenicity for gene: OGDH was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Hereditary ataxia, adult onset v9.2 OGDH Achchuthan Shanmugasundram Entity copied from Hereditary neuropathy or pain disorder v8.30
Hereditary ataxia, adult onset v9.2 OGDH Achchuthan Shanmugasundram gene: OGDH was added
gene: OGDH was added to Hereditary ataxia with onset in adulthood. Sources: Expert Review Red,Expert list
Mode of inheritance for gene: OGDH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OGDH were set to 42266417
Phenotypes for gene: OGDH were set to peripheral neuropathy, MONDO:0005244; cerebellar ataxia, MONDO:0000437; hereditary optic atrophy, MONDO:0043878
Mode of pathogenicity for gene: OGDH was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Hereditary neuropathy or pain disorder v8.30 OGDH Achchuthan Shanmugasundram Classified gene: OGDH as Red List (low evidence)
Hereditary neuropathy or pain disorder v8.30 OGDH Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated red with current evidence.
Hereditary neuropathy or pain disorder v8.30 OGDH Achchuthan Shanmugasundram Gene: ogdh has been classified as Red List (Low Evidence).
Hereditary neuropathy or pain disorder v8.29 OGDH Achchuthan Shanmugasundram Phenotypes for gene: OGDH were changed from peripheral neuropathy; cerebellar ataxia; optic neuropathy to peripheral neuropathy, MONDO:0005244; cerebellar ataxia, MONDO:0000437; hereditary optic atrophy, MONDO:0043878
Hereditary neuropathy or pain disorder v8.28 OGDH Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: RED
Hereditary neuropathy or pain disorder v8.28 OGDH Achchuthan Shanmugasundram reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 42266417; Phenotypes: peripheral neuropathy, MONDO:0005244, cerebellar ataxia, MONDO:0000437, hereditary optic atrophy, MONDO:0043878; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary spastic paraplegia, childhood onset v9.6 APOPT1 Achchuthan Shanmugasundram Classified gene: APOPT1 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v9.6 APOPT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic APOPT1 variants with childhood-onset spasticity (at least five unrelated cases). Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Hereditary spastic paraplegia, childhood onset v9.6 APOPT1 Achchuthan Shanmugasundram Gene: apopt1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v9.5 APOPT1 Achchuthan Shanmugasundram commented on gene: APOPT1: The 'new-gene-name' tag has been added as the official HGNC gene symbol for APOPT1 is COA8.
Hereditary spastic paraplegia, childhood onset v9.5 APOPT1 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: APOPT1.
Hereditary spastic paraplegia, childhood onset v9.5 APOPT1 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: APOPT1.
Hereditary spastic paraplegia, childhood onset v9.5 APOPT1 Achchuthan Shanmugasundram gene: APOPT1 was added
gene: APOPT1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: APOPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APOPT1 were set to 25175347
Phenotypes for gene: APOPT1 were set to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; mitochondrial complex IV deficiency, nuclear type 17, MONDO:0033652; hereditary spastic paraplegia, MONDO:0019064
Review for gene: APOPT1 was set to GREEN
Added comment: PMID:25175347 (2014) reported a total of six patients from five unrelated families identified with biallelic variants in APOPT1 gene. There were six different variants identified from these patients and all but one were homozygous, and one individual had compound heterozygous variants. Across the six individuals with APOPT1 mutations, all show infantile or childhood‑onset mitochondrial disease with profound COX deficiency, a characteristic cavitating leukodystrophy on MRI predominantly affecting posterior cerebral white matter and corpus callosum, and evidence of peripheral neuropathy. Clinically, they range from acute neurometabolic decompensation with spastic tetraparesis, seizures and cognitive impairment to much milder phenotypes with preserved cognition, but all have a chronic, long‑surviving course with stabilization or partial recovery of motor function despite persistent structural white matter changes. All patients except one of the two siblings presented with spastic tetraparesis with onset in early childhood (2-5 years of age).

This gene has been associated with relevant phenotype in OMIM (MIM #619061, last accessed 28 July 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and in ClinGen (associated with 'definitive' rating for mitochondrial disease (MONDO:0044970) by Mitochondrial Diseases GCEP - https://search.clinicalgenome.org/CCID:004493).
Sources: Literature
Hereditary neuropathy or pain disorder v8.28 APOPT1 Achchuthan Shanmugasundram Classified gene: APOPT1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v8.28 APOPT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients with biallelic APOPT1 variants and presenting with neuropathy. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Hereditary neuropathy or pain disorder v8.28 APOPT1 Achchuthan Shanmugasundram Gene: apopt1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v8.27 APOPT1 Achchuthan Shanmugasundram commented on gene: APOPT1: The 'new-gene-name' tag has been added as the official HGNC gene symbol for APOPT1 is COA8.
Hereditary neuropathy or pain disorder v8.27 APOPT1 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: APOPT1.
Hereditary neuropathy or pain disorder v8.27 APOPT1 Achchuthan Shanmugasundram Phenotypes for gene: APOPT1 were changed from 25175347; 38098475Encephalopathic episodes; loss of developmental milestones; seizures; spasticity; cavitating leukodystrophy to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; mitochondrial complex IV deficiency, nuclear type 17, MONDO:0033652; peripheral neuropathy, MONDO:0005244
Hereditary neuropathy or pain disorder v8.26 APOPT1 Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: APOPT1.
Tag Q3_26_promote_green tag was added to gene: APOPT1.
Hereditary neuropathy or pain disorder v8.26 APOPT1 Achchuthan Shanmugasundram changed review comment from: PMID:25175347 (2014) reported a total of six patients from five unrelated families identified with biallelic variants in APOPT1 gene. There were six different variants identified from these patients and all but one were homozygous, and one individual had compound heterozygous variants. The clinical features of all six patients varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. Peripheral neuropathy was reported in two patients; to: PMID:25175347 (2014) reported a total of six patients from five unrelated families identified with biallelic variants in APOPT1 gene. There were six different variants identified from these patients and all but one were homozygous, and one individual had compound heterozygous variants. Across the six individuals with APOPT1 mutations, all show infantile or childhood‑onset mitochondrial disease with profound COX deficiency, a characteristic cavitating leukodystrophy on MRI predominantly affecting posterior cerebral white matter and corpus callosum, and evidence of peripheral neuropathy. Clinically, they range from acute neurometabolic decompensation with spastic tetraparesis, seizures and cognitive impairment to much milder phenotypes with preserved cognition, but all have a chronic, long‑surviving course with stabilization or partial recovery of motor function despite persistent structural white matter changes. Sensorimotor polyneuropathy was reported in three of the six patients.

PMID:38098475 (2023) reported two female siblings from an Italian family with mitochondrial myopathy. Patient 1 presented with generalised epilepsy and retinitis pigmentosa at 10 years of age. She had cramps and myalgia after exercise and bilateral hearing loss since early adulthood. Last neurological examination (52 years of age) showed bilateral ptosis, muscle weakness, peripheral neuropathy, mild dysarthria, dysphonia and cognitive impairment. Muscle biopsy had shown the presence of ragged-red fibers. Patient 2 presented with fatigability, myalgia, and hearing loss. Neurological examination showed ptosis and muscle weakness. Muscle biopsy displayed a diffuse reduction of COX activity staining and ragged-red fibers. Both sisters presented secondary amenorrhea. A novel homozygous variant in COA8 (APOPT1) was identified via whole-exome sequencing in the probands (c.170_173dupGACC, p.Pro59fs).

This gene has been associated with relevant phenotype in OMIM (MIM #619061, last accessed 28 July 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and in ClinGen (associated with 'definitive' rating for mitochondrial disease (MONDO:0044970) by Mitochondrial Diseases GCEP - https://search.clinicalgenome.org/CCID:004493).
Intellectual disability v10.71 GPN2 Luke Stuart gene: GPN2 was added
gene: GPN2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPN2 were set to 42392036
Phenotypes for gene: GPN2 were set to Intellectual disability (MONDO:0001071)
Review for gene: GPN2 was set to RED
Added comment: Smith et al. 2026 (PMID 42392036) investigated a Perrault syndrome cohort via exome sequencing. All individuals had congenital or perinatal bilateral sensorineural hearing loss (SNHL) and primary ovarian insufficiency (POI; females). Neurological findings were reported in 2/3 families (F2 and F3) in which affected individuals harbored the same homozygous missense GPN2 variant, c.664A>G p.(Asn222Asp).

Family F3: a single proband presented with mild intellectual disability, in addition to profound SNHL and primary amenorrhea; cerebellar atrophy was noted on brain MRI.
Family F2: two affected sisters presented with bilateral profound SNHL, POI, and cerebellar ataxia; brain MRI also showed cerebellar atrophy. No intellectual disability was noted.
No additional putative variants were identified in any genes linked to Perrault syndrome, SNHL, or POI.

N.B. Haplotype analysis in the affected members of families F2 and F3 revealed a shared homozygous region of 662 kb encompassing the GPN2 locus, indicative of a shared ancestor. Consequently, the neurological findings derive from a single recurrent variant on a potentially shared genetic background.

Suggested rating: Red (low evidence); a single proband with mild intellectual disability is reported; no animal model or other functional evidence currently supports pathogenicity or validates a disease mechanism linking GPN2 to intellectual disability.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v9.13 GPN2 Luke Stuart gene: GPN2 was added
gene: GPN2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPN2 were set to 42392036
Phenotypes for gene: GPN2 were set to Cerebellar ataxia (MONDO:0000437)
Review for gene: GPN2 was set to RED
Added comment: Smith et al. 2026 (PMID 42392036) investigated a Perrault syndrome cohort via exome sequencing.
Family F2 comprised two affected sisters with bilateral profound sensorineural hearing loss (SNHL), primary ovarian insufficiency (POI), and cerebellar ataxia. Brain MRI revealed cerebellar atrophy in both. Both were homozygous for GPN2 c.664A>G p.Asn222Asp.
Family F3 comprised a single affected proband presenting with profound SNHL, primary amenorrhea, and mild intellectual disability, also homozygous for GPN2 c.664A>G p.Asn222Asp. Cerebellar atrophy was noted on brain MRI. N.B. Haplotype analysis in the affected members of families F2 and F3 revealed a shared homozygous region of 662 kb encompassing the GPN2 locus, indicative of a shared ancestor.
Age at onset for affected probands is unknown, however age at last examination was in the 2nd or 3rd decade (supplemental data), suggesting early onset.
Before this study, no Mendelian disease had been attributed to GPN2 or its paralogs, GPN1 and GPN3; no animal model exists supporting pathogenicity or delineating the potential mechanism.

Conclusion: A single variant with potential founder effect is implicated in ataxia (n= 2 probands from 1 family)/ cerebellar atrophy (n=3 probands from 2 families); age of onset for the probands cited is unknown.
Suggest red rating (low evidence).
Sources: Literature
Fetal anomalies v7.33 DHCR7 Arina Puzriakova Publications for gene: DHCR7 were set to 31840946
Fetal hydrops v1.108 DHCR7 Arina Puzriakova Classified gene: DHCR7 as Green List (high evidence)
Fetal hydrops v1.108 DHCR7 Arina Puzriakova Gene: dhcr7 has been classified as Green List (High Evidence).
Fetal hydrops v1.107 TAZ Arina Puzriakova Classified gene: TAZ as Green List (high evidence)
Fetal hydrops v1.107 TAZ Arina Puzriakova Gene: taz has been classified as Green List (High Evidence).
Fetal hydrops v1.106 RYR1 Arina Puzriakova Classified gene: RYR1 as Green List (high evidence)
Fetal hydrops v1.106 RYR1 Arina Puzriakova Gene: ryr1 has been classified as Green List (High Evidence).
Fetal hydrops v1.105 PTH1R Arina Puzriakova Classified gene: PTH1R as Green List (high evidence)
Fetal hydrops v1.105 PTH1R Arina Puzriakova Gene: pth1r has been classified as Green List (High Evidence).
Fetal hydrops v1.104 PHGDH Arina Puzriakova Classified gene: PHGDH as Green List (high evidence)
Fetal hydrops v1.104 PHGDH Arina Puzriakova Gene: phgdh has been classified as Green List (High Evidence).
Fetal hydrops v1.103 MVK Arina Puzriakova Classified gene: MVK as Green List (high evidence)
Fetal hydrops v1.103 MVK Arina Puzriakova Gene: mvk has been classified as Green List (High Evidence).
Fetal hydrops v1.102 MUSK Arina Puzriakova Classified gene: MUSK as Green List (high evidence)
Fetal hydrops v1.102 MUSK Arina Puzriakova Gene: musk has been classified as Green List (High Evidence).
Fetal hydrops v1.101 KLHL40 Arina Puzriakova Classified gene: KLHL40 as Amber List (moderate evidence)
Fetal hydrops v1.101 KLHL40 Arina Puzriakova Gene: klhl40 has been classified as Amber List (Moderate Evidence).
Fetal hydrops v1.100 DOK7 Arina Puzriakova Classified gene: DOK7 as Amber List (moderate evidence)
Fetal hydrops v1.100 DOK7 Arina Puzriakova Gene: dok7 has been classified as Amber List (Moderate Evidence).
Fetal hydrops v1.99 COL2A1 Arina Puzriakova Classified gene: COL2A1 as Green List (high evidence)
Fetal hydrops v1.99 COL2A1 Arina Puzriakova Gene: col2a1 has been classified as Green List (High Evidence).
Fetal hydrops v1.98 CHRNG Arina Puzriakova Classified gene: CHRNG as Green List (high evidence)
Fetal hydrops v1.98 CHRNG Arina Puzriakova Gene: chrng has been classified as Green List (High Evidence).
Fetal hydrops v1.97 CHRND Arina Puzriakova Classified gene: CHRND as Green List (high evidence)
Fetal hydrops v1.97 CHRND Arina Puzriakova Gene: chrnd has been classified as Green List (High Evidence).
Fetal hydrops v1.96 CHRNA1 Arina Puzriakova Classified gene: CHRNA1 as Green List (high evidence)
Fetal hydrops v1.96 CHRNA1 Arina Puzriakova Gene: chrna1 has been classified as Green List (High Evidence).
Hereditary neuropathy or pain disorder v8.26 EGR2 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 2 unrelated families reported in literature with biallelic EGR2 missense variants, as well as 1 case reported with a homozygous deletion of the EGR2 enhancer, where probands presented with a congenital neuropathy. The more common dominant CMT disease is caused by variants within three-ZNF DNA-binding domains of EGR2; the recessive variants are the only ones reported outside of that domain (PMID: 40262821 Cavalcanti et al., 2025). EGR2 knockout mouse models support the association, as they display disrupted hindbrain segmentation and development (phenotype not seen in het knockouts). Hence, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are 2 unrelated families reported in literature with biallelic EGR2 missense variants, as well as 1 case reported with a homozygous deletion of the EGR2 enhancer, where probands presented with a congenital neuropathy. The more common dominant CMT disease is caused by variants within three-ZNF DNA-binding domains of EGR2; the recessive variants are the only ones reported outside of that domain (PMID: 40262821 Cavalcanti et al., 2025). EGR2 knockout mouse models support the association, as mutant mice display disrupted hindbrain segmentation and development (phenotype not seen in het knockouts). Hence, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v8.26 EGR2 Ida Ertmanska commented on gene: EGR2: Comment on mode of inheritance: There are 2 unrelated families reported in literature with biallelic EGR2 missense variants, as well as 1 case reported with a homozygous deletion of the EGR2 enhancer, where probands presented with a congenital neuropathy. The more common dominant CMT disease is caused by variants within three-ZNF DNA-binding domains of EGR2; the recessive variants are the only ones reported outside of that domain (PMID: 40262821 Cavalcanti et al., 2025). EGR2 knockout mouse models support the association, as they display disrupted hindbrain segmentation and development (phenotype not seen in het knockouts). Hence, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v8.26 EGR2 Ida Ertmanska Phenotypes for gene: EGR2 were changed from Charcot-Marie-Tooth, Type 1; Charcot Marie Tooth disease, type 1D, 607678 to Charcot-Marie-Tooth disease, type 1D, MIM:607678; Dejerine-Sottas disease, MIM:145900; Hypomyelinating neuropathy, congenital, 1, MIM:605253
Hereditary neuropathy or pain disorder v8.25 EGR2 Ida Ertmanska Publications for gene: EGR2 were set to 9537424
Hereditary neuropathy or pain disorder v8.24 EGR2 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: EGR2.
Hereditary neuropathy or pain disorder v8.24 EGR2 Ida Ertmanska changed review comment from: PMID: 32896048 Lupo et al., 2020
3 affected sibs with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. All 3 individuals were homozygous for the c.791C>T; p.P264L variant in EGR2. Variant not present in gnomAD v4. Consanguineous parents (confirmed het) and wt/het sibs unaffected.

PMID: 9537424 Warner et al., 1998
Study included 94 neuropathy patients. Only exons of EGR2 were sequenced. Family HOU336 - 3 male sibs affected by a congenital hypomyelinating neuropathy (CHN). They were floppy at birth, had delayed motor milestones, and walked with crutches at the time of report. The c.803T>A, p.Ile268Asn homozygous missense variant was detected in EGR2 - not reported in gnomAD v4.
Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage - phenotype not seen in heterozygous +/- mice.

Reports of dominant EGR2-related CMT PMIDs: 9537424; 11523566; 17717711; 20513111; 26204789; 27159987; 30481651; 30843326; 31852952 - copied from ClinGen summary.

The association between EGR2 and Semidominant Charcot-Marie-Tooth disease was classified as Definitive (Charcot-Marie-Tooth GCEP, Nov 2021). The gene is associated with AD Charcot-Marie-Tooth disease, type 1D, MIM:607678, AD,AR Dejerine-Sottas disease, MIM:145900, and AD,AR Hypomyelinating neuropathy, congenital, 1, MIM:605253 in OMIM; EGR2-related neuropathy, congenital hypomyelinating (biallelic_autosomal) is ranked Definitive in Gene2Phenotype (accessed 28th July 2026).; to: PMID: 32896048 Lupo et al., 2020
3 affected sibs with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. All 3 individuals were homozygous for the c.791C>T; p.P264L variant in EGR2. Variant not present in gnomAD v4. Consanguineous parents (confirmed het) and wt/het sibs unaffected.

PMID: 9537424 Warner et al., 1998
Study included 94 neuropathy patients. Only exons of EGR2 were sequenced. Family HOU336 - 3 male sibs affected by a congenital hypomyelinating neuropathy (CHN). They were floppy at birth, had delayed motor milestones, and walked with crutches at the time of report. The c.803T>A, p.Ile268Asn homozygous missense variant was detected in EGR2 - not reported in gnomAD v4.
Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage - phenotype not seen in heterozygous +/- mice.

PMID: 22522483 Funalot et al., 2012
Female proband with a congenital amyelinating neuropathy; consanguineous parents of Moroccan origin. She presented with hypotonia at birth, EMG showed absence of peripheral response. No EGR2 immunoreactivity seen in Schwann cells. Detected a homozygous 10.7-kilobase-long deletion encompassing a myelin-specific enhancer of EGR2 in the proband (**non-coding regulatory variant**).

Reports of dominant EGR2-related CMT PMIDs: 9537424; 11523566; 17717711; 20513111; 26204789; 27159987; 30481651; 30843326; 31852952 - copied from ClinGen summary.

The association between EGR2 and Semidominant Charcot-Marie-Tooth disease was classified as Definitive (Charcot-Marie-Tooth GCEP, Nov 2021). The gene is associated with AD Charcot-Marie-Tooth disease, type 1D, MIM:607678, AD,AR Dejerine-Sottas disease, MIM:145900, and AD,AR Hypomyelinating neuropathy, congenital, 1, MIM:605253 in OMIM; EGR2-related neuropathy, congenital hypomyelinating (biallelic_autosomal) is ranked Definitive in Gene2Phenotype (accessed 28th July 2026).
Hereditary neuropathy or pain disorder v8.24 EGR2 Ida Ertmanska changed review comment from: PMID: 32896048 Lupo et al., 2020
3 affected sibs with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. All 3 individuals were homozygous for the c.791C>T; p.P264L variant in EGR2. Consanguineous parents (confirmed het) and wt/het sibs unaffected.

PMID: 9537424 Warner et al., 1998
p.I268N homozygous missense variant detected in EGR2.
Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage.

The association between EGR2 and Semidominant Charcot-Marie-Tooth disease was classified as Definitive (Charcot-Marie-Tooth GCEP, Nov 2021). The gene is associated with AD Charcot-Marie-Tooth disease, type 1D, MIM:607678, AD,AR Dejerine-Sottas disease, MIM:145900, and AD,AR Hypomyelinating neuropathy, congenital, 1, MIM:605253 in OMIM; EGR2-related neuropathy, congenital hypomyelinating (biallelic_autosomal) is ranked Definitive in Gene2Phenotype (accessed 28th July 2026).; to: PMID: 32896048 Lupo et al., 2020
3 affected sibs with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. All 3 individuals were homozygous for the c.791C>T; p.P264L variant in EGR2. Variant not present in gnomAD v4. Consanguineous parents (confirmed het) and wt/het sibs unaffected.

PMID: 9537424 Warner et al., 1998
Study included 94 neuropathy patients. Only exons of EGR2 were sequenced. Family HOU336 - 3 male sibs affected by a congenital hypomyelinating neuropathy (CHN). They were floppy at birth, had delayed motor milestones, and walked with crutches at the time of report. The c.803T>A, p.Ile268Asn homozygous missense variant was detected in EGR2 - not reported in gnomAD v4.
Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage - phenotype not seen in heterozygous +/- mice.

Reports of dominant EGR2-related CMT PMIDs: 9537424; 11523566; 17717711; 20513111; 26204789; 27159987; 30481651; 30843326; 31852952 - copied from ClinGen summary.

The association between EGR2 and Semidominant Charcot-Marie-Tooth disease was classified as Definitive (Charcot-Marie-Tooth GCEP, Nov 2021). The gene is associated with AD Charcot-Marie-Tooth disease, type 1D, MIM:607678, AD,AR Dejerine-Sottas disease, MIM:145900, and AD,AR Hypomyelinating neuropathy, congenital, 1, MIM:605253 in OMIM; EGR2-related neuropathy, congenital hypomyelinating (biallelic_autosomal) is ranked Definitive in Gene2Phenotype (accessed 28th July 2026).
Hereditary neuropathy or pain disorder v8.24 EGR2 Ida Ertmanska reviewed gene: EGR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9537424, 32896048; Phenotypes: Charcot-Marie-Tooth disease, type 1D, MIM:607678, Dejerine-Sottas disease, MIM:145900, Hypomyelinating neuropathy, congenital, 1, MIM:605253; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v6.33 GPN2 Luke Stuart gene: GPN2 was added
gene: GPN2 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPN2 were set to 42392036
Phenotypes for gene: GPN2 were set to Sensorineural hearing loss disorder (MONDO:0020678)
Review for gene: GPN2 was set to GREEN
Added comment: Smith et al. 2026 (PMID 42392036) investigated 3 Perrault syndrome (MIM: 233400, PRLTS1) families via exome sequencing in whom no diagnostic variants were previously found in known PRLTS1 genes or in genes associated with sensorineural hearing loss (SNHL) or primary ovarian insufficiency (POI). Homozygous missense variants in GPN2 were identified in the affected individuals in all three families.

Family 1 (PKDF1779): A consanguineous Pakistani family with 10 affected individuals presenting with congenital profound SNHL and POI (all POI diagnosed at <=20 years of age where known). Homozygous GPN2 c.363C>A p.(His121Gln) segregated with disease in all affected individuals (all 10 had profound congenital SNHL); the variant was noted absent from gnomAD v4.1.

Family F2 (Irish) comprised two affected sisters with bilateral profound SNHL, POI, and cerebellar ataxia. Both were homozygous for GPN2 c.664A>G p.(Asn222Asp). Brain imaging revealed cerebellar atrophy in both.

Family F3 (Australian of Irish ancestry), comprised one affected female proband presenting with profound SNHL, primary amenorrhea, and mild intellectual disability. Homozygous GPN2 c.664A>G p.(Asn222Asp), was identified. Haplotype analysis in the affected members of families F2 and F3 revealed a shared homozygous region of 662 kb indicative of a shared ancestor. The p.(Asn222Asp) variant was noted to be rare in gnomADv4.1 (0.0003763) with no homozygous occurrences. No additional candidate variants in known PRLTS1 genes or genes associated with SNHL or POI were identified.

Consistent with other PRLTS1 genes, Gpn2 mRNA was detected in spiral ganglion neurons (SGNs), auditory hair cells, and supporting cells in the mouse inner ear.

Conclusions: 13 probands with profound congenital SNHL (n =12), perinatal SNHL (n =1) from 3 kindreds. mRNA expression studies showed high expression in relevant inner-ear structures. No contradictory evidence found. There is sufficient evidence for this gene be promoted to green rating at the next GMS panel update.
Sources: Literature
Early onset or syndromic epilepsy v9.46 DNM1 Ida Ertmanska commented on gene: DNM1: Comment on mode of inheritance: 'Dominant-negative' heterozygous variants in DNM1 are a known cause of a dominant developmental and epileptic encephalopathy. There are now more than 3 unrelated individuals reported in literature with biallelic LoF DNM1 variants and a recessive Developmental and epileptic encephalopathy. Hence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v9.46 DNM1 Ida Ertmanska Publications for gene: DNM1 were set to 25262651; 27066543; 33372033; 34172529; 36413998
Early onset or syndromic epilepsy v9.45 DNM1 Ida Ertmanska Tag watchlist_moi was removed from gene: DNM1.
Tag Q3_26_MOI tag was added to gene: DNM1.
Early onset or syndromic epilepsy v9.45 DNM1 Ida Ertmanska reviewed gene: DNM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34172529, 36413998, 36553519, 37900685, 41340537; Phenotypes: Developmental and epileptic encephalopathy 31B, autosomal recessive, OMIM:620352, developmental and epileptic encephalopathy, 31B, MONDO:0957248, Developmental and epileptic encephalopathy 31A, autosomal dominant, OMIM:616346, developmental and epileptic encephalopathy, 31A, MONDO:0014598, DNM1 early infantile epileptic encephalopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v10.71 DNM1 Ida Ertmanska changed review comment from: BIALLELIC CASES:
PMID: 41340537 Drackley et al., 2026
24mo female proband with early infantile developmental and epileptic encephalopathy, including a burst suppression pattern with diffuse slowing on interictal EEG, probable tonic seizures, and profound developmental delay, as well as cerebral atrophy, hypotonia, and arthrogryposis. No head circumference measures given. NGS detected comp het DNM1 variants c.194C>A, p.Thr65Asn (de novo) and c.850C>T p.Gln284* (maternally inherited, mother unaffected).

PMID: 37900685 Afsar et al., 2023
Report of a consanguineous Pakistani family. Male proband presented with a neurodevelopmental disorder, mild microcephaly (head circumference: 48.9 cm <1 percentile (−2.8 SD)), moderate to severe ID, speech issues, seizures, epileptic encephalopathy, and hypotonia. WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene.

PMID: 36553519 AlTassan et al., 2022
Female proband presented with facial dysmorphism, global developmental delay, seizure disorder, and nystagmus. Head circumference 46 cm (25th percentile) at 18 months. Parents are consanguineous, Arab ancestry. Clinical WES revealed a homozygous deletion in DNM1 (NM_001288739.1: c.350del, p.Pro117Argfs*14).

PMID: 34172529 Yigit et al., 2022
Report of 2 families, probands affected by DEE. WES detected homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene.
F1 - Lebanese, consanguineous. Female proband presented with multifocal clonic seizures at 15 weeks. At 5yrs, her body weight was 14.35 kg (−2.1 SD); length was 99 cm (−2.4 SD); and OFC was 45.8 cm (−4.4 SD). Lack of verbal understanding and no speech development were noted.
F2 - Arab origins, consanguineous. Female proband presented with infantile spasms (onset around 6mo), severe GDD. At 2 years, she presented with microcephaly, visual disturbance and generalised muscular hypotonia. Mild bilateral optic atrophy observed at 3yrs. At 3yrs 8 mo her weight was 10 kg (−3.7 SD); length was 88 cm (−3.1 SD); and OFC was 45 cm (−4.5 SD).

MONOALLELIC CASES:
PMID: 36413998 Parthasarathy et al., 2022
Eight individuals harbor a recurrent de novo splice site variant, c.1197-8G>A, 3 individuals harboured p.Arg399Trp, p.Gly401Asp, and p.Pro405Leu missense variants. Importantly, exon 10 is alternatively spliced, with predominantly exon 10a isoform expressed in the brain. Thus, variants in exon 10a result in a more severe phenotype than in exon 10b. Variant p.Pro405Leu, which was the only variant affecting exon 10b isoform, resulted in a less severe neurological presentation (mild DD versus profound DD in all other patients in the cohort).; to: BIALLELIC CASES:
PMID: 41340537 Drackley et al., 2026
24mo female proband with early infantile developmental and epileptic encephalopathy, including a burst suppression pattern with diffuse slowing on interictal EEG, probable tonic seizures, and profound developmental delay, as well as cerebral atrophy, hypotonia, and arthrogryposis. No head circumference measures given. NGS detected comp het DNM1 variants c.194C>A, p.Thr65Asn (de novo) and c.850C>T p.Gln284* (maternally inherited, mother unaffected).

PMID: 37900685 Afsar et al., 2023
Report of a consanguineous Pakistani family. Male proband presented with a neurodevelopmental disorder, mild microcephaly (head circumference: 48.9 cm <1 percentile (−2.8 SD)), moderate to severe ID, speech issues, seizures, epileptic encephalopathy, and hypotonia. WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene.

PMID: 36553519 AlTassan et al., 2022
Female proband presented with facial dysmorphism, global developmental delay, seizure disorder, and nystagmus. Head circumference 46 cm (25th percentile) at 18 months. Parents are consanguineous, Arab ancestry. Clinical WES revealed a homozygous deletion in DNM1 (NM_001288739.1: c.350del, p.Pro117Argfs*14).

PMID: 34172529 Yigit et al., 2022
Report of 2 families, probands affected by DEE. WES detected homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene.
F1 - Lebanese, consanguineous. Female proband presented with multifocal clonic seizures at 15 weeks. At 5yrs, her body weight was 14.35 kg (−2.1 SD); length was 99 cm (−2.4 SD); and OFC was 45.8 cm (−4.4 SD). Lack of verbal understanding and no speech development were noted.
F2 - Arab origins, consanguineous. Female proband presented with infantile spasms (onset around 6mo), severe GDD. At 2 years, she presented with microcephaly, visual disturbance and generalised muscular hypotonia. Mild bilateral optic atrophy observed at 3yrs. At 3yrs 8 mo her weight was 10 kg (−3.7 SD); length was 88 cm (−3.1 SD); and OFC was 45 cm (−4.5 SD).

MONOALLELIC CASES:
PMID: 36413998 Parthasarathy et al., 2022
Eight individuals harbor a recurrent de novo splice site variant, c.1197-8G>A, 3 individuals harboured p.Arg399Trp, p.Gly401Asp, and p.Pro405Leu missense variants. Importantly, exon 10 is alternatively spliced, with predominantly exon 10a isoform expressed in the brain. Thus, variants in exon 10a result in a more severe phenotype than in exon 10b. Variant p.Pro405Leu, which was the only variant affecting exon 10b isoform, resulted in a less severe neurological presentation (mild DD versus profound DD in all other patients in the cohort).

DNM1 is associated with both AD and AR Developmental and epileptic encephalopathy entities in OMIM (accessed 28th July 2026). The recessive association is classified as Moderate, while dominant disease link is Definitive in ClinGen (Epilepsy GCEP, Feb 2024).
Intellectual disability v10.71 DNM1 Ida Ertmanska commented on gene: DNM1: Comment on mode of inheritance: 'Dominant-negative' heterozygous variants in DNM1 are a known cause of a dominant developmental and epileptic encephalopathy. There are now more than 3 unrelated individuals reported in literature with biallelic LoF DNM1 variants and a recessive Developmental and epileptic encephalopathy. Hence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v9.45 DNM1 Ida Ertmanska Phenotypes for gene: DNM1 were changed from Developmental and epileptic encephalopathy 31, OMIM:616346 to Developmental and epileptic encephalopathy 31B, autosomal recessive, OMIM:620352; developmental and epileptic encephalopathy, 31B, MONDO:0957248; Developmental and epileptic encephalopathy 31A, autosomal dominant, OMIM:616346; developmental and epileptic encephalopathy, 31A, MONDO:0014598; DNM1 early infantile epileptic encephalopathy
Intellectual disability v10.71 DNM1 Ida Ertmanska Phenotypes for gene: DNM1 were changed from Developmental and epileptic encephalopathy 31, OMIM:616346 to Developmental and epileptic encephalopathy 31B, autosomal recessive, OMIM:620352; developmental and epileptic encephalopathy, 31B, MONDO:0957248; Developmental and epileptic encephalopathy 31A, autosomal dominant, OMIM:616346; developmental and epileptic encephalopathy, 31A, MONDO:0014598; DNM1 early infantile epileptic encephalopathy
Intellectual disability v10.70 DNM1 Ida Ertmanska Publications for gene: DNM1 were set to 0
Intellectual disability v10.69 DNM1 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: DNM1.
Intellectual disability v10.69 DNM1 Ida Ertmanska reviewed gene: DNM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34172529, 36413998, 36553519, 37900685, 41340537; Phenotypes: Developmental and epileptic encephalopathy 31B, autosomal recessive, OMIM:620352, developmental and epileptic encephalopathy, 31B, MONDO:0957248, Developmental and epileptic encephalopathy 31A, autosomal dominant, OMIM:616346, developmental and epileptic encephalopathy, 31A, MONDO:0014598, DNM1 early infantile epileptic encephalopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v10.69 KDM5B Ida Ertmanska changed review comment from: PMID: 40657596 Sabetfakhri et al., 2025
Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID.

PMID: 39202393 Borroto et al., 2024
Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown.
In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants.
Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted.
Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD.

PMID: 37231097 Chen et al., 2023
Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR).
This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice.

The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026).; to: PMID: 40657596 Sabetfakhri et al., 2025
Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID.

PMID: 39202393 Borroto et al., 2024
Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown.
In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Method: exome seq.
Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted.
Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD.

PMID: 37231097 Chen et al., 2023
Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR).
This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice.

The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026).
Intellectual disability v10.69 KDM5B Ida Ertmanska edited their review of gene: KDM5B: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.69 KDM5B Ida Ertmanska changed review comment from: PMID: 39202393 Borroto et al., 2024
Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown.
In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants.
Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted.
Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD.

PMID: 37231097 Chen et al., 2023
Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR).
This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice.

The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026).; to: PMID: 40657596 Sabetfakhri et al., 2025
Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID.

PMID: 39202393 Borroto et al., 2024
Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown.
In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants.
Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted.
Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD.

PMID: 37231097 Chen et al., 2023
Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR).
This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice.

The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026).
Intellectual disability v10.69 KDM5B Ida Ertmanska edited their review of gene: KDM5B: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v8.24 APOPT1 Achchuthan Shanmugasundram commented on gene: APOPT1: PMID:25175347 (2014) reported a total of six patients from five unrelated families identified with biallelic variants in APOPT1 gene. There were six different variants identified from these patients and all but one were homozygous, and one individual had compound heterozygous variants. The clinical features of all six patients varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. Peripheral neuropathy was reported in two patients
Intellectual disability v10.69 KDM5B Ida Ertmanska reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 37231097, 39202393; Phenotypes: Intellectual developmental disorder, autosomal recessive 65, OMIM:618109; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v9.3 FIG4 Ida Ertmanska changed review comment from: PMID: 38695966 Ferreira et al., 2024
Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases.

PMID: 36090855 Yilihamu et al., 2022
Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS.

PMID: 35021275 Liu et al., 2021
Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4.
2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4.

PMID: 29464931 Bertolin et al., 2018
Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile.

PMID: 28051077 Osmanovic et al., 2017
German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES.
5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L).

FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022).; to: PMID: 38695966 Ferreira et al., 2024
Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases.

PMID: 36090855 Yilihamu et al., 2022
Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS.

PMID: 35021275 Liu et al., 2021
Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4.
2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4.

PMID: 29464931 Bertolin et al., 2018
Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile.

PMID: 28051077 Osmanovic et al., 2017
German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES.
5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L).

FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022).
Neurodegenerative disorders, adult onset v9.3 FIG4 Ida Ertmanska changed review comment from: PMID: 38695966 Ferreira et al., 2024
Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases.

PMID: 36090855 Yilihamu et al., 2022
Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS.

PMID: 35021275 Liu et al., 2021
Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4.
2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS; c.2158G>T [p.E720X] - classified LP.

PMID: 29464931 Bertolin et al., 2018
Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile.

PMID: 28051077 Osmanovic et al., 2017
German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES.
5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L).

FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022).; to: PMID: 38695966 Ferreira et al., 2024
Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases.

PMID: 36090855 Yilihamu et al., 2022
Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS.

PMID: 35021275 Liu et al., 2021
Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4.
2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4.

PMID: 29464931 Bertolin et al., 2018
Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile.

PMID: 28051077 Osmanovic et al., 2017
German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES.
5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L).

FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022).
Neurodegenerative disorders, adult onset v9.3 FIG4 Ida Ertmanska reviewed gene: FIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28051077, 29464931, 35021275, 36090855, 38695966; Phenotypes: Amyotrophic lateral sclerosis 11, OMIM:612577; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v8.24 APOPT1 Achchuthan Shanmugasundram reviewed gene: APOPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25175347, 38098475; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061, mitochondrial complex IV deficiency, nuclear type 17, MONDO:0033652, peripheral neuropathy, MONDO:0005244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v8.24 FAT3 Achchuthan Shanmugasundram Classified gene: FAT3 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v8.24 FAT3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there is sufficient evidence available (three unrelated cases and functional evidence) for the association of FAT3 with neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v8.24 FAT3 Achchuthan Shanmugasundram Gene: fat3 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v8.23 FAT3 Achchuthan Shanmugasundram Phenotypes for gene: FAT3 were changed from axonal sensory and motor peripheral neuropathy; cranial neuropathy; scoliosis; respiratory failure; pseudoobstruction to peripheral neuropathy, MONDO:0005244
Hereditary neuropathy or pain disorder v8.22 FAT3 Achchuthan Shanmugasundram Publications for gene: FAT3 were set to PMID: 41937739
Hereditary neuropathy or pain disorder v8.21 FAT3 Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: FAT3.
Tag Q3_26_promote_green tag was added to gene: FAT3.
Hereditary neuropathy or pain disorder v8.21 FAT3 Achchuthan Shanmugasundram reviewed gene: FAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 41937739; Phenotypes: peripheral neuropathy, MONDO:0005244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v6.13 NUP205 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: NUP205.
Proteinuric renal disease v6.13 NUP205 Achchuthan Shanmugasundram Classified gene: NUP205 as Amber List (moderate evidence)
Proteinuric renal disease v6.13 NUP205 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases and functional evidence reported in support of the association of NUP205 with nephrotic syndrome. Hence, this gene can be promoted to green rating in the next GMS update.
Proteinuric renal disease v6.13 NUP205 Achchuthan Shanmugasundram Gene: nup205 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v6.12 NUP205 Achchuthan Shanmugasundram Phenotypes for gene: NUP205 were changed from ?Nephrotic syndrome, type 13 #616893 to ?Nephrotic syndrome, type 13 , OMIM:616893; nephrotic syndrome, type 13, MONDO:0014818
Proteinuric renal disease v6.11 NUP205 Achchuthan Shanmugasundram Publications for gene: NUP205 were set to 26878725
Proteinuric renal disease v6.10 NUP205 Achchuthan Shanmugasundram Mode of inheritance for gene: NUP205 was changed from to BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v6.9 NUP205 Achchuthan Shanmugasundram changed review comment from: PMID:26878725 (2016) reported a homozygous missense variant in the nucleoporin NUP205 gene (p.Phe1995Ser) in two siblings of Turkish descent with early-onset steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS), identified via genetic mapping and whole exome sequencing.

PMID:29127259 (2018) reported the same family from PMID:26878725 (2016), and an unrelated patient of Arabic descent with SRNS and FSGS and identified with homozygous p.Cys1032Tyr variant.

PMID:36245711 (2022) reported a homozygous variant in NUP205 gene (p.Leu1110Pro) identified via trio exome sequencing in an Iranian paediatric patient with SRNS (age of onset - 12 months).

PMID:33065118 (2021) reported supportive functional studies from Xenopus knockout which demonstrated abnormal left right patterning and dysfunctional pronephric development.; to: PMID:26878725 (2016) reported a homozygous missense variant in the nucleoporin NUP205 gene (p.Phe1995Ser) in two siblings of Turkish descent with early-onset steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS), identified via genetic mapping and whole exome sequencing.

PMID:29127259 (2018) reported the same family from PMID:26878725 (2016), and an unrelated patient of Arabic descent with SRNS and FSGS and identified with homozygous p.Cys1032Tyr variant.

PMID:36245711 (2022) reported a homozygous variant in NUP205 gene (p.Leu1110Pro) identified via trio exome sequencing in an Iranian paediatric patient with SRNS (age of onset - 12 months).

PMID:33065118 (2021) reported supportive functional studies from Xenopus knockout which demonstrated abnormal left right patterning and dysfunctional pronephric development.

PMID:37565816 (2023) reported NUP205 as a key inner‑ring nucleoporin that physically associates with YAP/TAZ and is required for their nuclear import, TEAD‑mediated transcription, and podocyte survival under stress. Functionally, NUP205 knockdown reduces nuclear YAP/TAZ, down‑regulates canonical Hippo target genes, and increases podocyte death, providing strong mechanistic support that NUP205 dysfunction can drive glomerular disease.

This gene has tentatively been associated with MIM #616893 in OMIM (?Nephrotic syndrome, type 13) - last accessed 27 July 2026. It is associated with nephrotic syndrome, type 13 (MONDO:0014818) with 'limited' rating by Glomerulopathy GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009001).
Proteinuric renal disease v6.9 NUP205 Achchuthan Shanmugasundram edited their review of gene: NUP205: Changed rating: GREEN; Changed publications to: 26878725, 29127259, 33065118, 36245711, 37565816; Changed phenotypes to: ?Nephrotic syndrome, type 13 , OMIM:616893, nephrotic syndrome, type 13, MONDO:0014818; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v6.9 NUP205 Achchuthan Shanmugasundram reviewed gene: NUP205: Rating: ; Mode of pathogenicity: None; Publications: 26878725, 29127259, 33065118, 36245711; Phenotypes: ; Mode of inheritance: None
Congenital hyperinsulinism v3.9 CACNA1C Arina Puzriakova Tag Q3_26_expert_review tag was added to gene: CACNA1C.
Hereditary neuropathy or pain disorder v8.21 LAS1L Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance.

Hence, this gene should be rated amber with the current evidence.

However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.; to: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance. Hence, this gene should be rated amber with the current evidence.

However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.
Hereditary neuropathy or pain disorder v8.21 LAS1L Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. The main phenotype reported for this gene is syndromic intellectual disability (Wilson-Turner syndrome, MIM# 309585).

Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance.

Hence, this gene should be rated amber with the current evidence.

However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.; to: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance.

Hence, this gene should be rated amber with the current evidence.

However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.
Hereditary neuropathy or pain disorder v8.21 LAS1L Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. The main phenotype reported for this gene is syndromic intellectual disability (Wilson-Turner syndrome, MIM# 309585). Hence, this gene should be rated amber with the current evidence.

However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.; to: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. The main phenotype reported for this gene is syndromic intellectual disability (Wilson-Turner syndrome, MIM# 309585).

Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance.

Hence, this gene should be rated amber with the current evidence.

However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.
Hereditary neuropathy or pain disorder v8.21 LAS1L Achchuthan Shanmugasundram changed review comment from: LAS1L is associated with Wilson-Turner syndrome, which is a syndromic intellectual developmental disorder in OMIM (MIM #309585, last accessed 26 July 2026).

PMID:24647030 (2014) reported the identification of a de novo hemizygous missense variant (c.1430G>A, p.Ser477Asn) in a male neonate proband with fatal congenital spinal muscular atrophy with respiratory distress (SMARD)-like motor neuron disease. There is supporting evidence available from zebrafish rescue experiments.

PMID:35627110 (2022) reported the identification of a novel hemizygous synonymous variant in the LAS1L gene inherited from an unaffected mother (c.846G>C, p.Thr282=) in an eighteen-month old male patient with a SMARD phenotype. Maternal fibroblasts showed no coding-region transcript, suggesting skewed X-inactivation silencing the variant allele in her cells.; to: LAS1L is associated with Wilson-Turner syndrome, which is a syndromic intellectual developmental disorder in OMIM (MIM #309585, last accessed 26 July 2026).

PMID:24647030 (2014) reported the identification of a de novo hemizygous missense variant (c.1430G>A, p.Ser477Asn) in a male neonate proband with fatal congenital spinal muscular atrophy with respiratory distress (SMARD)-like motor neuron disease. There is supporting evidence available from zebrafish rescue experiments.

PMID:35627110 (2022) reported the identification of a novel hemizygous synonymous variant in the LAS1L gene inherited from an unaffected mother (c.846G>C, p.Thr282=) in an eighteen-month old male patient with a SMARD phenotype. Maternal fibroblasts showed no coding-region transcript, suggesting skewed X-inactivation silencing the variant allele in her cells.
Hereditary neuropathy or pain disorder v8.21 LAS1L Achchuthan Shanmugasundram Tag watchlist tag was added to gene: LAS1L.
Hereditary neuropathy or pain disorder v8.21 LAS1L Achchuthan Shanmugasundram Classified gene: LAS1L as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v8.21 LAS1L Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. The main phenotype reported for this gene is syndromic intellectual disability (Wilson-Turner syndrome, MIM# 309585). Hence, this gene should be rated amber with the current evidence.

However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.
Hereditary neuropathy or pain disorder v8.21 LAS1L Achchuthan Shanmugasundram Gene: las1l has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v8.20 LAS1L Achchuthan Shanmugasundram Phenotypes for gene: LAS1L were changed from to Wilson-Turner syndrome, OMIM:309585; Spinal muscular atrophy with respiratory distress (SMARD)-like motor neuron disease
Hereditary neuropathy or pain disorder v8.19 LAS1L Achchuthan Shanmugasundram edited their review of gene: LAS1L: Changed phenotypes to: Wilson-Turner syndrome, OMIM:309585, Spinal muscular atrophy with respiratory distress (SMARD)-like motor neuron disease
Hereditary neuropathy or pain disorder v8.19 LAS1L Achchuthan Shanmugasundram Publications for gene: LAS1L were set to 24647030
Hereditary neuropathy or pain disorder v8.18 LAS1L Achchuthan Shanmugasundram Mode of inheritance for gene: LAS1L was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hereditary neuropathy or pain disorder v8.17 LAS1L Achchuthan Shanmugasundram reviewed gene: LAS1L: Rating: AMBER; Mode of pathogenicity: None; Publications: 24647030, 35627110; Phenotypes: Wilson-Turner syndrome, OMIM:309585, motor neuron disorder, MONDO:0020128; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v9.44 PRRT2 Ida Ertmanska Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis; Episodic kinesigenic dyskinesia 1; Seizures, benign familial infantile, 2; BENIGN FAMILIAL INFANTILE EPILEPSY AND INFANTILE CONVULSIONS WITH CHOREOATHETOSIS SYNDROME to PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Convulsions, familial infantile, with paroxysmal choreoathetosis; Episodic kinesigenic dyskinesia 1; Seizures, benign familial infantile, 2; BENIGN FAMILIAL INFANTILE EPILEPSY AND INFANTILE CONVULSIONS WITH CHOREOATHETOSIS SYNDROME
Early onset or syndromic epilepsy v9.43 PRRT2 Ida Ertmanska Publications for gene: PRRT2 were set to Wan et al (2011) Brain 134: 3493_3501; Chen et al (2011) Nature Genet 43(12): 1252-1256; Heron et al (2012) Am J Hum Genet 90: 152_160
Early onset or syndromic epilepsy v9.42 PRRT2 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: PRRT2.
Early onset or syndromic epilepsy v9.42 PRRT2 Ida Ertmanska commented on gene: PRRT2: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' and benign familial infantile seizures - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Epilepsy is the most consistent feature in reported patients. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v9.42 PRRT2 Ida Ertmanska reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23126439, 25595153, 31193310, 36247910, 38316952; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v4.6 PRRT2 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Dystonia, chorea or related movement disorder, childhood onset v8.7 PRRT2 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Dystonia, chorea or related movement disorder, childhood onset v8.7 PRRT2 Ida Ertmanska Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066; Episodic kinesigenic dyskinesia 1, 128200; dystonia and occasionally hemiplegic migraine and epilepsy; Paroxysmal kinesigenic choreoathetosis (PKD1) and infantile convulsions; episodic kinesigenic dyskinesia to PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066; Episodic kinesigenic dyskinesia 1, 128200; dystonia and occasionally hemiplegic migraine and epilepsy; Paroxysmal kinesigenic choreoathetosis (PKD1) and infantile convulsions; episodic kinesigenic dyskinesia
Dystonia, chorea or related movement disorder, childhood onset v8.6 PRRT2 Ida Ertmanska Publications for gene: PRRT2 were set to 22744660; 20301334; 22399141; 22120146; 22101681
Dystonia, chorea or related movement disorder, childhood onset v8.5 PRRT2 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: PRRT2.
Paroxysmal central nervous system disorders v4.6 PRRT2 Ida Ertmanska Phenotypes for gene: PRRT2 were changed from Seizures, benign familial infantile, 2, 605751; dystonia and occasionally hemiplegic migraine and epilepsy; Episodic kinesigenic dyskinesia 1, 128200; Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066 to PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Seizures, benign familial infantile, 2, 605751; dystonia and occasionally hemiplegic migraine and epilepsy; Episodic kinesigenic dyskinesia 1, 128200; Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066
Paroxysmal central nervous system disorders v4.5 PRRT2 Ida Ertmanska Publications for gene: PRRT2 were set to 22744660; 22101681; 22120146; 22399141
Dystonia, chorea or related movement disorder, childhood onset v8.5 PRRT2 Ida Ertmanska commented on gene: PRRT2: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Dystonia, chorea or related movement disorder, childhood onset v8.5 PRRT2 Ida Ertmanska reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23126439, 25595153, 31193310, 36247910, 38316952; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v4.4 PRRT2 Ida Ertmanska commented on gene: PRRT2: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Paroxysmal central nervous system disorders v4.4 PRRT2 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: PRRT2.
Paroxysmal central nervous system disorders v4.4 PRRT2 Ida Ertmanska reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23126439, 25595153, 31193310, 36247910, 38316952; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v9.13 PRRT2 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset episodic ataxia. Cerebellar atrophy was also confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - childhood onset v9.13 PRRT2 Ida Ertmanska commented on gene: PRRT2: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset episodic ataxia. Cerebellar atrophy was also confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - childhood onset v9.13 PRRT2 Ida Ertmanska Publications for gene: PRRT2 were set to
Ataxia and cerebellar anomalies - childhood onset v9.12 PRRT2 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: PRRT2.
Ataxia and cerebellar anomalies - childhood onset v9.12 PRRT2 Ida Ertmanska reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23126439, 25595153, 31193310, 36247910, 38316952; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v10.69 PRRT2 Ida Ertmanska edited their review of gene: PRRT2: Changed phenotypes to: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556
Intellectual disability v10.69 PRRT2 Ida Ertmanska commented on gene: PRRT2: Comment on list classification: While there are a few individuals reported in literature with biallelic PRRT2 variants and severe intellectual disability (e.g., PMID: 36247910), most patients have normal cognition. More consistent features include early onset epilepsy, episodic ataxia, and dyskinesia. Hence, this gene should remain Amber on Intellectual disability.
Intellectual disability v10.69 PRRT2 Ida Ertmanska edited their review of gene: PRRT2: Changed publications to: 23126439, 25595153, 31193310, 36247910, 38316952; Changed phenotypes to: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066
Intellectual disability v10.69 PRRT2 Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.

PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD.

PMID: 31193310 El Achkar et al., 2019
Report of a male patient with a severe phenotype including infantile epilepsy with status epilepticus, paroxysmal dyskinesia and episodic ataxia. He harboured comp het PRRT2 variants c.649dupC, p.Arg217Profs*8 (maternal) and c.916G>A, p.Ala306Thr (paternal). Mother and brother het for c.649dupC were asymptomatic. On father's side, there is family history of episodic confusion and episodic hemiparesis (only father genotyped). Normal development noted at 5 years old, not cognitive impairment.

PMID: 25595153 Delcourt et al., 2015
Report of 5 patients with biallelic PRRT2 variants: 3 homozygous for c.649dupC, P1 was comp het for c.649dupC and a de novo whole PRRT2 gene deletion, and P5 was homozygous for PRRT2 c.913G>A, p.Gly305Arg. While 4 individuals had some learning difficulties and ADHD, their cognition was normal. All 5 patients had seizures with onset before 6 months of life; episodic ataxia was present in patients 1-4 (not normally seen in heterozygous individuals); cerebellar atrophy was seen on MRI in 2 cases.

https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017
Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.

The PRRT2-related neurodevelopmental and movement disorder with or without seizures (biallelic_autosomal) entry has Moderate confidence in G2P. PRRT2 is not yet associated with a recessive disorder in OMIM or ClinGen (accessed 27th July 2026).; to: PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the splice variant.

PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD.

PMID: 31193310 El Achkar et al., 2019
Report of a male patient with a severe phenotype including infantile epilepsy with status epilepticus, paroxysmal dyskinesia and episodic ataxia. He harboured comp het PRRT2 variants c.649dupC, p.Arg217Profs*8 (maternal) and c.916G>A, p.Ala306Thr (paternal). Mother and brother het for c.649dupC were asymptomatic. On father's side, there is family history of episodic confusion and episodic hemiparesis (only father genotyped). Normal development noted at 5 years old, no cognitive impairment seen in the proband.

PMID: 25595153 Delcourt et al., 2015
Report of 5 patients with biallelic PRRT2 variants: 3 homozygous for c.649dupC, P1 was comp het for c.649dupC and a de novo whole PRRT2 gene deletion, and P5 was homozygous for PRRT2 c.913G>A, p.Gly305Arg. While 4 individuals had some learning difficulties and ADHD, their cognition was normal. All 5 patients had seizures with onset before 6 months of life; episodic ataxia was present in patients 1-4 (not normally seen in heterozygous individuals); cerebellar atrophy was seen on MRI in 2 cases.

PMID: 23126439 Labate et al., 2012
Homozygous c.649dupC mutation in PRRT2 detected in 2 sibs from a consanguineous Italian family resulted in ID, episodic ataxia, and absences. 4 other affected family members, het for the same mutation, presented only with benign familial infantile seizures / familial paroxysmal kinesigenic dystonia.

DOI: 10.1055/s-0045-1810051 Eshrif & Adofani, 2025
Case report of a family with epilepsy and dyskinesia due to a homozygous PRRT2 variant c.649dup, p.(Arg217Profs8). 3 sibs affected, all 3 presented with focal seizures at 3-8 months old, and 2/3 individuals also had dyskinesia. Family history not discussed, parents assumed to be unaffected from the pedigree.

https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017
Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.

The PRRT2-related neurodevelopmental and movement disorder with or without seizures (biallelic_autosomal) entry has Moderate confidence in G2P. PRRT2 is not yet associated with a recessive disorder in OMIM or ClinGen (accessed 27th July 2026).
Intellectual disability v10.69 PRRT2 Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.

PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD.

PMID: 25595153 Delcourt et al., 2015


https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017
Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.; to: PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.

PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD.

PMID: 31193310 El Achkar et al., 2019
Report of a male patient with a severe phenotype including infantile epilepsy with status epilepticus, paroxysmal dyskinesia and episodic ataxia. He harboured comp het PRRT2 variants c.649dupC, p.Arg217Profs*8 (maternal) and c.916G>A, p.Ala306Thr (paternal). Mother and brother het for c.649dupC were asymptomatic. On father's side, there is family history of episodic confusion and episodic hemiparesis (only father genotyped). Normal development noted at 5 years old, not cognitive impairment.

PMID: 25595153 Delcourt et al., 2015
Report of 5 patients with biallelic PRRT2 variants: 3 homozygous for c.649dupC, P1 was comp het for c.649dupC and a de novo whole PRRT2 gene deletion, and P5 was homozygous for PRRT2 c.913G>A, p.Gly305Arg. While 4 individuals had some learning difficulties and ADHD, their cognition was normal. All 5 patients had seizures with onset before 6 months of life; episodic ataxia was present in patients 1-4 (not normally seen in heterozygous individuals); cerebellar atrophy was seen on MRI in 2 cases.

https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017
Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.

The PRRT2-related neurodevelopmental and movement disorder with or without seizures (biallelic_autosomal) entry has Moderate confidence in G2P. PRRT2 is not yet associated with a recessive disorder in OMIM or ClinGen (accessed 27th July 2026).
Hereditary neuropathy v1.513 POLR3A Arina Puzriakova Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, 607694; Adolescent onset progressive spastic ataxia, tremor, involvement of central sensory tracts, dental complications; Bilateral hyperintensities on MRI from the superior cerebellar peduncle to the dentate nucleus / midbrain to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694; leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897; peripheral neuropathy, MONDO:0005244
Hereditary neuropathy v1.512 POLR3A Arina Puzriakova Publications for gene: POLR3A were set to 28459997
Hereditary neuropathy v1.511 POLR3A Arina Puzriakova Added comment: Comment on mode of inheritance: There are 8 unrelated families reported with monoallelic variants and early-onset peripheral neuropathy. Hence, MOI was updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.
Hereditary neuropathy v1.511 POLR3A Arina Puzriakova Mode of inheritance for gene: POLR3A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.510 POLR3A Arina Puzriakova reviewed gene: POLR3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 42260910; Phenotypes: Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694, leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897, peripheral neuropathy, MONDO:0005244; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v10.69 PRRT2 Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.

PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD.

https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017
Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.; to: PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.

PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD.

PMID: 25595153 Delcourt et al., 2015


https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017
Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.
Intellectual disability v10.69 PRRT2 Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.

PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side. Proband diagnosed with severe ID and ASD.

https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017
Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.; to: PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.

PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD.

https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017
Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.
Intellectual disability v10.69 PRRT2 Ida Ertmanska changed review comment from: PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side. Proband diagnosed with severe ID and ASD.

PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.; to: PMID: 38316952 Koko et al., 2024
Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.

PMID: 36247910 Martorell et al., 2022
Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side. Proband diagnosed with severe ID and ASD.

https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017
Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.
Intellectual disability v10.69 PRRT2 Ida Ertmanska reviewed gene: PRRT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36247910, 38316952; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal tubulopathies v6.9 TFCP2L1 Ida Ertmanska Classified gene: TFCP2L1 as Amber List (moderate evidence)
Renal tubulopathies v6.9 TFCP2L1 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harbouring biallelic TFCP2L1 variants presented with early-onset kidney dysfunction diagnosed as renal tubulopathy (among other less specific findings). Tfcp2l1-deficient mice showed defects in renal duct maturation. Taken together, there is enough evidence to promote this gene to Green at the next GMS update.
Renal tubulopathies v6.9 TFCP2L1 Ida Ertmanska Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v6.8 TFCP2L1 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: TFCP2L1.
Renal tubulopathies v6.8 TFCP2L1 Ida Ertmanska edited their review of gene: TFCP2L1: Changed rating: GREEN
Renal tubulopathies v6.8 TFCP2L1 Ida Ertmanska edited their review of gene: TFCP2L1: Changed publications to: 17079272, 33097957, 40569305, 42362802
Renal tubulopathies v6.8 TFCP2L1 Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026
Family 22 - 2 sibs with exon 1-2 deletion in TFCP2L1; presentation: microcrephaly, CKD (diagnosis of renal tubulopathy), SNHL. Seq method: exome seq.

PMID: 40569305 Graña et al., 2025
'Ultra-rare severe kidney dysplasia mimicking salt-wasting tubulopathy associated with TFCP2L1 gene variants'
Study described a consanguineous preterm male infant with advanced kidney dysfunction and severe renal salt-wasting, suggestive of Bartter syndrome. Follow-up showed severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. No cataracts or seizures seen in this patient. He was homozygous for TFCP2L1 (NM_014553.3):c.1279 del; p.(Gln427Serfs*18)). Method: WES.

PMID: 33097957 Klämbt et al., 2021
Report of a 4yo female patient (B2033-21) from a consanguineous Arabic Yemeni family, harbouring a homozygous TFCP2L1 variant c.869del, p. Ser290Phefs*50. Method: WES. Parents confirmed het. Patient presented with echogenic kindeys and CKD developed before 2 months of age; ESRD age 3.5 years, hypochloremic, hypokalemic alkalosis, small echogenic kidneys. In addition, she had cataracts, seizures, developmental delay, hypotonia.

TFCP2L1 is not yet associated with a disease in OMIM, Gene2Phenotype, or ClinGen (accessed 27th July 2026).
Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026
Family 22 - 2 sibs with exon 1-2 deletion in TFCP2L1; presentation: microcrephaly, CKD (diagnosis of renal tubulopathy), SNHL. Seq method: exome seq.

PMID: 40569305 Graña et al., 2025
'Ultra-rare severe kidney dysplasia mimicking salt-wasting tubulopathy associated with TFCP2L1 gene variants'
Study described a consanguineous preterm male infant with advanced kidney dysfunction and severe renal salt-wasting, suggestive of Bartter syndrome. Follow-up showed severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. No cataracts or seizures seen in this patient. He was homozygous for TFCP2L1 (NM_014553.3):c.1279 del; p.(Gln427Serfs*18)). Method: WES.

PMID: 33097957 Klämbt et al., 2021
Report of a 4yo female patient (B2033-21) from a consanguineous Arabic Yemeni family, harbouring a homozygous TFCP2L1 variant c.869del, p. Ser290Phefs*50. Method: WES. Parents confirmed het. Patient presented with echogenic kindeys and CKD developed before 2 months of age; ESRD age 3.5 years, hypochloremic, hypokalemic alkalosis, small echogenic kidneys. In addition, she had cataracts, seizures, developmental delay, hypotonia.

FUNCTIONAL EVIDENCE:
PMID: 17079272 Yamaguchi, Yonemura, & Takada, 2006
TFCP2L1 is required for the maturation of the ducts of the salivary gland and kidney, as it coordinates the expression of several genes that are involved in physiological function and generate the appropriate cellular architecture. In Cp2l1-deficient mice, the expression of genes directly involved in functional maturation of the ducts was specifically reduced in both the salivary gland and kidney. Furthermore, the composition of saliva and urine was abnormal in these mice. Tfcp2l1−/− mice were evaluated for urinary excretion of electrolytes and showed a urinary potassium loss similar to patient B2033-21 in PMID: 33097957.

TFCP2L1 is not yet associated with a disease in OMIM, Gene2Phenotype, or ClinGen (accessed 27th July 2026).
Sources: Literature
Renal tubulopathies v6.8 TFCP2L1 Ida Ertmanska gene: TFCP2L1 was added
gene: TFCP2L1 was added to Renal tubulopathies. Sources: Literature
Mode of inheritance for gene: TFCP2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TFCP2L1 were set to 33097957; 40569305; 42362802
Phenotypes for gene: TFCP2L1 were set to chronic kidney disease, MONDO:0005300; Renal tubular dysfunction, HP:0000124
Review for gene: TFCP2L1 was set to AMBER
Added comment: PMID: 42362802 Chaurasia et al., 2026
Family 22 - 2 sibs with exon 1-2 deletion in TFCP2L1; presentation: microcrephaly, CKD (diagnosis of renal tubulopathy), SNHL. Seq method: exome seq.

PMID: 40569305 Graña et al., 2025
'Ultra-rare severe kidney dysplasia mimicking salt-wasting tubulopathy associated with TFCP2L1 gene variants'
Study described a consanguineous preterm male infant with advanced kidney dysfunction and severe renal salt-wasting, suggestive of Bartter syndrome. Follow-up showed severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. No cataracts or seizures seen in this patient. He was homozygous for TFCP2L1 (NM_014553.3):c.1279 del; p.(Gln427Serfs*18)). Method: WES.

PMID: 33097957 Klämbt et al., 2021
Report of a 4yo female patient (B2033-21) from a consanguineous Arabic Yemeni family, harbouring a homozygous TFCP2L1 variant c.869del, p. Ser290Phefs*50. Method: WES. Parents confirmed het. Patient presented with echogenic kindeys and CKD developed before 2 months of age; ESRD age 3.5 years, hypochloremic, hypokalemic alkalosis, small echogenic kidneys. In addition, she had cataracts, seizures, developmental delay, hypotonia.

TFCP2L1 is not yet associated with a disease in OMIM, Gene2Phenotype, or ClinGen (accessed 27th July 2026).
Sources: Literature
Hereditary neuropathy or pain disorder v8.17 DHTKD1 Arina Puzriakova Tag Q3_26_expert_review tag was added to gene: DHTKD1.
Intellectual disability v10.69 PDS5B Achchuthan Shanmugasundram edited their review of gene: PDS5B: Changed rating: RED
Intellectual disability v10.69 PDS5B Achchuthan Shanmugasundram Classified gene: PDS5B as Red List (low evidence)
Intellectual disability v10.69 PDS5B Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are eight unrelated patients reported with PDS5B variants and variable neurodevelopmental features, intellectual disability was only reported in one. Hence, this gene should be rated red with the current evidence.
Intellectual disability v10.69 PDS5B Achchuthan Shanmugasundram Gene: pds5b has been classified as Red List (Low Evidence).
Intellectual disability v10.68 PDS5B Achchuthan Shanmugasundram gene: PDS5B was added
gene: PDS5B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDS5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDS5B were set to 42431198
Phenotypes for gene: PDS5B were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: PDS5B was set to AMBER
Added comment: PMID:42431198 (2026) reported eight unrelated patients with rare heterozygous loss of function variants in PDS5B gene, of which inheritance was de novo in four, unknown in three, and inherited from unaffected parent in one. They presented with variable neurodevelopmental features and intellectual disability was reported only in one. No functional evidence available.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia.
Sources: Literature
Intellectual disability v10.67 PDS5A Achchuthan Shanmugasundram changed review comment from: PMID:30158690 (2019) reoported a cohort that had undergone exome sequencing of which one patient with intellectual disability/ developmental delay was identified with a paternally inherited PDS5A variant (p.Glu759Ter) and a de novo ASXL3 variant.

PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia.
Sources: Literature; to: PMID:30158690 (2019) reoported a cohort that had undergone exome sequencing of which one patient with intellectual disability/ developmental delay was identified with a paternally inherited PDS5A variant (p.Glu759Ter) and a de novo ASXL3 variant.

PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients. No functional evidence available.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia.
Sources: Literature
Intellectual disability v10.67 PDS5A Achchuthan Shanmugasundram Publications for gene: PDS5A were set to 42431198
Hereditary neuropathy or pain disorder v8.17 MT-TV Arina Puzriakova Tag Q3_26_NHS_review tag was added to gene: MT-TV.
Intellectual disability v10.66 PDS5A Achchuthan Shanmugasundram changed review comment from: PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia.
Sources: Literature; to: PMID:30158690 (2019) reoported a cohort that had undergone exome sequencing of which one patient with intellectual disability/ developmental delay was identified with a paternally inherited PDS5A variant (p.Glu759Ter) and a de novo ASXL3 variant.

PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia.
Sources: Literature
Intellectual disability v10.66 PDS5A Achchuthan Shanmugasundram edited their review of gene: PDS5A: Changed publications to: 30158690, 42431198
Intellectual disability v10.66 PDS5A Achchuthan Shanmugasundram Classified gene: PDS5A as Amber List (moderate evidence)
Intellectual disability v10.66 PDS5A Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are four unrelated patients reported with only heterozygous variants from PDS5A gene and with intellectual disability/ global developmental delay, the phenotype is not consistent across the eight reported patients with heterozygous PDS5A variants. Hence, the gene should be rated amber with current evidence.

The 'watchlist' tag has been added to review the gene upon any new evidence.
Intellectual disability v10.66 PDS5A Achchuthan Shanmugasundram Gene: pds5a has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.65 PDS5A Achchuthan Shanmugasundram Tag watchlist tag was added to gene: PDS5A.
Intellectual disability v10.65 PDS5A Achchuthan Shanmugasundram gene: PDS5A was added
gene: PDS5A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDS5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDS5A were set to 42431198
Phenotypes for gene: PDS5A were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: PDS5A was set to AMBER
Added comment: PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia.
Sources: Literature
Intellectual disability v10.64 WAPL Achchuthan Shanmugasundram Classified gene: WAPL as Amber List (moderate evidence)
Intellectual disability v10.64 WAPL Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of WAPL gene with intellectual disability/ global developmental delay, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v10.64 WAPL Achchuthan Shanmugasundram Gene: wapl has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.63 WAPL Achchuthan Shanmugasundram gene: WAPL was added
gene: WAPL was added to Intellectual disability. Sources: Literature
Q3_26_promote_green tags were added to gene: WAPL.
Mode of inheritance for gene: WAPL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WAPL were set to 42431198
Phenotypes for gene: WAPL were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: WAPL was set to GREEN
Added comment: PMID:42431198 (2026) reported the identification of heterozygous WAPL variants in 27 patients, of which 19 patients had confirmed de novo variants. The WAPL-related disorder was characterised by developmental delay, intellectual disability, and risk of other developmental anomalies. Syndromic intellectual disability was reported in 6 patients and Global developmental delay (GDD) was reported in 10 patients.

Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes. Mice with 50% Wapl expression exhibited mild deficits of growth and learning/memory, whereas those with 25% residual Wapl displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with green rating on the intellectual disability panel of PanelApp Australia.
Sources: Literature
Intellectual disability v10.62 VPS36 Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.

VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026).
Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5, not assessed in F52), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.

VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026).
Sources: Literature
Intellectual disability v10.62 VPS36 Ida Ertmanska edited their review of gene: VPS36: Changed rating: GREEN
Intellectual disability v10.62 VPS36 Ida Ertmanska Classified gene: VPS36 as Amber List (moderate evidence)
Intellectual disability v10.62 VPS36 Ida Ertmanska Added comment: Comment on list classification: 3 unrelated families have been reported with biallelic VPS36 variants and intellectual disability, and developmental delay including motor & speech delay. Hence, this gene can be promoted to Green at the next GMS update.
Intellectual disability v10.62 VPS36 Ida Ertmanska Gene: vps36 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.61 VPS36 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: VPS36.
Early onset or syndromic epilepsy v9.42 VPS36 Ida Ertmanska Classified gene: VPS36 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.42 VPS36 Ida Ertmanska Added comment: Comment on list classification: Seizures have been reported in 3 families with biallelic VPS36 variants and seizures. However, two of these families harboured the same variant and shared ancestry was seen in haplotype analysis. Hence, this gene can only be rated Amber with the current evidence.
Early onset or syndromic epilepsy v9.42 VPS36 Ida Ertmanska Gene: vps36 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.41 VPS36 Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.

VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026).
Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6, not in family 52), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.

VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026).
Sources: Literature
Severe microcephaly v9.13 VPS36 Ida Ertmanska Classified gene: VPS36 as Amber List (moderate evidence)
Severe microcephaly v9.13 VPS36 Ida Ertmanska Added comment: Comment on list classification: While there are 3 unrelated pedigrees reported in literature with biallelic VPS36 variants and microcephaly, the severity of microcephaly is not stated. Hence, it is unclear whether this association fits into the scope of the Severe microcephaly panel.
Severe microcephaly v9.13 VPS36 Ida Ertmanska Gene: vps36 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.61 VPS36 Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.
Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.

VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026).
Sources: Literature
Early onset or syndromic epilepsy v9.41 VPS36 Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.
Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.

VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026).
Sources: Literature
Severe microcephaly v9.12 VPS36 Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.
Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.

VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026).
Sources: Literature
Early onset or syndromic epilepsy v9.41 VPS36 Ida Ertmanska gene: VPS36 was added
gene: VPS36 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: VPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS36 were set to 28600779; 42362802
Phenotypes for gene: VPS36 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: VPS36 was set to AMBER
Added comment: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.
Sources: Literature
Intellectual disability v10.61 VPS36 Ida Ertmanska gene: VPS36 was added
gene: VPS36 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: VPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS36 were set to 28600779; 42362802
Phenotypes for gene: VPS36 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: VPS36 was set to AMBER
Added comment: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.
Sources: Literature
Severe microcephaly v9.12 VPS36 Ida Ertmanska gene: VPS36 was added
gene: VPS36 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: VPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS36 were set to 28600779; 42362802
Phenotypes for gene: VPS36 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: VPS36 was set to AMBER
Added comment: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.
Sources: Literature
Hereditary neuropathy or pain disorder v8.17 POLR3A Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Alexander Rossor, there are 8 unrelated families reported with monoallelic variants and early-onset peripheral neuropathy. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Hereditary neuropathy or pain disorder v8.17 POLR3A Achchuthan Shanmugasundram Mode of inheritance for gene: POLR3A was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v8.16 POLR3A Achchuthan Shanmugasundram Tag Q3_26_promote_green was removed from gene: POLR3A.
Tag Q3_26_NHS_review tag was added to gene: POLR3A.
Tag Q3_26_MOI tag was added to gene: POLR3A.
Hereditary neuropathy or pain disorder v8.16 POLR3A Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: POLR3A.
Hereditary neuropathy or pain disorder v8.16 POLR3A Achchuthan Shanmugasundram Phenotypes for gene: POLR3A were changed from Bilateral hyperintensities on MRI from the superior cerebellar peduncle to the dentate nucleus / midbrain; Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, 607694; Adolescent onset progressive spastic ataxia, tremor, involvement of central sensory tracts, dental complications to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694; leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897; peripheral neuropathy, MONDO:0005244
Hereditary neuropathy or pain disorder v8.15 POLR3A Achchuthan Shanmugasundram Publications for gene: POLR3A were set to 28459997
Hereditary neuropathy or pain disorder v8.14 DHTKD1 Ida Ertmanska Tag Q3_26_NHS_review tag was added to gene: DHTKD1.
Hereditary neuropathy or pain disorder v8.14 DHTKD1 Ida Ertmanska Phenotypes for gene: DHTKD1 were changed from ?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025 to ?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025; Charcot-Marie-Tooth disease axonal type 2Q, MONDO:0014012
Hereditary neuropathy or pain disorder v8.13 DHTKD1 Ida Ertmanska Publications for gene: DHTKD1 were set to 23141294; 28902413; 29661920; 34571524
Hereditary neuropathy or pain disorder v8.12 POLR3A Achchuthan Shanmugasundram edited their review of gene: POLR3A: Added comment: PMID:42260910 (2026) reported 11 patients from 8 unrelated families identified with heterozygous missense variants in POLR3A. The patients presented with an early-onset, progressive sensorimotor peripheral polyneuropathy with intermediate to demyelinating ranges of nerve conduction slowing, occasionally accompanied with neurological or non-neurological features. White matter abnormalities that are characteristic for the biallelic Pol III-related disorders were not observed in the brain magnetic resonance imaging.

Although biallelic variants in this gene has already been associated with phenotypes relevant for this panel on OMIM (MIM #607694, last accessed 26 July 2026) and ClinGen (with 'definitive; rating by Leukodystrophy and Leukoencephalopathy GCEP), monoallelic variants are not yet associated with relevant phenotypes in these resources.; Changed publications to: 42260910; Changed phenotypes to: Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694, leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897, peripheral neuropathy, MONDO:0005244; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v8.12 DHTKD1 Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: DHTKD1.
Hereditary neuropathy or pain disorder v8.12 DHTKD1 Ida Ertmanska commented on gene: DHTKD1: Comment on list classification: While there are several patients reported with CMT and DHTKD1 variants (including the recurrent p.Tyr485Ter variant), the variants are of uncertain significance, and evidence for the association is limited. A knock in Dhtkd1 Y486* mouse model showed some signs of neuropathy on histology, but the motor performance was normal in the mutant mice. As reviewed by James Polke, high frequency of LOF variants in gnomAD and lack of a phenotype in carriers of AAKAD can be seen as refuting evidence. Hence, this gene should be downgraded from Green to Amber at the next GMS update.
Hereditary neuropathy or pain disorder v8.12 DHTKD1 Ida Ertmanska edited their review of gene: DHTKD1: Changed publications to: 32169121, 35052424, 37880984, 41169655
Hereditary neuropathy or pain disorder v8.12 DHTKD1 Ida Ertmanska changed review comment from: PMID: 41169655 Başdemirci et al., 2025
Cohort of 58 patients with suspected CMT. Method: MLPA + NGS.
Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1.

PMID: 37880984 Menon et al., 2024
Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter.

PMID: 35052424 Osmanovic et al., 2021
Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.

Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail:
https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13.

Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter).

https://doi.org/10.4103/nsn.nsn_91_25 Beton et al. 2026 - case report of a 36-year-old male with a longstanding history of gait disturbances, presented with bilateral scapular winging, proximal upper limb weakness, pes cavus, and steppage gait. Genetic testing identified a heterozygous pathogenic variant in the DHTKD1 gene, consistent with CMT2Q (variant not specified).; to: PMID: 41169655 Başdemirci et al., 2025
Cohort of 58 patients with suspected CMT. Method: MLPA + NGS.
Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1.

PMID: 37880984 Menon et al., 2024
Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter.

PMID: 35052424 Osmanovic et al., 2021
Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.

PMID: 32169121 Luan et al. 2020 - Knock-in mouse model Dhtkd1 Y486* - partially recapitulated the clinical phenotypes of CMT2Q patients. Dhtkd1 expression level in sciatic nerve of knock-in mice was significantly lower than in wild-type mice; histopathological phenotype was reminiscent of a peripheral neuropathy (reduced large axon diameter and abnormal myelination in peripheral nerves); mice displayed clear sensory defects, while no abnormalities in the motor performance were observed; also observed accumulation of mitochondria and an elevated energy metabolic state.

Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail:
https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13.

Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter).

https://doi.org/10.4103/nsn.nsn_91_25 Beton et al. 2026 - case report of a 36-year-old male with a longstanding history of gait disturbances, presented with bilateral scapular winging, proximal upper limb weakness, pes cavus, and steppage gait. Genetic testing identified a heterozygous pathogenic variant in the DHTKD1 gene, consistent with CMT2Q (variant not specified).
Hereditary neuropathy or pain disorder v8.12 DHTKD1 Ida Ertmanska changed review comment from: PMID: 41169655 Başdemirci et al., 2025
Cohort of 58 patients with suspected CMT. Method: MLPA + NGS.
Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1.

PMID: 37880984 Menon et al., 2024
Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter.

PMID: 35052424 Osmanovic et al., 2021
Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.

Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail:
https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13.
Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter).; to: PMID: 41169655 Başdemirci et al., 2025
Cohort of 58 patients with suspected CMT. Method: MLPA + NGS.
Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1.

PMID: 37880984 Menon et al., 2024
Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter.

PMID: 35052424 Osmanovic et al., 2021
Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.

Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail:
https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13.

Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter).

https://doi.org/10.4103/nsn.nsn_91_25 Beton et al. 2026 - case report of a 36-year-old male with a longstanding history of gait disturbances, presented with bilateral scapular winging, proximal upper limb weakness, pes cavus, and steppage gait. Genetic testing identified a heterozygous pathogenic variant in the DHTKD1 gene, consistent with CMT2Q (variant not specified).
Hereditary neuropathy or pain disorder v8.12 DHTKD1 Ida Ertmanska changed review comment from: PMID: 41169655 Başdemirci et al., 2025
Cohort of 58 patients with suspected CMT. Method: MLPA + NGS.
Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1.

PMID: 37880984 Menon et al., 2024
Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter.

PMID: 35052424 Osmanovic et al., 2021
Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.; to: PMID: 41169655 Başdemirci et al., 2025
Cohort of 58 patients with suspected CMT. Method: MLPA + NGS.
Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1.

PMID: 37880984 Menon et al., 2024
Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter.

PMID: 35052424 Osmanovic et al., 2021
Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.

Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail:
https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13.
Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter).
Hereditary neuropathy or pain disorder v8.12 DHTKD1 Ida Ertmanska changed review comment from: PMID: 41169655 Başdemirci et al., 2025
Cohort of 58 patients with suspected CMT. Method: MLPA + NGS.
Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1.

PMID: 37880984 Menon et al., 2024
Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: c.1445T>C, p.Tyr485Ter.

PMID: 35052424 Osmanovic et al., 2021
Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.; to: PMID: 41169655 Başdemirci et al., 2025
Cohort of 58 patients with suspected CMT. Method: MLPA + NGS.
Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1.

PMID: 37880984 Menon et al., 2024
Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter.

PMID: 35052424 Osmanovic et al., 2021
Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.
Hereditary neuropathy or pain disorder v8.12 DHTKD1 Ida Ertmanska reviewed gene: DHTKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35052424, 37880984, 41169655; Phenotypes: ?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025, Charcot-Marie-Tooth disease axonal type 2Q, MONDO:0014012; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v8.12 MT-TV Achchuthan Shanmugasundram Classified gene: MT-TV as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v8.12 MT-TV Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor and Christopher Record, there is sufficient scientific evidence available for the association of MT-TV variants with hereditary neuropathy.

However, it should be noted that the GMS reviewers previously disagreed on the inclusion of genes of the mitochondrial genome including MT-TV with green rating on other WGS/ non-WGS panels suggesting that an alternative test is more suitable for syndromic mitochondrial disease: R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing.

Hence, this gene has been tagged for expert review from GLH experts.
Hereditary neuropathy or pain disorder v8.12 MT-TV Achchuthan Shanmugasundram Gene: mt-tv has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v8.11 MT-TV Achchuthan Shanmugasundram Phenotypes for gene: MT-TV were changed from peripheral neuropathy; spasticity to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Hereditary neuropathy or pain disorder v8.10 MT-TV Achchuthan Shanmugasundram Publications for gene: MT-TV were set to 32715519: 39468830: 38371303
Hereditary neuropathy or pain disorder v8.9 MT-TV Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TV.
Hereditary neuropathy or pain disorder v8.9 MT-TV Achchuthan Shanmugasundram Tag Q3_26_expert_review tag was added to gene: MT-TV.
Tag Q3_26_promote_green tag was added to gene: MT-TV.
Hereditary neuropathy or pain disorder v8.9 MT-TV Achchuthan Shanmugasundram reviewed gene: MT-TV: Rating: GREEN; Mode of pathogenicity: None; Publications: 32715519, 38371303, 39468830, 39243325; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: MITOCHONDRIAL
Ectodermal dysplasia v5.4 FAM210A Achchuthan Shanmugasundram Classified gene: FAM210A as Amber List (moderate evidence)
Ectodermal dysplasia v5.4 FAM210A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with ectodermal dysplasia and biallelic FAM210A variants. Hence, this gene can be promoted to green rating in the next GMS update.
Ectodermal dysplasia v5.4 FAM210A Achchuthan Shanmugasundram Gene: fam210a has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v5.3 FAM210A Achchuthan Shanmugasundram commented on gene: FAM210A: The 'new-gene-name' tag has been added as the official HGNC gene symbol is MIMS1.
Ectodermal dysplasia v5.3 FAM210A Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: FAM210A.
Skeletal dysplasia v9.33 FAM210A Achchuthan Shanmugasundram Classified gene: FAM210A as Amber List (moderate evidence)
Skeletal dysplasia v9.33 FAM210A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with skeletal dysplasia and biallelic FAM210A variants. Hence, this gene can be promoted to green rating in the next GMS update.
Skeletal dysplasia v9.33 FAM210A Achchuthan Shanmugasundram Gene: fam210a has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.32 FAM210A Achchuthan Shanmugasundram commented on gene: FAM210A: The 'new-gene-name' tag has been added as the official HGNC gene symbol is MIMS1.
Skeletal dysplasia v9.32 FAM210A Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: FAM210A.
Ectodermal dysplasia v5.3 FAM210A Achchuthan Shanmugasundram gene: FAM210A was added
gene: FAM210A was added to Ectodermal dysplasia. Sources: Literature
Q3_26_promote_green tags were added to gene: FAM210A.
Mode of inheritance for gene: FAM210A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM210A were set to 42410297
Phenotypes for gene: FAM210A were set to Spondyloepimetaphyseal dysplasia with tracheal stenosis and ectodermal dysplasia, OMIM:621650
Review for gene: FAM210A was set to GREEN
Added comment: PMID:42410297 (2026) reported five patients from four unrelated families with skeletal dysplasia phenotype characterised by spondyloepimetaphyseal dysplasiachondrodysplasia with short stature (all patents), tracheal stenosis (all patients), conical teeth and/or early tooth decay, and sparse hair suggestive of ectodermal dysplasia (in three unrelated patients).

They were identified with biallelic variants in FAM210A gene (new gene name - MIMS1) - homozygous missense variants in three families and compound heterozygous nonsense variants in the first family with two siblings.

This gene has been associated with relevant phenotype in OMIM (MIM #621650, last accessed 24 July 2026), but not in Gene2Phenotype or ClinGen.
Sources: Literature
Skeletal dysplasia v9.32 FAM210A Achchuthan Shanmugasundram gene: FAM210A was added
gene: FAM210A was added to Skeletal dysplasia. Sources: Literature
Q3_26_promote_green tags were added to gene: FAM210A.
Mode of inheritance for gene: FAM210A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM210A were set to 42410297
Phenotypes for gene: FAM210A were set to Spondyloepimetaphyseal dysplasia with tracheal stenosis and ectodermal dysplasia, OMIM:621650
Review for gene: FAM210A was set to GREEN
Added comment: PMID:42410297 (2026) reported five patients from four unrelated families with skeletal dysplasia phenotype characterised by spondyloepimetaphyseal dysplasiachondrodysplasia with short stature (all patents), tracheal stenosis (all patients), conical teeth and/or early tooth decay, and sparse hair suggestive of ectodermal dysplasia (in three unrelated patients).

They were identified with biallelic variants in FAM210A gene (new gene name - MIMS1) - homozygous missense variants in three families and compound heterozygous nonsense variants in the first family with two siblings.

This gene has been associated with relevant phenotype in OMIM (MIM #621650, last accessed 24 July 2026), but not in Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v10.60 SNW1 Achchuthan Shanmugasundram Classified gene: SNW1 as Amber List (moderate evidence)
Intellectual disability v10.60 SNW1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of this gene with intellectual disability (moderate-severe), it should be promoted to green rating in the next GMS update.
Intellectual disability v10.60 SNW1 Achchuthan Shanmugasundram Gene: snw1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.59 SNW1 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SNW1.
Intellectual disability v10.59 SNW1 Achchuthan Shanmugasundram changed review comment from: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature; to: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 July 2026), Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature
Early onset or syndromic epilepsy v9.40 SNW1 Achchuthan Shanmugasundram Classified gene: SNW1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.40 SNW1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of this gene with seizures, it should be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v9.40 SNW1 Achchuthan Shanmugasundram Gene: snw1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.39 SNW1 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SNW1.
Early onset or syndromic epilepsy v9.39 SNW1 Achchuthan Shanmugasundram changed review comment from: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature; to: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 July 2026), Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature
Severe microcephaly v9.11 SNW1 Achchuthan Shanmugasundram Classified gene: SNW1 as Amber List (moderate evidence)
Severe microcephaly v9.11 SNW1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of this gene with severe microcephaly, it should be promoted to green rating in the next GMS update.
Severe microcephaly v9.11 SNW1 Achchuthan Shanmugasundram Gene: snw1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v9.10 SNW1 Achchuthan Shanmugasundram changed review comment from: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature; to: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 July 2026), Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature
Severe microcephaly v9.10 SNW1 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SNW1.
Early onset or syndromic epilepsy v9.39 SNW1 Achchuthan Shanmugasundram gene: SNW1 was added
gene: SNW1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: SNW1 was set to GREEN
Added comment: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature
Intellectual disability v10.59 SNW1 Achchuthan Shanmugasundram gene: SNW1 was added
gene: SNW1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: SNW1 was set to GREEN
Added comment: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature
Severe microcephaly v9.10 SNW1 Achchuthan Shanmugasundram gene: SNW1 was added
gene: SNW1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: SNW1 was set to GREEN
Added comment: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v9.12 ATN1_CAG Ida Ertmanska Phenotypes for STR: ATN1_CAG were changed from Dentatorubral-pallidoluysian atrophy, OMIM:125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370; dentatorubral-pallidoluysian atrophy, MONDO:0007435
Ataxia and cerebellar anomalies - childhood onset v9.11 ATN1_CAG Ida Ertmanska Publications for STR: ATN1_CAG were set to 20301664; 8136840; 20301664; 8136840; 8136826; 7614090
Leukodystrophy, adult onset v7.7 ATN1_CAG Ida Ertmanska Tag Q3_26_NHS_review tag was added to STR: ATN1_CAG.
Tag Q3_26_promote_green tag was added to STR: ATN1_CAG.
Leukodystrophy, adult onset v7.7 ATN1_CAG Ida Ertmanska Phenotypes for STR: ATN1_CAG were changed from to Dentatorubral-pallidoluysian atrophy, OMIM:125370; dentatorubral-pallidoluysian atrophy, MONDO:0007435
Leukodystrophy, adult onset v7.6 ATN1_CAG Ida Ertmanska Publications for STR: ATN1_CAG were set to
Leukodystrophy, adult onset v7.5 ATN1_CAG Ida Ertmanska Classified STR: ATN1_CAG as Amber List (moderate evidence)
Leukodystrophy, adult onset v7.5 ATN1_CAG Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there are numerous individuals reported in literature with ATN1 CAG repeats and adult-onset Dentatorubral-Pallidoluysian Atrophy, which entails widespread white matter atrophy. Hence, this STR should be promoted to Green on Adult onset leukodystrophy.
Leukodystrophy, adult onset v7.5 ATN1_CAG Ida Ertmanska Str: atn1_cag has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v9.10 ATN1_CAG Ida Ertmanska reviewed STR: ATN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v9.10 ATN1_CAG Ida Ertmanska Tag Q3_26_promote_green tag was added to STR: ATN1_CAG.
Ataxia and cerebellar anomalies - childhood onset v9.10 ATN1_CAG Ida Ertmanska Tag watchlist was removed from STR: ATN1_CAG.
Ataxia and cerebellar anomalies - childhood onset v9.10 ATN1_CAG Luke Stuart reviewed STR: ATN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20589872, 22527233; Phenotypes: Dentatorubral-pallidoluysian atrophy, 125370; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Leukodystrophy, adult onset v7.4 ATN1_CAG Luke Stuart reviewed STR: ATN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 8586978, 8370212, 1837247, 9409354, 40298952, 15210537, 8167052; Phenotypes: Dentatorubral-pallidoluysian atrophy, 125370; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v9.29 LONP1 Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373) to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092
Likely inborn error of metabolism v9.28 LONP1 Achchuthan Shanmugasundram Publications for gene: LONP1 were set to 25574826; 25808063
Likely inborn error of metabolism v9.27 LONP1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Likely inborn error of metabolism v9.27 LONP1 Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v9.26 LONP1 Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: LONP1.
Likely inborn error of metabolism v9.26 LONP1 Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v10.16 LONP1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Mitochondrial disorders v10.16 LONP1 Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v10.15 LONP1 Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373) to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092
Mitochondrial disorders v10.14 LONP1 Achchuthan Shanmugasundram Publications for gene: LONP1 were set to PMID: 25574826; PMID: 25808063
Mitochondrial disorders v10.13 LONP1 Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: LONP1.
Mitochondrial disorders v10.13 LONP1 Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v5.15 LONP1 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.; to: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Possible mitochondrial disorder, nuclear genes v5.15 LONP1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Possible mitochondrial disorder, nuclear genes v5.15 LONP1 Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v5.14 LONP1 Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS syndrome, 600373 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092
Possible mitochondrial disorder, nuclear genes v5.13 LONP1 Achchuthan Shanmugasundram Publications for gene: LONP1 were set to
Possible mitochondrial disorder, nuclear genes v5.12 LONP1 Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: LONP1.
Possible mitochondrial disorder, nuclear genes v5.12 LONP1 Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v10.58 LONP1 Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS syndrome, 600373; Cerebral, ocular, dental, auricular, and skeletal anomalies syndrome to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v10.57 LONP1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least three unrelated individuals reported with monoallelic LONP1 variants and syndromic intellectual disability. Hence, the MOI for this gene can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Intellectual disability v10.57 LONP1 Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.56 LONP1 Achchuthan Shanmugasundram edited their review of gene: LONP1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v10.56 LONP1 Achchuthan Shanmugasundram Publications for gene: LONP1 were set to 25574826; 20503327; 11471171; 1887855
Intellectual disability v10.55 LONP1 Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: LONP1.
Intellectual disability v10.55 LONP1 Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.55 CDK20 Achchuthan Shanmugasundram Tag Q3_26_promote_green was removed from gene: CDK20.
Intellectual disability v10.55 CDK20 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are two unrelated live individuals reported with biallelic CDK20 variants and with a multisystem phenotype including global developmental delay and/or intellectual disability. Hence, this gene should be rated amber with the current evidence.
Intellectual disability v10.55 CDK20 Achchuthan Shanmugasundram changed review comment from: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Ventriculomegaly and/ or hydrocephalus was reported in four foetuses from two unrelated families and a live child from another family.

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature; to: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay.

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature
Intellectual disability v10.55 CDK20 Achchuthan Shanmugasundram edited their review of gene: CDK20: Changed rating: AMBER; Changed phenotypes to: ciliopathy, MONDO:0005308, Ventriculomegaly, HP:0002119, hydrocephalus, MONDO:0001150, Global developmental delay, HP:0001263
Intellectual disability v10.55 CDK20 Achchuthan Shanmugasundram Entity copied from Hydrocephalus v5.14
Intellectual disability v10.55 CDK20 Achchuthan Shanmugasundram gene: CDK20 was added
gene: CDK20 was added to Intellectual disability. Sources: Expert Review Amber,Literature
Q3_26_promote_green tags were added to gene: CDK20.
Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK20 were set to 42409022
Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150
Holoprosencephaly v6.3 CDK20 Achchuthan Shanmugasundram gene: CDK20 was added
gene: CDK20 was added to Holoprosencephaly. Sources: Literature
Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK20 were set to 42409022
Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150; holoprosencephaly, MONDO:0016296
Review for gene: CDK20 was set to RED
Added comment: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Semilobar holoprosencephaly was identified by ultrasound in one foetus (family III).

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature
Clefting v7.8 CDK20 Achchuthan Shanmugasundram changed review comment from: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Midline cleft lip/ palate was reported in five individuals from four families, of which three are foetuses.

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature; to: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Midline cleft lip/ palate was reported in five individuals from four families, of which four are foetuses.

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature
Clefting v7.8 CDK20 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are Fien individuals from four unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including midline cleft lip/ palate. Hence, this gene can be promoted to green rating in the next GMS update.
Clefting v7.8 CDK20 Achchuthan Shanmugasundram changed review comment from: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Ventriculomegaly and/ or hydrocephalus was reported in four foetuses from two unrelated families and a live child from another family.

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature; to: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Midline cleft lip/ palate was reported in five individuals from four families, of which three are foetuses.

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature
Clefting v7.8 CDK20 Achchuthan Shanmugasundram Entity copied from Hydrocephalus v5.14
Clefting v7.8 CDK20 Achchuthan Shanmugasundram gene: CDK20 was added
gene: CDK20 was added to Clefting. Sources: Expert Review Amber,Literature
Q3_26_promote_green tags were added to gene: CDK20.
Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK20 were set to 42409022
Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150
Hydrocephalus v5.14 CDK20 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green raring in the next GMS update.; to: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green rating in the next GMS update.
Hydrocephalus v5.14 CDK20 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are five unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype, which included five foetuses from three families (resulting in termination of pregnancies) and two live children. This gene can therefore promoted to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green raring in the next GMS update.
Hydrocephalus v5.14 CDK20 Achchuthan Shanmugasundram changed review comment from: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay.

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature; to: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Ventriculomegaly and/ or hydrocephalus was reported in four foetuses from two unrelated families and a live child from another family.

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature
Hydrocephalus v5.14 CDK20 Achchuthan Shanmugasundram Entity copied from Fetal anomalies v7.32
Hydrocephalus v5.14 CDK20 Achchuthan Shanmugasundram gene: CDK20 was added
gene: CDK20 was added to Hydrocephalus. Sources: Expert Review Amber,Literature
Q3_26_promote_green tags were added to gene: CDK20.
Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK20 were set to 42409022
Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150
Fetal anomalies v7.32 CDK20 Achchuthan Shanmugasundram Classified gene: CDK20 as Amber List (moderate evidence)
Fetal anomalies v7.32 CDK20 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype, which included five foetuses from three families (resulting in termination of pregnancies) and two live children. This gene can therefore promoted to green rating in the next GMS update.
Fetal anomalies v7.32 CDK20 Achchuthan Shanmugasundram Gene: cdk20 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v7.31 CDK20 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: CDK20.
Fetal anomalies v7.31 CDK20 Achchuthan Shanmugasundram gene: CDK20 was added
gene: CDK20 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK20 were set to 42409022
Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150
Review for gene: CDK20 was set to GREEN
Added comment: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies.

Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay.

These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total.

Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness.

This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype.
Sources: Literature
Monogenic hearing loss v6.33 COL4A6 Ida Ertmanska Mode of inheritance for gene: COL4A6 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Monogenic hearing loss v6.32 COL4A6 Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated male individuals reported in literature with hemizygous COL4A6 variants and non-syndromic hearing loss. Hence, this gene can be promoted to Green at the next update. MOI should be set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as little segregation evidence is provided for the families - unclear if female carriers may also present with deafness.; to: Comment on list classification: There are more than 3 unrelated male individuals reported in literature with hemizygous COL4A6 variants and non-syndromic hearing loss. Hence, this gene can be promoted to Green at the next update. MOI should be set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as little segregation evidence is provided for the families - unclear if female carriers may also present with COL4A6-related deafness.
Monogenic hearing loss v6.32 COL4A6 Ida Ertmanska commented on gene: COL4A6: Comment on list classification: There are more than 3 unrelated male individuals reported in literature with hemizygous COL4A6 variants and non-syndromic hearing loss. Hence, this gene can be promoted to Green at the next update. MOI should be set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as little segregation evidence is provided for the families - unclear if female carriers may also present with deafness.
Monogenic hearing loss v6.32 COL4A6 Ida Ertmanska edited their review of gene: COL4A6: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Monogenic hearing loss v6.32 COL4A6 Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP).; to: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). Parents unaffected, not genotyped.

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous affected mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP).
Monogenic hearing loss v6.32 COL4A6 Ida Ertmanska Phenotypes for gene: COL4A6 were changed from Deafness, X-linked 6, OMIM:300914 to ?Deafness, X-linked 6 , OMIM:300914; hearing loss, X-linked 6, MONDO:0010484
Monogenic hearing loss v6.31 COL4A6 Ida Ertmanska Publications for gene: COL4A6 were set to PMID: 23714752; 7592929; 7711741; 7972123; 8125972; 8175748; 8356449; 8661006; 9463311
Monogenic hearing loss v6.30 COL4A6 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: COL4A6.
Monogenic hearing loss v6.30 COL4A6 Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).; to: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP).
Monogenic hearing loss v6.30 COL4A6 Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951 + 1 G > T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 varinats in the two kindreds, which are also likely to contribute to hearing loss.

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).; to: PMID: 41092388 Owrang et al., 2026
Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features.
The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.

PMID: 40928595 Jagannath et al., 2025
Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu).

PMID: 39272213 Feng et al., 2024
Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S.

PMID: 33840813 O'Brien et al., 2022
Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15.
Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss.

Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss

The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).
Intellectual disability v10.54 NSF Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene is now associated with a relevant phenotype in OMIM (MIM #619340), but not in Gene2Phenotype.; to: Comment on phenotypes: This gene is now associated with a relevant phenotype in OMIM (MIM #619340, last accessed 22 July 2026), but not in Gene2Phenotype.
Intellectual disability v10.54 NSF Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v10.54 NSF Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v10.54 NSF Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v9.38 NSF Achchuthan Shanmugasundram Classified gene: NSF as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.38 NSF Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with monoallelic variants in NSF gene and with infantile-onset epileptic encephalopathy. Hence, this gene can be promote to green rating in the next GMS update.
Early onset or syndromic epilepsy v9.38 NSF Achchuthan Shanmugasundram Gene: nsf has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.30 COL4A6 Ida Ertmanska reviewed gene: COL4A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 33840813, 39272213, 40928595, 41092388; Phenotypes: ?Deafness, X-linked 6 , OMIM:300914, hearing loss, X-linked 6, MONDO:0010484; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v9.37 NSF Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: NSF.
Early onset or syndromic epilepsy v9.37 NSF Achchuthan Shanmugasundram Publications for gene: NSF were set to 31675180; 36645181
Early onset or syndromic epilepsy v9.36 NSF Achchuthan Shanmugasundram Phenotypes for gene: NSF were changed from Developmental and epileptic encephalopathy 96, OMIM:619340 to Developmental and epileptic encephalopathy 96, OMIM:619340; developmental and epileptic encephalopathy 96, MONDO:0023659
Early onset or syndromic epilepsy v9.35 NSF Achchuthan Shanmugasundram Mode of inheritance for gene: NSF was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.34 NSF Achchuthan Shanmugasundram changed review comment from: PMID:36645181 describes the two previously reported cases from PMID:31675180. The third case reported had a very mild phenotype and did not present with epilepsy and had normal development. Hence, this gene should remain AMBER.

This gene has now been associated with relevant phenotype in OMIM (MIM #619340), but not in Gene2Phenotype.; to: PMID:36645181 (2023) described the two previously reported cases from PMID:31675180 (2019) with de novo pathogenic variants in NSF gene and with early infantile epileptic encephalopathy. The third case reported with a de novo missense variant in NSF gene had a very mild phenotype and did not present with epilepsy and had normal development.

PMID:42045022 (2026) reported a cohort of 38 previously unsolved infantile-onset developmental epileptic encephalopathy (DEE) probands that were sequenced with long-read genome sequencing, of which one proband was identified with a heterozygous c.664G>A (p.Gly222Ser) variant in NSF gene. This patient was not previously identified with a variant in this gene through exome sequencing because the NSF gene is known to be in a multiple alignment region.

This gene has been associated with relevant phenotype in OMIM (MIM #619340, last accessed 22 July 2026), but not in Gene2Phenotype.
Early onset or syndromic epilepsy v9.34 NSF Achchuthan Shanmugasundram edited their review of gene: NSF: Changed rating: GREEN; Changed publications to: 31675180, 36645181, 42045022; Changed phenotypes to: Developmental and epileptic encephalopathy 96, OMIM:619340, developmental and epileptic encephalopathy 96, MONDO:0023659
Congenital fibrosis of the extraocular muscles v2.7 ZFHX4 Ida Ertmanska Tag Q3_26_expert_review was removed from gene: ZFHX4.
Tag Q3_26_NHS_review tag was added to gene: ZFHX4.
Congenital hyperinsulinism v3.9 CACNA1C Ida Ertmanska Tag Q3_26_NHS_review tag was added to gene: CACNA1C.
Tag Q3_26_demote_red tag was added to gene: CACNA1C.
Congenital hyperinsulinism v3.9 CACNA1C Ida Ertmanska reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: None; Publications: 30067485, 35897673, 39420001; Phenotypes: Timothy syndrome, OMIM:601005; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital fibrosis of the extraocular muscles v2.7 ZFHX4 Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: ZFHX4.
Tag Q3_26_promote_green tag was added to gene: ZFHX4.
Congenital fibrosis of the extraocular muscles v2.7 ZFHX4 Ida Ertmanska Phenotypes for gene: ZFHX4 were changed from Isolated congenital ptosis to congenital ptosis, MONDO:0008340
Congenital fibrosis of the extraocular muscles v2.6 ZFHX4 Ida Ertmanska Publications for gene: ZFHX4 were set to PMID: 41524020; 11935336; 32962661
Congenital fibrosis of the extraocular muscles v2.5 ZFHX4 Ida Ertmanska Classified gene: ZFHX4 as Amber List (moderate evidence)
Congenital fibrosis of the extraocular muscles v2.5 ZFHX4 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated patients reported in literature with heterozygous ZFHX4 variants and isolated congenital ptosis. Hence, this gene can be promoted to Green at the next update.
Congenital fibrosis of the extraocular muscles v2.5 ZFHX4 Ida Ertmanska Gene: zfhx4 has been classified as Amber List (Moderate Evidence).
Congenital fibrosis of the extraocular muscles v2.4 ZFHX4 Ida Ertmanska edited their review of gene: ZFHX4: Changed publications to: 41524020, 32962661, 17987257, 11935336
Congenital fibrosis of the extraocular muscles v2.4 ZFHX4 Ida Ertmanska changed review comment from: PMID: 41524020 Zhang et al., 2026
Cohort of patients with isolated congenital ptosis. Seq method: WES. Three novel heterozygous variants in ZFHX4, c.5145C>A (p.N1715K), c.10382C>T (p.A3461V), and c.10795G>A (p.A3599T), were identified in three patients of Han Chinese origin.

PMID: 32962661 Adhikari et al., 2020
Report of a Nepalese proband with congenital ptosis and a c.12411G>T, p.Leu4137Phe variant in exon 12 of ZFHX4.
Same variant reported in a Japanese kindred with hereditary congenital blepharoptosis (PMID: 17987257, Nakashima et al., 2008).

This gene is not yet associated with a disease entity in OMIM. ZFHX4 association with AD syndromic complex neurodevelopmental disorder was classified as Strong in ClinGen in December 2025 (Intellectual Disability and Autism GCEP).; to: PMID: 41524020 Zhang et al., 2026
Cohort of patients with isolated congenital ptosis. Seq method: WES. Three novel heterozygous variants in ZFHX4, c.5145C>A (p.N1715K), c.10382C>T (p.A3461V), and c.10795G>A (p.A3599T), were identified in three patients of Han Chinese origin.

PMID: 32962661 Adhikari et al., 2020
Report of a Nepalese proband with congenital ptosis and a c.12411G>T, p.Leu4137Phe variant in exon 12 of ZFHX4.
Same variant reported in a Japanese kindred with hereditary congenital blepharoptosis (PMID: 17987257, Nakashima et al., 2008).

PMID: 11935336 McMullan et al., 2002
Report of a patient with congenital bilateral isolated ptosis and a de novo balanced translocation 46,XY,t(1;8)(p34.3;q21.12). The 1p breakpoint does not disrupt a coding sequence, whereas the chromosome 8 breakpoint disrupts the ZFHX4 gene.

This gene is not yet associated with a disease entity in OMIM. ZFHX4 association with AD syndromic complex neurodevelopmental disorder was classified as Strong in ClinGen in December 2025 (Intellectual Disability and Autism GCEP).
Congenital fibrosis of the extraocular muscles v2.4 ZFHX4 Ida Ertmanska reviewed gene: ZFHX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 41524020, 32962661, 17987257; Phenotypes: congenital ptosis, MONDO:0008340; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder, nuclear genes v5.12 TIMM8A Ida Ertmanska Phenotypes for gene: TIMM8A were changed from Mohr-Tranebjaerg syndrome, 304700 to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578
Possible mitochondrial disorder, nuclear genes v5.11 TIMM8A Ida Ertmanska Publications for gene: TIMM8A were set to
Possible mitochondrial disorder, nuclear genes v5.10 TIMM8A Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A.
Possible mitochondrial disorder, nuclear genes v5.10 TIMM8A Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Possible mitochondrial disorder, nuclear genes v5.10 TIMM8A Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11601506, 22736418, 40597358; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Monogenic hearing loss v6.30 TIMM8A Ida Ertmanska Phenotypes for gene: TIMM8A were changed from #304700:Mohr-Tranebjaerg syndrome; hearing loss; Deafness, X-linked 1, progressive to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578
Monogenic hearing loss v6.29 TIMM8A Ida Ertmanska Publications for gene: TIMM8A were set to PMID: 10051608; 10878669; 11405816; 11601506; 11875042; 11956200; 15037720; 15254020; 15710860; 16411215; 8380905; 8841189
Monogenic hearing loss v6.28 TIMM8A Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A.
Monogenic hearing loss v6.28 TIMM8A Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females (1 presenting with deafness) reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Monogenic hearing loss v6.28 TIMM8A Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11601506, 22736418, 40597358; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mitochondrial disorders v10.13 TIMM8A Ida Ertmanska Phenotypes for gene: TIMM8A were changed from Disorders of the mitochondrial import system; Deafness, X-linked 1, progressive; Mohr-Tranebjaerg syndrome, 304700; Jensen syndrome, 311150 to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578
Mitochondrial disorders v10.12 TIMM8A Ida Ertmanska Publications for gene: TIMM8A were set to
Mitochondrial disorders v10.11 TIMM8A Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A.
Mitochondrial disorders v10.11 TIMM8A Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Mitochondrial disorders v10.11 TIMM8A Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11601506, 22736418, 40597358; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Likely inborn error of metabolism v9.26 TIMM8A Ida Ertmanska Phenotypes for gene: TIMM8A were changed from Mohr-Tranebjaerg syndrome, 304700; Jensen syndrome, 311150; Disorders of the mitochondrial import system; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Deafness, X-linked 1, progressive to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578
Likely inborn error of metabolism v9.25 TIMM8A Ida Ertmanska Publications for gene: TIMM8A were set to 27604308
Likely inborn error of metabolism v9.24 TIMM8A Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A.
Likely inborn error of metabolism v9.24 TIMM8A Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Likely inborn error of metabolism v9.24 TIMM8A Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11601506, 22736418, 40597358; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Dystonia, chorea or related movement disorder, adult onset v6.6 TIMM8A Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Dystonia, chorea or related movement disorder, adult onset v6.6 TIMM8A Ida Ertmanska Phenotypes for gene: TIMM8A were changed from Mohr-Tranebjaerg syndrome, OMIM:304700 to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578
Dystonia, chorea or related movement disorder, adult onset v6.5 TIMM8A Ida Ertmanska Publications for gene: TIMM8A were set to 22736418; 32820032
Dystonia, chorea or related movement disorder, adult onset v6.4 TIMM8A Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A.
Dystonia, chorea or related movement disorder, adult onset v6.4 TIMM8A Ida Ertmanska edited their review of gene: TIMM8A: Changed publications to: 11601506, 22736418, 40597358
Dystonia, chorea or related movement disorder, adult onset v6.4 TIMM8A Ida Ertmanska changed review comment from: PMID: 40597358 Ventura et al., 2025
Report of a 16yo male with 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI; no hearing loss. WES detected a hemizygous TIMM8A variant c.98_101dupAGCA.
The variant was inherited from a heterozygous mother, 43yo, who had recurrent muscle spasms - confirmed generalized dystonia, particularly affecting the upper extremities and cervical muscles. Maternal uncle showed motor clumsiness and finger spasms in childhood. Neither had hearing loss or visual impairment.

PMID: 22736418 Ha et al., 2012
Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs. Cognitive decline was noted in her 50s.; to: PMID: 40597358 Ventura et al., 2025
Report of a 16yo male with 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI; no hearing loss. WES detected a hemizygous TIMM8A variant c.98_101dupAGCA.
The variant was inherited from a heterozygous mother, 43yo, who had recurrent muscle spasms - confirmed generalized dystonia, particularly affecting the upper extremities and cervical muscles. Maternal uncle showed motor clumsiness and finger spasms in childhood. Neither had hearing loss or visual impairment.

PMID: 22736418 Ha et al., 2012
Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs. Cognitive decline was noted in her 50s.

PMID: 11601506 Swerdlow & Wooten, 2001
Kindred with Mohr-Tranebjaerg syndrome. Proband is a 30yo male with congenital deafness, and generalised dystonia starting around 28yo. Proband's mother reported head shaking, chronic neck muscle pain, and writer's cramp since age 25yrs. 1 female sibling of the proband was unaffected, while the other reported head shaking and writer's cramp with onset in late teens / early 20s. Affected patients harboured TIMM8A (old name DDP1) c.108del.
Dystonia, chorea or related movement disorder, adult onset v6.4 TIMM8A Ida Ertmanska edited their review of gene: TIMM8A: Changed phenotypes to: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578
Dystonia, chorea or related movement disorder, adult onset v6.4 TIMM8A Ida Ertmanska edited their review of gene: TIMM8A: Changed publications to: 22736418, 40597358
Dystonia, chorea or related movement disorder, adult onset v6.4 TIMM8A Ida Ertmanska changed review comment from: PMID: 22736418 Ha et al., 2012
Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs.; to: PMID: 40597358 Ventura et al., 2025
Report of a 16yo male with 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI; no hearing loss. WES detected a hemizygous TIMM8A variant c.98_101dupAGCA.
The variant was inherited from a heterozygous mother, 43yo, who had recurrent muscle spasms - confirmed generalized dystonia, particularly affecting the upper extremities and cervical muscles. Maternal uncle showed motor clumsiness and finger spasms in childhood. Neither had hearing loss or visual impairment.

PMID: 22736418 Ha et al., 2012
Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs. Cognitive decline was noted in her 50s.
Leukodystrophy, adult onset v7.4 ATN1_CAG Eleanor Williams ATN1 was changed to ATN1_CAG
Source NHS GMS was removed from STR: ATN1_CAG.
Source Literature was added to STR: ATN1_CAG.
Tag STR was added to STR: ATN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v6.4 TIMM8A Ida Ertmanska changed review comment from: PMID: 22736418 Ha et al., 2012
Report of a female proband (kindred B) hemizygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs.; to: PMID: 22736418 Ha et al., 2012
Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs.
Dystonia, chorea or related movement disorder, adult onset v6.4 TIMM8A Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22736418; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v7.30 TMEM251 Eleanor Williams Publications for gene: TMEM251 were set to
Fetal anomalies v7.29 TMEM251 Eleanor Williams Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex, Ain-Naz type, OMIM:619345 to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156
Leukodystrophy, adult onset v7.3 ATN1 Lucy Jackson edited their review of STR: ATN1: Changed rating: GREEN
Leukodystrophy, adult onset v7.3 ATN1 Lucy Jackson STR: ATN1 was added
STR: ATN1 was added to Adult onset leukodystrophy. Sources: NHS GMS
Mode of inheritance for STR: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
STR: ATN1 was marked as current diagnostic
Added comment: National Inherited White Matter Disorders MDT requests that this STR is added to the R62 panel
Sources: NHS GMS
Hereditary neuropathy or pain disorder v8.9 OGDH Alexander Rossor gene: OGDH was added
gene: OGDH was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: OGDH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OGDH were set to 42266417
Phenotypes for gene: OGDH were set to peripheral neuropathy; cerebellar ataxia; optic neuropathy
Mode of pathogenicity for gene: OGDH was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: OGDH was set to AMBER
Added comment: Only two families described so far
Sources: Expert list
Hereditary neuropathy or pain disorder v8.9 POLR3A Alexander Rossor edited their review of gene: POLR3A: Added comment: 8 unrelated patients. Should also add monoalleleic POLR3A variants to the panel (not just bialleleic); Changed publications to: 42260910; Changed phenotypes to: Early onset peripheral neuropathy; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arthrogryposis v10.15 TMEM251 Ida Ertmanska changed review comment from: Comment on list classification: There are now three unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now three unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update.
Arthrogryposis v10.15 TMEM251 Ida Ertmanska changed review comment from: Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET.; to: Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET.
Arthrogryposis v10.15 TMEM251 Ida Ertmanska changed review comment from: Comment on list classification: There are now four unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now three unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update.
Arthrogryposis v10.15 TMEM251 Ida Ertmanska Classified gene: TMEM251 as Amber List (moderate evidence)
Arthrogryposis v10.15 TMEM251 Ida Ertmanska Added comment: Comment on list classification: There are now four unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update.
Arthrogryposis v10.15 TMEM251 Ida Ertmanska Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v10.14 TMEM251 Ida Ertmanska changed review comment from: PMID: 41858182 Sperb-Ludwig et al., 2026
Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more).

PMID: 40171858 Kariminejad et al., 2025
Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD.

PMID:33252156 Ain et al., 2021
Report of two unrelated families (from Pakistan and Iran) with individuals presenting with a severe skeletal disorder. WES identified two homozygous variants (missense and nonsense) in TMEM251. The candidate variants segregated with 5 affected members of the first family. In the second family there was only 1 affected individual who was homozygous for the variant, 22 other unaffected members were either heterozygous or and wild type alleles. P2 had developmental delay and craniosynostosis in addition to skeletal abnormalities.
Abnormal activities of three lysosomal enzymes detected from the sample of the patient from one family suggest that TMEM251 may have a metabolic role. (It was not possible to perform these tests in affected individuals in the other family).
Some functional data: p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate in Golgi in osteosarcoma cells, and Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes).
Sources: Literature; to: PMID: 41858182 Sperb-Ludwig et al., 2026
Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more).

PMID: 40171858 Kariminejad et al., 2025
Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD.

PMID:33252156 Ain et al., 2021
Report of two unrelated families (from Pakistan and Iran) with individuals presenting with a severe skeletal disorder. WES identified two homozygous variants (missense and nonsense) in TMEM251. The candidate variants segregated with 5 affected members of the first family. In the second family there was only 1 affected individual who was homozygous for the variant, 22 other unaffected members were either heterozygous or and wild type alleles. P2 had developmental delay and craniosynostosis in addition to skeletal abnormalities. 2 individuals from family NMD02 were noted to have severe joint contractures, which led to losing their ability to walk.
Abnormal activities of three lysosomal enzymes detected from the sample of the patient from one family suggest that TMEM251 may have a metabolic role. (It was not possible to perform these tests in affected individuals in the other family).
Some functional data: p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate in Golgi in osteosarcoma cells, and Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes).
Sources: Literature
Arthrogryposis v10.14 TMEM251 Ida Ertmanska Tag new-gene-name tag was added to gene: TMEM251.
Arthrogryposis v10.14 TMEM251 Ida Ertmanska commented on gene: TMEM251: Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET.
Likely inborn error of metabolism v9.24 TMEM251 Ida Ertmanska commented on gene: TMEM251: Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET.
Likely inborn error of metabolism v9.24 TMEM251 Ida Ertmanska Tag new-gene-name tag was added to gene: TMEM251.
Likely inborn error of metabolism v9.24 TMEM251 Ida Ertmanska Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156 to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156; lysosomal storage disease with skeletal involvement, MONDO:0800088
Likely inborn error of metabolism v9.23 TMEM251 Ida Ertmanska edited their review of gene: TMEM251: Changed phenotypes to: Dysostosis multiplex, Ain-Naz type, OMIM:619345, dysostosis multiplex, Ain-Naz type, MONDO:0859156, lysosomal storage disease with skeletal involvement, MONDO:0800088
Likely inborn error of metabolism v9.23 TMEM251 Ida Ertmanska Classified gene: TMEM251 as Amber List (moderate evidence)
Likely inborn error of metabolism v9.23 TMEM251 Ida Ertmanska Added comment: Comment on list classification: There are now four unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, stemming from abnormal lysosomal enzyme activity. Hence, this gene can be promoted to Green at the next update.
Likely inborn error of metabolism v9.23 TMEM251 Ida Ertmanska Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v10.14 TMEM251 Ida Ertmanska gene: TMEM251 was added
gene: TMEM251 was added to Arthrogryposis. Sources: Literature
Q3_26_promote_green tags were added to gene: TMEM251.
Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM251 were set to 33252156; 40171858; 41858182
Phenotypes for gene: TMEM251 were set to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156
Review for gene: TMEM251 was set to GREEN
Added comment: PMID: 41858182 Sperb-Ludwig et al., 2026
Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more).

PMID: 40171858 Kariminejad et al., 2025
Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD.

PMID:33252156 Ain et al., 2021
Report of two unrelated families (from Pakistan and Iran) with individuals presenting with a severe skeletal disorder. WES identified two homozygous variants (missense and nonsense) in TMEM251. The candidate variants segregated with 5 affected members of the first family. In the second family there was only 1 affected individual who was homozygous for the variant, 22 other unaffected members were either heterozygous or and wild type alleles. P2 had developmental delay and craniosynostosis in addition to skeletal abnormalities.
Abnormal activities of three lysosomal enzymes detected from the sample of the patient from one family suggest that TMEM251 may have a metabolic role. (It was not possible to perform these tests in affected individuals in the other family).
Some functional data: p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate in Golgi in osteosarcoma cells, and Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes).
Sources: Literature
Likely inborn error of metabolism v9.22 TMEM251 Ida Ertmanska gene: TMEM251 was added
gene: TMEM251 was added to Likely inborn error of metabolism. Sources: Literature
Q3_26_promote_green tags were added to gene: TMEM251.
Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM251 were set to 33252156; 40171858; 41858182
Phenotypes for gene: TMEM251 were set to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156
Review for gene: TMEM251 was set to GREEN
Added comment: PMID: 41858182 Sperb-Ludwig et al., 2026
Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more).

PMID: 40171858 Kariminejad et al., 2025
Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD.

PMID:33252156 Ain et al., 2021
Report of two unrelated families (from Pakistan and Iran) with individuals presenting with a severe skeletal disorder. WES identified two homozygous variants (missense and nonsense) in TMEM251. The candidate variants segregated with 5 affected members of the first family. In the second family there was only 1 affected individual who was homozygous for the variant, 22 other unaffected members were either heterozygous or and wild type alleles. P2 had developmental delay and craniosynostosis in addition to skeletal abnormalities.
Abnormal activities of three lysosomal enzymes detected from the sample of the patient from one family suggest that TMEM251 may have a metabolic role. (It was not possible to perform these tests in affected individuals in the other family).
Some functional data: p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate in Golgi in osteosarcoma cells, and Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.12 TMEM251 Ida Ertmanska Classified gene: TMEM251 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.12 TMEM251 Ida Ertmanska Added comment: Comment on list classification: Updated rating to Amber as second patient reported in PMID:41858182 (brachycephaly).
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.12 TMEM251 Ida Ertmanska Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 TMEM251 Ida Ertmanska reviewed gene: TMEM251: Rating: AMBER; Mode of pathogenicity: None; Publications: 41858182, 40171858; Phenotypes: Dysostosis multiplex, Ain-Naz type, OMIM:619345, craniosynostosis, MONDO:0015469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.31 ZBTB20 Ida Ertmanska Classified gene: ZBTB20 as Amber List (moderate evidence)
Skeletal dysplasia v9.31 ZBTB20 Ida Ertmanska Gene: zbtb20 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.30 ZBTB20 Ida Ertmanska edited their review of gene: ZBTB20: Changed rating: AMBER
Skeletal dysplasia v9.30 ZBTB20 Ida Ertmanska changed review comment from: Comment on list classification: As skeletal dysplasia is a relatively rare feature in Primrose syndrome patients (5 of more than 50 cases reported to have skeletal dysplasia), this gene should remain Red on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.; to: Comment on list classification: As skeletal dysplasia is a relatively rare feature in Primrose syndrome patients (5 of more than 50 cases reported to have skeletal dysplasia), this gene should remain Amber on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.
Dystonia, chorea or related movement disorder, adult onset v6.4 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Dystonia, chorea or related movement disorder, adult onset v6.3 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v10.54 ATP6AP2 Ida Ertmanska Tag Q3_26_MOI tag was added to gene: ATP6AP2.
Intellectual disability v10.54 ATP6AP2 Ida Ertmanska commented on gene: ATP6AP2: Comment on mode of inheritance: As there is an affected female reported in literature with a heterozygous ATP6AP2 variant and intellectual disability, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Intellectual disability v10.54 ATP6AP2 Ida Ertmanska reviewed gene: ATP6AP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11782983, 15746149, 26467484, 30985297, 38274877, 41131679; Phenotypes: Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, syndromic X-linked intellectual disability Hedera type, MONDO:0010319; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v9.34 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Likely inborn error of metabolism v9.21 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v9.33 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Likely inborn error of metabolism v9.20 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.24 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital disorders of glycosylation v8.7 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital disorders of glycosylation v8.6 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Cholestasis v4.17 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Cholestasis v4.17 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 GPR15 Boaz Palterer gene: GPR15 was added
gene: GPR15 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: GPR15 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: GPR15 were set to 42259915
Phenotypes for gene: GPR15 were set to Inflammatory bowel disease; IBD; VEOIBD
Penetrance for gene: GPR15 were set to Incomplete
Review for gene: GPR15 was set to RED
Added comment: Cui et al. described multiple patients from multiple kindreds, harboring homozygous or compound heterozygous mutations in the GPR15 gene. They presented with severe early-onset inflammatory bowel disease. The underlying mechanism and phenotype were validated in vivo using complete Gpr15 knockout (KO) mouse models, demonstrating impaired colonic homing of regulatory CD8+ TIGR cells, an accumulation of inflammatory macrophages, and increased susceptibility to colitis.
Sources: Literature
Likely inborn error of metabolism v9.20 ATP6AP2 Eleanor Williams Entity copied from Congenital disorders of glycosylation v8.6
Likely inborn error of metabolism v9.20 ATP6AP2 Eleanor Williams gene: ATP6AP2 was added
gene: ATP6AP2 was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber
Q3_26_promote_green tags were added to gene: ATP6AP2.
Mode of inheritance for gene: ATP6AP2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ATP6AP2 were set to 29127204; 38075676; 41131679
Phenotypes for gene: ATP6AP2 were set to Congenital disorder of glycosylation, type IIr, OMIM:301045; congenital disorder of glycosylation, type IIr, MONDO:0026765; congenital disorder of glycosylation, type IIr, X-linked recessive
Mode of pathogenicity for gene: ATP6AP2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Cholestasis v4.16 ATP6AP2 Eleanor Williams Publications for gene: ATP6AP2 were set to 29127204; 41131679
Ichthyosis and erythrokeratoderma v4.16 ISCA-37417-Loss Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed 9th July 2026
Ichthyosis and erythrokeratoderma v4.16 ISCA-37417-Loss Eleanor Williams Phenotypes for Region: ISCA-37417-Loss were changed from 308100; Ichthyosis, X-linked to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269
Proteinuric renal disease v6.9 ISCA-37417-Loss Eleanor Williams Phenotypes for Region: ISCA-37417-Loss were changed from Ichthyosis, X-linked, OMIM:308100 to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269
Intellectual disability v10.54 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636 to Neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder, OMIM:620782; Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636
Early onset or syndromic epilepsy v9.33 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636 to Neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder, OMIM:620782
Intellectual disability v10.53 SYP Ida Ertmanska reviewed gene: SYP: Rating: AMBER; Mode of pathogenicity: None; Publications: 19377476, 24721225, 28887151, 32193494, 34310040; Phenotypes: Intellectual developmental disorder, X-linked 96, OMIM:300802; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska Tag Q3_26_promote_green was removed from gene: ATP6AP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed rating: AMBER
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no recurrent infections noted. Hence, this gene should be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease, based on cases with missense variants.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). However, only 2 probands presented with recurrent infections. Hence, this gene should remain Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. No immunodeficiency noted.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature
Neurodegenerative disorders, adult onset v9.3 ATP6AP2 Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from ?Parkinsonism with spasticity, X-linked, OMIM:300911; Mental retardation, X-linked, syndromic, Hedera type, OMIM:300423 to ?Parkinsonism with spasticity, X-linked, OMIM:300911; Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319
Dystonia, chorea or related movement disorder, adult onset v6.2 ATP6AP2 Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from ?Parkinsonism with spasticity, X-linked 300911; Mental retardation, X-linked, syndromic, Hedera type 300423 to ?Parkinsonism with spasticity, X-linked 300911; Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319
Intellectual disability v10.53 ATP6AP2 Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423 syndromic X-linked intellectual disability Hedera type, MONDO:0010319 to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska Classified gene: ATP6AP2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska Gene: atp6ap2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.22 ATP6AP2 Ida Ertmanska Mode of pathogenicity for gene: ATP6AP2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v9.21 ATP6AP2 Ida Ertmanska Publications for gene: ATP6AP2 were set to 29127204; 41131679
Primary immunodeficiency or monogenic inflammatory bowel disease v9.20 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no recurrent infections noted. Hence, this gene should be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease, based on cases with missense variants.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Liver features reported: early-onset cirrhosis and steatosis, neonatal liver failure, hepatosplenomegaly, liver transplant before 1 year of age. Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Liver features reported: early-onset cirrhosis and steatosis, neonatal liver failure, hepatosplenomegaly, liver transplant before 1 year of age. Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.; Changed publications to: 29127204, 38075676, 41131679; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cholestasis v4.15 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cholestasis v4.15 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed publications to: 29127204, 38075676, 41131679
Cholestasis v4.15 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cholestasis v4.14 ATP6AP2 Ida Ertmanska Mode of pathogenicity for gene: ATP6AP2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Cholestasis v4.13 ATP6AP2 Ida Ertmanska Classified gene: ATP6AP2 as Amber List (moderate evidence)
Cholestasis v4.13 ATP6AP2 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Liver features reported: early-onset cirrhosis and steatosis, neonatal liver failure, hepatosplenomegaly, liver transplant before 1 year of age. Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Cholestasis, based on cases with missense variants.
Cholestasis v4.13 ATP6AP2 Ida Ertmanska Gene: atp6ap2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature
Cholestasis v4.12 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature
Intellectual disability v10.52 ATP6AP2 Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from Mental retardation, X-linked, syndromic, Hedera type, 300423; MENTAL RETARDATION X-LINKED WITH EPILEPSY; X-linked intellectual disability, Hedera type to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423 syndromic X-linked intellectual disability Hedera type, MONDO:0010319
Early onset or syndromic epilepsy v9.32 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38274877 Liang et al., 2024
Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume.

PMID: 30985297 Hirose et al., 2019
Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts).

Other reports not curated in detail:
PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism'
PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor'
PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4'

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38274877 Liang et al., 2024
Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation of p.Phe247_Ala286del. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume.

PMID: 30985297 Hirose et al., 2019
Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts).

Other reports not curated in detail:
PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism'
PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor'
PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4'

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Early onset or syndromic epilepsy v9.32 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38274877 Liang et al., 2024
Report of a patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume.

PMID: 30985297 Hirose et al., 2019
Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts).

Other reports not curated in detail:
PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism'
PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor'
PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4'

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38274877 Liang et al., 2024
Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume.

PMID: 30985297 Hirose et al., 2019
Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts).

Other reports not curated in detail:
PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism'
PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor'
PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4'

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Early onset or syndromic epilepsy v9.32 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed publications to: 11782983, 15746149, 26467484, 30985297, 38274877, 41131679
Early onset or syndromic epilepsy v9.32 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 30985297 Hirose et al., 2019
Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts).

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38274877 Liang et al., 2024
Report of a patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume.

PMID: 30985297 Hirose et al., 2019
Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts).

Other reports not curated in detail:
PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism'
PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor'
PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4'

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Early onset or syndromic epilepsy v9.32 ATP6AP2 Ida Ertmanska Classified gene: ATP6AP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.32 ATP6AP2 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 splicing variants (causing exon skipping), and presented with intellectual disability and early-onset severe epilepsy. Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.32 ATP6AP2 Ida Ertmanska Gene: atp6ap2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.31 ATP6AP2 Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319 to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319
Early onset or syndromic epilepsy v9.31 ATP6AP2 Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from Mental retardation, X-linked, syndromic, Hedera type to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319
Early onset or syndromic epilepsy v9.30 ATP6AP2 Ida Ertmanska Publications for gene: ATP6AP2 were set to
Early onset or syndromic epilepsy v9.29 ATP6AP2 Ida Ertmanska Tag watchlist was removed from gene: ATP6AP2.
Tag Q3_26_promote_green tag was added to gene: ATP6AP2.
Early onset or syndromic epilepsy v9.29 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed publications to: 26467484, 30985297, 41131679
Early onset or syndromic epilepsy v9.29 ATP6AP2 Ida Ertmanska reviewed gene: ATP6AP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30985297, 41131679; Phenotypes: Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, syndromic X-linked intellectual disability Hedera type, MONDO:0010319; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Congenital disorders of glycosylation v8.6 ATP6AP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype - a DEE-type neurological presentation. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation based on the cases with missense variants.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype (DEE-type neurological presentation), though glycosylation abnormalities were also seen in patient fibroblasts. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.
Congenital disorders of glycosylation v8.6 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature
Congenital disorders of glycosylation v8.6 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Congenital disorders of glycosylation v8.5 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Congenital disorders of glycosylation v8.5 ATP6AP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype - a DEE-type neurological presentation. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation based on the cases with missense variants.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype - a DEE-type neurological presentation. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation based on the cases with missense variants.
Congenital disorders of glycosylation v8.5 ATP6AP2 Ida Ertmanska Publications for gene: ATP6AP2 were set to 29127204; 41131679
Congenital disorders of glycosylation v8.4 ATP6AP2 Ida Ertmanska Mode of pathogenicity for gene: ATP6AP2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Congenital disorders of glycosylation v8.3 ATP6AP2 Ida Ertmanska Classified gene: ATP6AP2 as Amber List (moderate evidence)
Congenital disorders of glycosylation v8.3 ATP6AP2 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype - a DEE-type neurological presentation. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation based on the cases with missense variants.
Congenital disorders of glycosylation v8.3 ATP6AP2 Ida Ertmanska Gene: atp6ap2 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v8.2 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature
Congenital disorders of glycosylation v8.2 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Congenital disorders of glycosylation v8.2 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed publications to: 29127204, 38075676, 41131679
Congenital disorders of glycosylation v8.2 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 38075676 Fang et al., 2023
Chinese patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature
Congenital disorders of glycosylation v8.2 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 38075676 Fang et al., 2023
Chinese patient with a novel ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 38075676 Fang et al., 2023
Chinese patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature
Congenital disorders of glycosylation v8.2 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 38075676 Fang et al., 2023
Chinese patient with a novel ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature
Cholestasis v4.12 ATP6AP2 Ida Ertmanska gene: ATP6AP2 was added
gene: ATP6AP2 was added to Cholestasis. Sources: Literature
Q3_26_promote_green tags were added to gene: ATP6AP2.
Mode of inheritance for gene: ATP6AP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ATP6AP2 were set to 29127204; 41131679
Phenotypes for gene: ATP6AP2 were set to Congenital disorder of glycosylation, type IIr, OMIM:301045; congenital disorder of glycosylation, type IIr, MONDO:0026765; congenital disorder of glycosylation, type IIr, X-linked recessive
Review for gene: ATP6AP2 was set to GREEN
Added comment: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska gene: ATP6AP2 was added
gene: ATP6AP2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Q3_26_promote_green tags were added to gene: ATP6AP2.
Mode of inheritance for gene: ATP6AP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ATP6AP2 were set to 29127204; 41131679
Phenotypes for gene: ATP6AP2 were set to Congenital disorder of glycosylation, type IIr, OMIM:301045; congenital disorder of glycosylation, type IIr, MONDO:0026765; congenital disorder of glycosylation, type IIr, X-linked recessive
Review for gene: ATP6AP2 was set to GREEN
Added comment: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature
Congenital disorders of glycosylation v8.2 ATP6AP2 Ida Ertmanska gene: ATP6AP2 was added
gene: ATP6AP2 was added to Congenital disorders of glycosylation. Sources: Literature
Q3_26_promote_green tags were added to gene: ATP6AP2.
Mode of inheritance for gene: ATP6AP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ATP6AP2 were set to 29127204; 41131679
Phenotypes for gene: ATP6AP2 were set to Congenital disorder of glycosylation, type IIr, OMIM:301045; congenital disorder of glycosylation, type IIr, MONDO:0026765; congenital disorder of glycosylation, type IIr, X-linked recessive
Review for gene: ATP6AP2 was set to GREEN
Added comment: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature
Intellectual disability v10.51 UNC79 Ida Ertmanska Classified gene: UNC79 as Amber List (moderate evidence)
Intellectual disability v10.51 UNC79 Ida Ertmanska Added comment: Comment on list classification: There are 5 unrelated individuals reported in literature with heterozygous de novo UNC79 variants and a neurodevelopmental disorder, including intellectual disability (mild to moderate). Hence, this gene should be promoted to Green at the next update.
Intellectual disability v10.51 UNC79 Ida Ertmanska Gene: unc79 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.29 UNC79 Ida Ertmanska Classified gene: UNC79 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.29 UNC79 Ida Ertmanska Added comment: Comment on list classification: There are 4 unrelated individuals reported in literature with heterozygous de novo UNC79 variants and syndromic epilepsy. Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.29 UNC79 Ida Ertmanska Gene: unc79 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.50 UNC79 Ida Ertmanska changed review comment from: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia.
Sources: Literature; to: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Sequencing method: trio WES (5 individuals) / duo WES (1).
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia.
Sources: Literature
Early onset or syndromic epilepsy v9.28 UNC79 Ida Ertmanska changed review comment from: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia.
Sources: Literature; to: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Sequencing method: trio WES (5 individuals) / duo WES (1).
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia.
Sources: Literature
Early onset or syndromic epilepsy v9.28 UNC79 Ida Ertmanska changed review comment from: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P.
Sources: Literature; to: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia.
Sources: Literature
Intellectual disability v10.50 UNC79 Ida Ertmanska changed review comment from: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P.
Sources: Literature; to: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia.
Sources: Literature
Early onset or syndromic epilepsy v9.28 UNC79 Ida Ertmanska gene: UNC79 was added
gene: UNC79 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_26_promote_green tags were added to gene: UNC79.
Mode of inheritance for gene: UNC79 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC79 were set to 37183800
Phenotypes for gene: UNC79 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: UNC79 was set to GREEN
Added comment: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P.
Sources: Literature
Intellectual disability v10.50 UNC79 Ida Ertmanska gene: UNC79 was added
gene: UNC79 was added to Intellectual disability. Sources: Literature
Q3_26_promote_green tags were added to gene: UNC79.
Mode of inheritance for gene: UNC79 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC79 were set to 37183800
Phenotypes for gene: UNC79 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: UNC79 was set to GREEN
Added comment: PMID: 37183800 Bayat et al., 2023
Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum:
- 4/6 autistic features
- 5/6 patients mild-moderate ID
- 4/6 behavioural issues (aggression, stereotypies)
- 4/6 epilepsy (focal / tonic-clonic seizures)
- 5/6 hypotonia
Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory.

This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P.
Sources: Literature
Early onset or syndromic epilepsy v9.27 SHANK3 Ida Ertmanska Classified gene: SHANK3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.27 SHANK3 Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals reported in literature with heterozygous SHANK3 variants and Phelan-McDermid syndrome. Around 30% of patients reported to date had seizures. Hence, this gene should be promoted to Green on Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v9.27 SHANK3 Ida Ertmanska Gene: shank3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.26 SHANK3 Ida Ertmanska gene: SHANK3 was added
gene: SHANK3 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_26_promote_green tags were added to gene: SHANK3.
Mode of inheritance for gene: SHANK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SHANK3 were set to 29719671; 36967043
Phenotypes for gene: SHANK3 were set to Phelan-McDermid syndrome, OMIM:606232; Phelan-McDermid syndrome, MONDO:0011652
Review for gene: SHANK3 was set to GREEN
Added comment: PMID: 29719671 De Rubeis et al., 2018
Report of 17 individuals with Phelan-McDermid syndrome, and literature review of 60 other previously reported patients. Most mutations were truncating, often de novo, with 4 recurrent variants p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A. Seizures were present in 5/17 individuals (29%).

PMID: 36967043 de Coo et al., 2023
Publication is part of European guidelines for Phelan-McDermid syndrome (PMS). In the largest cohort of PMS patients (n=201), prevalence of seizures was 27%. The prevalence goes up with age e.g., seizure onset under age 5yrs was 11%, but 43% between ages 10-18yrs. Pooled prevalence of seizures from 14 PMS studies was 32%. All types of seizures, febrile and non-febrile, have been recorded.
Sources: Literature
Fetal anomalies v7.28 ZBTB20 Arina Puzriakova Phenotypes for gene: ZBTB20 were changed from PRIMROSE SYNDROME to Primrose syndrome, OMIM:259050
Intellectual disability v10.49 ZBTB20 Arina Puzriakova Phenotypes for gene: ZBTB20 were changed from PRIMROSE SYNDROME to Primrose syndrome, OMIM:259050
Neurodegenerative disorders, adult onset v9.2 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

PMID: 31312839 Lee et al., 2019
Reported a 32yo female proband with MLD, comp het for ARSA variants p.L300S and p.C174Y. Her father and paternal uncle had Parkinson's disease, and were heterozygous for the ARSA p.L300S variant - thought to be a potential risk factor.
Also analysed 92 cases with familial dominant Parkinson's disease. ARSA p.N352S was found to be a protective variant (more common in controls than PD cohort).
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein." In cell lines, authors showed that ARSA deficiency correlates with an increase in α-synuclein aggregation.; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

PMID: 31312839 Lee et al., 2019
Reported a 32yo female proband with MLD, comp het for ARSA variants p.L300S and p.C174Y. Her father and paternal uncle had Parkinson's disease, and were heterozygous for the ARSA p.L300S variant - thought to be a potential risk factor.
Also analysed 92 cases with familial dominant Parkinson's disease. ARSA p.N352S was found to be a protective variant (more common in controls than PD cohort).
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein." In cell lines, authors showed that ARSA deficiency correlates with an increase in α-synuclein aggregation.
Congenital hyperinsulinism v3.9 CACNA1C Sarah Flanagan reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 30067485, PMID: 35897673, PMID: 39420001; Phenotypes: Congenital Hyperinsulinism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska commented on gene: ARSA: Comment on list classification: ARSA deficiency is a well-established cause of recessive metachromatic leukodystrophy. There is also some emerging evidence that heterozygous variants in ARSA may be a genetic modifier of Parkinson's disease. However, heterozygous variants act as risk factors, rather than causing familial dominant disease. Hence, the mode of inheritance should remain as 'BIALLELIC, autosomal or pseudoautosomal' on this panel.
Likely inborn error of metabolism v9.19 ARSA Ida Ertmanska Phenotypes for gene: ARSA were changed from Metachromatic leukodystrophy to Metachromatic leukodystrophy, OMIM:250100; metachromatic leukodystrophy, MONDO:0018868; arylsulfatase A deficiency
Intellectual disability v10.48 ARSA Ida Ertmanska Phenotypes for gene: ARSA were changed from ARYLSULFATASE A DEFICIENCY to Metachromatic leukodystrophy, OMIM:250100; metachromatic leukodystrophy, MONDO:0018868; arylsulfatase A deficiency
Neurodegenerative disorders, adult onset v9.2 ARSA Ida Ertmanska commented on gene: ARSA: Comment on mode of inheritance: ARSA deficiency is a well-established cause of recessive metachromatic leukodystrophy. There is also some emerging evidence that heterozygous variants in ARSA may be a genetic modifier of Parkinson's disease. However, heterozygous variants act as risk factors, rather than causing familial dominant disease. Hence, the mode of inheritance should remain as 'BIALLELIC, autosomal or pseudoautosomal' on this panel.
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska edited their review of gene: ARSA: Changed phenotypes to: Metachromatic leukodystrophy, OMIM:250100, metachromatic leukodystrophy, MONDO:0018868, arylsulfatase A deficiency
Neurodegenerative disorders, adult onset v9.2 ARSA Ida Ertmanska reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31312839, 37381728; Phenotypes: Metachromatic leukodystrophy, OMIM:250100, metachromatic leukodystrophy, MONDO:0018868, arylsulfatase A deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska edited their review of gene: ARSA: Changed phenotypes to: Metachromatic leukodystrophy, OMIM:250100
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

p.L300V variant found in two cases and one controls

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

PMID: 31312839 Lee et al., 2019
Reported a 32yo female proband with MLD, comp het for ARSA variants p.L300S and p.C174Y. Her father and paternal uncle had Parkinson's disease, and were heterozygous for the ARSA p.L300S variant - thought to be a potential risk factor.
Also analysed 92 cases with familial dominant Parkinson's disease. ARSA p.N352S was found to be a protective variant (more common in controls than PD cohort).
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein." In cell lines, authors showed that ARSA deficiency correlates with an increase in α-synuclein aggregation.
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

p.L300V variant found in two cases and one control

Also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. However, one of the patients, II-4 from the first family, was also a carrier of the GBA1 variant RecNcil - which impossible to estimate the role of the ARSA variant in PD. The variant was not found in any controls.
Caveat: the variant is referred to as p.E382K and p.E384K in different parts of the publication. Likely to be the c.1150G>A, p.Glu384Lys variant - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

p.L300V variant found in two cases and one controls

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

p.L300V variant found in two cases and one control

Also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. However, one of the patients, II-4 from the first family, was also a carrier of the GBA1 variant RecNcil - which impossible to estimate the role of the ARSA variant in PD. The variant was not found in any controls.
Caveat: the variant is referred to as p.E382K and p.E384K in different parts of the publication. Likely to be the c.1150G>A, p.Glu384Lys variant - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska reviewed gene: ARSA: Rating: AMBER; Mode of pathogenicity: None; Publications: 31312839, 37381728; Phenotypes: Menkes disease, OMIM:309400, Neuronopathy, distal hereditary motor, X-linked, OMIM:300489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Proteinuric renal disease v6.8 STS Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease. ; to: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease. Instead, the ISCA-37417-Loss (Xp22.31 recurrent region (includes STS) Loss) has been suggested for promotion to Green on this panel.
Proteinuric renal disease v6.8 ISCA-37417-Loss Ida Ertmanska Classified Region: ISCA-37417-Loss as Amber List (moderate evidence)
Proteinuric renal disease v6.8 ISCA-37417-Loss Ida Ertmanska Added comment: Comment on list classification: There are at least 3 unrelated male individuals with ichthyosis and renal disease including proteinuria, harbouring heterozygous deletions affecting the ISCA-37417-Loss region (particularly full STS deletions). Hence, this region should be promoted to Green at the next update.
Proteinuric renal disease v6.8 ISCA-37417-Loss Ida Ertmanska Region: isca-37417-loss has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v6.7 ISCA-37417-Loss Ida Ertmanska Region: ISCA-37417-Loss was added
Region: ISCA-37417-Loss was added to Proteinuric renal disease. Sources: Literature
Q3_26_expert_review, Q3_26_promote_green tags were added to Region: ISCA-37417-Loss.
Mode of inheritance for Region: ISCA-37417-Loss was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for Region: ISCA-37417-Loss were set to 17468528; 22419362; 23939749; 29672931; 35115028
Phenotypes for Region: ISCA-37417-Loss were set to Ichthyosis, X-linked, OMIM:308100
Review for Region: ISCA-37417-Loss was set to GREEN
Added comment: PMID: 17468528 Krishnamurthy, Kapoor, and Yadav, 2007
Reported a 4yo proband with ichthyosis and a steroid-resistant nephrotic syndrome. Generalised edema and proteinuria of 4.25g/day were noted. Many male family members also had ichthyosis. Renal biopsy showed no segmental sclerosis, tubular atrophy, fibrosis, or deposits; diagnosed with minimal change disease. STS deletion detected by multiplex PCR (targeted STS gene specifically).

PMID: 22419362 Mishra et al., 2012
Report of a 4yo boy with steroid-resistant nephrotic syndrome (SRNS) with an underlying ichthyotic skin present since birth. Genetic analysis showed full deletion of the STS gene.

PMID: 23939749 Song et al., 2013
12yo male patient with X-linked ichthyosis (XLI) in association with glomerular sclerosis. Complete deletion of STS and flanking regions was detected. Renal features: renal failure, anemia, hypocalcemia, mild proteinuria (0.4g/day). Uncles also affected by ichthyosis and short stature. Authors highlight that it is unknown whether STS or the flanking regions were causal in the renal presentation.

PMID: 29672931 Diociaiuti et al., 2019
Cohort of 35 Italian male patients with X-linked ichthyosis. 27 patients showed complete STS deletion - 1 de novo, others maternally inherited. 7 patients had microdeletions of 1.3-1.6Mb, and 2 patients had large deletions of 8.2 and 9.7Mb - resulting in contiguous gene syndrome. Lastly, 7 individuals from 4 unrelated families had 4 different missense mutations in STS. Seq method: MLPA + ichthyosis NGS panel. Apart from cutaneous changes, other findings included cryptorchidism, neuropsychiatric findings, motor disabilities. No mention of renal disease. Authors note that only 10% of patients have point mutations in STS, with majority of cases harbouring STS deletions.

PMID: 35115028 Schierz et al., 2022
Male newborn with CAKUT with kidney failure and progressive vomiting. "Comparative whole-genome hybridization detected a maternal inherited interstitial deletion of 1.56 Mb on Xp22.31(6,552,712_8,115,153) × 0 involving the STS gene, but not the KAL1 gene." Other affected genes: VCX, PUDP, PNPLA4, as well as microRNAs MIR4767 and MIR651.
Sources: Literature
Proteinuric renal disease v6.6 STS Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease. ; to: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease.
Proteinuric renal disease v6.6 STS Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuria. ; to: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease.
Proteinuric renal disease v6.6 STS Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline and STS should remain Amber for Proteinuria.; to: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuria.
Proteinuric renal disease v6.6 STS Ida Ertmanska edited their review of gene: STS: Changed rating: AMBER
Proteinuric renal disease v6.6 STS Ida Ertmanska Classified gene: STS as Amber List (moderate evidence)
Proteinuric renal disease v6.6 STS Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline and STS should remain Amber for Proteinuria.
Proteinuric renal disease v6.6 STS Ida Ertmanska Gene: sts has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v6.5 STS Ida Ertmanska edited their review of gene: STS: Changed publications to: 17468528, 22419362, 23939749, 29672931, 35115028
Proteinuric renal disease v6.5 STS Ida Ertmanska changed review comment from: PMID: 17468528 Krishnamurthy, Kapoor, and Yadav, 2007
Reported a 4yo proband with ichthyosis and a steroid-resistant nephrotic syndrome. Generalised edema and proteinuria of 4.25g/day were noted. Many male family members also had ichthyosis. Renal biopsy showed no segmental sclerosis, tubular atrophy, fibrosis, or deposits; diagnosed with minimal change disease. STS deletion detected by multiplex PCR (targeted STS gene specifically).

PMID: 22419362 Mishra et al., 2012
Report of a 4yo boy with steroid-resistant nephrotic syndrome (SRNS) with an underlying ichthyotic skin present since birth. Genetic analysis showed full deletion of the STS gene.

PMID: 23939749 Song et al., 2013
12yo male patient with X-linked ichthyosis (XLI) in association with glomerular sclerosis. Complete deletion of STS and flanking regions was detected. Renal features: renal failure, anemia, hypocalcemia, mild proteinuria (0.4g/day). Uncles also affected by ichthyosis and short stature. Authors highlight that it is unknown whether STS or the flanking regions were causal in the renal presentation.

PMID: 35115028 Schierz et al., 2022
Male newborn with CAKUT with kidney failure and progressive vomiting. "Comparative whole-genome hybridization detected a maternal inherited interstitial deletion of 1.56 Mb on Xp22.31(6,552,712_8,115,153) × 0 involving the STS gene, but not the KAL1 gene." Other affected genes: VCX, PUDP, PNPLA4, as well as microRNAs MIR4767 and MIR651.; to: PMID: 17468528 Krishnamurthy, Kapoor, and Yadav, 2007
Reported a 4yo proband with ichthyosis and a steroid-resistant nephrotic syndrome. Generalised edema and proteinuria of 4.25g/day were noted. Many male family members also had ichthyosis. Renal biopsy showed no segmental sclerosis, tubular atrophy, fibrosis, or deposits; diagnosed with minimal change disease. STS deletion detected by multiplex PCR (targeted STS gene specifically).

PMID: 22419362 Mishra et al., 2012
Report of a 4yo boy with steroid-resistant nephrotic syndrome (SRNS) with an underlying ichthyotic skin present since birth. Genetic analysis showed full deletion of the STS gene.

PMID: 23939749 Song et al., 2013
12yo male patient with X-linked ichthyosis (XLI) in association with glomerular sclerosis. Complete deletion of STS and flanking regions was detected. Renal features: renal failure, anemia, hypocalcemia, mild proteinuria (0.4g/day). Uncles also affected by ichthyosis and short stature. Authors highlight that it is unknown whether STS or the flanking regions were causal in the renal presentation.

PMID: 29672931 Diociaiuti et al., 2019
Cohort of 35 Italian male patients with X-linked ichthyosis. 27 patients showed complete STS deletion - 1 de novo, others maternally inherited. 7 patients had microdeletions of 1.3-1.6Mb, and 2 patients had large deletions of 8.2 and 9.7Mb - resulting in contiguous gene syndrome. Lastly, 7 individuals from 4 unrelated families had 4 different missense mutations in STS. Seq method: MLPA + ichthyosis NGS panel. Apart from cutaneous changes, other findings included cryptorchidism, neuropsychiatric findings, motor disabilities. No mention of renal disease. Authors note that only 10% of patients have point mutations in STS, with majority of cases harbouring STS deletions.

PMID: 35115028 Schierz et al., 2022
Male newborn with CAKUT with kidney failure and progressive vomiting. "Comparative whole-genome hybridization detected a maternal inherited interstitial deletion of 1.56 Mb on Xp22.31(6,552,712_8,115,153) × 0 involving the STS gene, but not the KAL1 gene." Other affected genes: VCX, PUDP, PNPLA4, as well as microRNAs MIR4767 and MIR651.
Proteinuric renal disease v6.5 STS Ida Ertmanska Phenotypes for gene: STS were changed from Proteinuria; ichthyosis to Ichthyosis, X-linked, OMIM:308100
Proteinuric renal disease v6.4 STS Ida Ertmanska Publications for gene: STS were set to 22419362; 17468528
Proteinuric renal disease v6.3 STS Ida Ertmanska Mode of inheritance for gene: STS was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Proteinuric renal disease v6.2 STS Ida Ertmanska reviewed gene: STS: Rating: RED; Mode of pathogenicity: None; Publications: 17468528, 22419362, 23939749, 35115028; Phenotypes: Ichthyosis, X-linked, OMIM:308100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Skeletal dysplasia v9.30 TMEM251 Ida Ertmanska changed review comment from: PMID: 41858182 Sperb-Ludwig et al., 2026
Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more).

PMID: 40171858 Kariminejad et al., 2025
Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1.; to: PMID: 41858182 Sperb-Ludwig et al., 2026
Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more).

PMID: 40171858 Kariminejad et al., 2025
Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD.
Skeletal dysplasia v9.30 TMEM251 Ida Ertmanska Classified gene: TMEM251 as Amber List (moderate evidence)
Skeletal dysplasia v9.30 TMEM251 Ida Ertmanska Added comment: Comment on list classification: There are now four unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia. Hence, this gene can be promoted to Green at the next update.
Skeletal dysplasia v9.30 TMEM251 Ida Ertmanska Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.29 TMEM251 Ida Ertmanska Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex, Ain-Naz type, OMIM:19345; severe short stature to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156
Skeletal dysplasia v9.28 TMEM251 Ida Ertmanska Publications for gene: TMEM251 were set to 33252156
Skeletal dysplasia v9.27 TMEM251 Ida Ertmanska Mode of pathogenicity for gene: TMEM251 was changed from None to None
Skeletal dysplasia v9.26 TMEM251 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: TMEM251.
Skeletal dysplasia v9.26 TMEM251 Ida Ertmanska reviewed gene: TMEM251: Rating: GREEN; Mode of pathogenicity: None; Publications: 40171858, 41858182; Phenotypes: Dysostosis multiplex, Ain-Naz type, OMIM:619345, dysostosis multiplex, Ain-Naz type, MONDO:0859156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v6.28 ZBTB20 Ida Ertmanska Publications for gene: ZBTB20 were set to 32473227
Monogenic hearing loss v6.27 ZBTB20 Ida Ertmanska Classified gene: ZBTB20 as Amber List (moderate evidence)
Monogenic hearing loss v6.27 ZBTB20 Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals (at least 36) reported in literature with de novo heterozygous ZBTB20 variants and hearing loss. Hence, this gene can be promoted to Green at the next update.
Monogenic hearing loss v6.27 ZBTB20 Ida Ertmanska Gene: zbtb20 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ZBTB20.
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska changed review comment from: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature; to: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).

https://www.ncbi.nlm.nih.gov/books/NBK570205/ - Primrose syndrome GeneReviews entry mentions 52 reported individuals. Skeletal abnormalities are not noted to be the main characteristic features. Some patients present with scoliosis and skull specific abormalities e.g., wormian bones, without wider skeletal involvement. The primary features consistent in most cases are: intellectual disability (100%), hearing loss (83%), dysmorphic facial features (>70%), hypotonia (76%), and autism (70%), with many other less specific features.

ZBTB20 is associated with AD Primrose syndrome, OMIM:259050 (OMIM accessed 7th July 2026).
Sources: Literature
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska edited their review of gene: ZBTB20: Changed rating: GREEN
Skeletal dysplasia v9.26 ZBTB20 Ida Ertmanska changed review comment from: Comment on list classification: As skeletal dysplasia is a relatively rare feature in Primrose syndrome patients (5 of more than 50 cases reported to have skeletal dysplasia), this gene should remain Red on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.; to: Comment on list classification: As skeletal dysplasia is a relatively rare feature in Primrose syndrome patients (5 of more than 50 cases reported to have skeletal dysplasia), this gene should remain Red on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.
Skeletal dysplasia v9.26 ZBTB20 Ida Ertmanska changed review comment from: Comment on list classification: As skeletal dysplasia is a relatively rare feature in Primrose syndrome patients (5 of more than 50 cases reported to have skeletal dysplasia), this gene should remain Red on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.; to: Comment on list classification: As skeletal dysplasia is a relatively rare feature in Primrose syndrome patients (5 of more than 50 cases reported to have skeletal dysplasia), this gene should remain Red on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.
Skeletal dysplasia v9.26 ZBTB20 Ida Ertmanska edited their review of gene: ZBTB20: Changed rating: RED
Skeletal dysplasia v9.26 ZBTB20 Ida Ertmanska Classified gene: ZBTB20 as Red List (low evidence)
Skeletal dysplasia v9.26 ZBTB20 Ida Ertmanska Gene: zbtb20 has been classified as Red List (Low Evidence).
Skeletal dysplasia v9.25 ZBTB20 Ida Ertmanska Classified gene: ZBTB20 as Amber List (moderate evidence)
Skeletal dysplasia v9.25 ZBTB20 Ida Ertmanska Added comment: Comment on list classification: As skeletal dysplasia is a relatively rare feature in Primrose syndrome patients (5 of more than 50 cases reported to have skeletal dysplasia), this gene should remain Red on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.
Skeletal dysplasia v9.25 ZBTB20 Ida Ertmanska Gene: zbtb20 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.24 ZBTB20 Ida Ertmanska Publications for gene: ZBTB20 were set to 32473227
Skeletal dysplasia v9.23 ZBTB20 Ida Ertmanska changed review comment from: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature; to: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).

https://www.ncbi.nlm.nih.gov/books/NBK570205/ - Primrose syndrome GeneReviews entry mentions 52 reported individuals. Skeletal abnormalities are not noted to be the main characteristic features. Some patients present with scoliosis and skull specific abormalities e.g., wormian bones, without wider skeletal involvement. The primary features consistent in most cases are: intellectual disability (100%), hearing loss (83%), dysmorphic facial features (>70%), hypotonia (76%), and autism (70%), with many other less specific features.

ZBTB20 is associated with AD Primrose syndrome, OMIM:259050 (OMIM accessed 7th July 2026).

Sources: Literature
Skeletal dysplasia v9.23 ZBTB20 Ida Ertmanska edited their review of gene: ZBTB20: Changed publications to: 31321892, 32473227
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska gene: ZBTB20 was added
gene: ZBTB20 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: ZBTB20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB20 were set to 32473227
Phenotypes for gene: ZBTB20 were set to Primrose syndrome, OMIM:259050; Primrose syndrome, MONDO:0009798; intellectual disability-cataracts-calcified pinnae-myopathy syndrome
Review for gene: ZBTB20 was set to AMBER
Added comment: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature
Skeletal dysplasia v9.23 ZBTB20 Ida Ertmanska gene: ZBTB20 was added
gene: ZBTB20 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ZBTB20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB20 were set to 32473227
Phenotypes for gene: ZBTB20 were set to Primrose syndrome, OMIM:259050; Primrose syndrome, MONDO:0009798; intellectual disability-cataracts-calcified pinnae-myopathy syndrome
Review for gene: ZBTB20 was set to AMBER
Added comment: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature
Early onset or syndromic epilepsy v9.25 BCL11A Ida Ertmanska changed review comment from: Comment on list classification: There are at least 13 unrelated patients with heterozygous BCL11A variants and early-onset epilepsy. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are at least 13 unrelated patients with heterozygous BCL11A variants and early-onset epilepsy (as part of Dias-Logan syndrome spectrum). Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.25 BCL11A Ida Ertmanska Classified gene: BCL11A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.25 BCL11A Ida Ertmanska Added comment: Comment on list classification: There are at least 13 unrelated patients with heterozygous BCL11A variants and early-onset epilepsy. Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.25 BCL11A Ida Ertmanska Gene: bcl11a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska changed review comment from: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with heterozygous BCL11A variants had seizures, with median age of onset of 3 years.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature; to: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with heterozygous BCL11A variants had seizures, with median age of onset of 3 years. In 33/40 cases with inheritance information, the het variants were confirmed de novo. DD/IDD was noted in 97% of individuals reported, though severity varied. Only 17% of the cases had severe/profound ID.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska changed review comment from: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with biallelic BCL11A variants had seizures, with median age of onset of 3 years.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature; to: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with heterozygous BCL11A variants had seizures, with median age of onset of 3 years.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska changed review comment from: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with biallelic BCL11A variants had seizures, with median age of onset of 3 years.

PMID: 39835253 Shu et al., 2025
Report of an 8-year-old Han Chinese male patient with Dias-Logan syndrome who carries a de novo heterozygous pathogenic variant, c.1078dupC (p.Leu360Profs*212), in the BCL11A gene, leading to ID and γ-globin suppression, identified through trio-WES.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature; to: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with biallelic BCL11A variants had seizures, with median age of onset of 3 years.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska edited their review of gene: BCL11A: Changed publications to: 28589569, 32903878, 39448799
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska gene: BCL11A was added
gene: BCL11A was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_26_promote_green tags were added to gene: BCL11A.
Mode of inheritance for gene: BCL11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BCL11A were set to 28589569; 32903878; 39835253
Phenotypes for gene: BCL11A were set to Dias-Logan syndrome, OMIM:617101; Dias-Logan syndrome, MONDO:0014914; BCL11A-related intellectual developmental disorder with persistence of fetal hemoglobin
Review for gene: BCL11A was set to GREEN
Added comment: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with biallelic BCL11A variants had seizures, with median age of onset of 3 years.

PMID: 39835253 Shu et al., 2025
Report of an 8-year-old Han Chinese male patient with Dias-Logan syndrome who carries a de novo heterozygous pathogenic variant, c.1078dupC (p.Leu360Profs*212), in the BCL11A gene, leading to ID and γ-globin suppression, identified through trio-WES.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature
DDG2P v7.8 BCL11A Ida Ertmanska Phenotypes for gene: BCL11A were changed from INTELLECTUAL DISABILITY to BCL11A-related intellectual disability; Dias-Logan syndrome, OMIM:617101
Intellectual disability v10.47 BCL11A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 7th July 2026
Intellectual disability v10.47 BCL11A Ida Ertmanska Phenotypes for gene: BCL11A were changed from INTELLECTUAL DISABILITY to Dias-Logan syndrome, OMIM:617101; Dias-Logan syndrome, MONDO:0014914; BCL11A-related intellectual developmental disorder with persistence of fetal hemoglobin
Fetal anomalies v7.27 BCL11A Ida Ertmanska Phenotypes for gene: BCL11A were changed from INTELLECTUAL DISABILITY to Dias-Logan syndrome, OMIM:617101; Dias-Logan syndrome, MONDO:0014914; BCL11A-related intellectual developmental disorder with persistence of fetal hemoglobin
Proteinuric renal disease v6.2 WDR4 John Sayer gene: WDR4 was added
gene: WDR4 was added to Proteinuric renal disease. Sources: Expert list
Mode of inheritance for gene: WDR4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR4 were set to 30079490; 40533795
Phenotypes for gene: WDR4 were set to growth deficiency; microcephaly; developmental delay; intellectual disability; proteinuria; nephrotic syndrome
Penetrance for gene: WDR4 were set to Complete
Review for gene: WDR4 was set to RED
Added comment: Additional case report not on pubmed 10.5734/jgm.2020.17.2.97
Sources: Expert list
Ataxia and cerebellar anomalies - childhood onset v9.10 ATP6V0C Lucy Jackson reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Inherited polyposis and early onset colorectal cancer - germline testing v4.2 MSH3 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: MSH3.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 ZBTB7B Boaz Palterer gene: ZBTB7B was added
gene: ZBTB7B was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ZBTB7B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB7B were set to 40392549
Phenotypes for gene: ZBTB7B were set to CD4+ T-cell deficiency; Allergic disease; Interstitial lung disease; Corneal neovascularization; Corneal scarring; Global developmental delay; Growth failure
Penetrance for gene: ZBTB7B were set to unknown
Review for gene: ZBTB7B was set to RED
Added comment: Vaseghi-Shanjani et al. described 1 patient from 1 kindred, harboring a de novo heterozygous mutation in the ZBTB7B gene encoding ThPOK. They presented with persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The underlying mechanism and phenotype were validated in vitro using lentivirally transduced healthy control T cells and fibroblasts, demonstrating impaired T cell receptor activation and increased profibrotic gene expression. The study did not specify whether the phenotype was successfully recreated with complete knockout (KO) models or if the defect was corrected via rescue experiments.
Sources: Literature
Intellectual disability v10.46 WAC Ida Ertmanska Phenotypes for gene: WAC were changed from Paper out in august to Desanto-Shinawi syndrome, OMIM:616708; WAC-related facial dysmorphism-developmental delay-behavioral abnormalities syndrome; DeSanto-Shinawi syndrome, MONDO:0018760
Hereditary neuropathy or pain disorder v8.9 MT-TV Christopher Record reviewed gene: MT-TV: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32715519, 38371303, 39468830, 39243325; Phenotypes: Peripheral neuropathy, spasticity; Mode of inheritance: MITOCHONDRIAL
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFB Ida Ertmanska Tag Q2_26_promote_green was removed from gene: CFB.
Monogenic hearing loss v6.25 DSPP Ida Ertmanska changed review comment from: Comment on list classification: There is limited and conflicting evidence regarding the association between DSPP variants and dominant hearing loss. There are 3 Chinese families reported with DSPP missense variants and hearing loss, including one pedigree with a common likely benign variant. The other two families had both dentinogenesis imperfecta and hearing loss, and harboured the same DSPP variant detected by linkage analysis/targeted DSPP seq - another gene likely responsible for hearing loss. In addition, numerous other cases with 59+ different DSPP variants have been reported in literature with isolated dentinogenesis imperfecta.; to: Comment on list classification: There is limited and conflicting evidence regarding the association between DSPP variants and dominant hearing loss. There are 3 Chinese families reported with DSPP missense variants and hearing loss, including one pedigree with a common likely benign variant. The other two families had both dentinogenesis imperfecta and hearing loss, and harboured the same DSPP variant detected by linkage analysis/targeted DSPP seq - another gene likely responsible for hearing loss. In addition, numerous other cases with 59+ different DSPP variants have been reported in literature with isolated dentinogenesis imperfecta. As this is a demotion from Green rating, this gene is tagged for expert review.
Monogenic hearing loss v6.25 DSPP Ida Ertmanska Tag Q2_26_expert_review tag was added to gene: DSPP.
Fetal anomalies v7.26 NPR2 Achchuthan Shanmugasundram Phenotypes for gene: NPR2 were changed from ACROMESOMELIC DYSPLASIA MAROTEAUX TYPE to Short stature with nonspecific skeletal abnormalities, OMIM:616255
Fetal anomalies v7.25 NPR2 Achchuthan Shanmugasundram Publications for gene: NPR2 were set to
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.14 CFH Ida Ertmanska Tag Q2_26_MOI was removed from gene: CFH.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.14 CFH Ida Ertmanska changed review comment from: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported more than 30 individuals with rare CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 21 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.; to: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported more than 30 individuals with rare monoallelic CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 21 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.
Likely inborn error of metabolism v9.18 PTPMT1 Arina Puzriakova Tag Q2_26_NHS_review was removed from gene: PTPMT1.
Likely inborn error of metabolism v9.18 PTPMT1 Arina Puzriakova Entity copied from Mitochondrial disorders v10.11
Likely inborn error of metabolism v9.18 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Likely inborn error of metabolism. Sources: Expert Review Amber,Literature
Q2_26_promote_green, Q2_26_expert_review, Q2_26_NHS_review tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova edited their review of gene: PTPMT1: Changed phenotypes to: Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Possible mitochondrial disorder, nuclear genes v5.10 PTPMT1 Arina Puzriakova edited their review of gene: PTPMT1: Changed phenotypes to: Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Possible mitochondrial disorder, nuclear genes v5.10 PTPMT1 Arina Puzriakova Tag watchlist was removed from gene: PTPMT1.
Tag Q2_26_promote_green tag was added to gene: PTPMT1.
Tag Q2_26_expert_review tag was added to gene: PTPMT1.
Possible mitochondrial disorder, nuclear genes v5.10 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Possible mitochondrial disorder, nuclear genes v5.10 PTPMT1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England Clinical Team (William Macken and Helen Brittain) it was decided that it may be possible to classify this gene as green given the reasonably extensive functional work (further outlined below); however, inclusion should first be reviewed by the GMS expert team. As the phenotype is nonspecific, only tagging for promotion on more phenotypically broad panels.
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Functional evidence (PMID: 39279645):

All patient fibroblasts showed decreased PTPMT1 protein expression. Cardiolipin content was decreased in one case but normal in another unrelated individual. Mitochondria in fibroblasts from 2 cases (distantly related) displayed fragmentation and abnormal shape - rescued using expression of WT PTPMT1.

A ptpmt1 knockout zebrafish model showed abnormalities in head and body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.
Possible mitochondrial disorder, nuclear genes v5.10 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Tag Q2_26_expert_review tag was added to gene: PTPMT1.
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Tag watchlist was removed from gene: PTPMT1.
Tag Q2_26_promote_green tag was added to gene: PTPMT1.
Tag Q2_26_NHS_review tag was added to gene: PTPMT1.
Possible mitochondrial disorder, nuclear genes v5.9 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Possible mitochondrial disorder, nuclear genes v5.9 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England Clinical Team (William Macken and Helen Brittain) it was decided that it may be possible to classify this gene as green given the reasonably extensive functional work (further outlined below); however, inclusion should first be reviewed by the GMS expert team. As the phenotype is nonspecific, only tagging for promotion on more phenotypically broad panels.
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Functional evidence (PMID: 39279645):

All patient fibroblasts showed decreased PTPMT1 protein expression. Cardiolipin content was decreased in one case but normal in another unrelated individual. Mitochondria in fibroblasts from 2 cases (distantly related) displayed fragmentation and abnormal shape - rescued using expression of WT PTPMT1.

A ptpmt1 knockout zebrafish model showed abnormalities in head and body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.45 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Intellectual disability v10.45 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Early onset or syndromic epilepsy v9.23 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Early onset or syndromic epilepsy v9.23 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Severe microcephaly v9.9 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Severe microcephaly v9.9 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Ataxia and cerebellar anomalies - childhood onset v9.10 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Ataxia and cerebellar anomalies - childhood onset v9.10 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Mitochondrial disorders v10.10 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Mitochondrial disorders v10.10 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Endocrine neoplasia v3.8 GPR101 Arina Puzriakova Classified gene: GPR101 as Amber List (moderate evidence)
Endocrine neoplasia v3.8 GPR101 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple cases with germline variants causing syndromic overgrowth with pituitary macroadenoma or hyperplasia which is within the scope of this panel.
Endocrine neoplasia v3.8 GPR101 Arina Puzriakova Gene: gpr101 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v8.8 GPR101 Arina Puzriakova Classified gene: GPR101 as Amber List (moderate evidence)
Paediatric disorders - additional genes v8.8 GPR101 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple cases with germline variants causing syndromic overgrowth which is within the scope of this panel.
Paediatric disorders - additional genes v8.8 GPR101 Arina Puzriakova Gene: gpr101 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v8.7 GPR101 Arina Puzriakova gene: GPR101 was added
gene: GPR101 was added to Paediatric disorders - additional genes. Sources: Literature
Q2_26_promote_green tags were added to gene: GPR101.
Mode of inheritance for gene: GPR101 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GPR101 were set to 29389097; 25470569; 25806920; 26982009; 27245663; 27743704; 32958754
Phenotypes for gene: GPR101 were set to Pituitary adenoma 2, GH-secreting, OMIM:300943
Review for gene: GPR101 was set to GREEN
Added comment: Heterozygous or hemizygous germline variants or somatic duplications in GPR101 lead to X-linked pituitary gigantism/acrogigantism characterised by marked overgrowth in early childhood, often within the first months of life, due to excess of GH. Most patients present with concomitant hyperprolactinaemia. Histopathology shows pituitary hyperplasia or pituitary adenoma with or without associated hyperplasia. At least 30 individuals have been reported to date - mostly females harbouring germline variants, while males typically carry somatic mosaic variants although a small number of males with a germline duplication inherited from their affected mother have also been reported.
Sources: Literature
Endocrine neoplasia v3.7 GPR101 Arina Puzriakova gene: GPR101 was added
gene: GPR101 was added to Endocrine neoplasia. Sources: Literature
Q2_26_promote_green tags were added to gene: GPR101.
Mode of inheritance for gene: GPR101 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GPR101 were set to 29389097; 25470569; 25806920; 26982009; 27245663; 27743704; 32958754
Phenotypes for gene: GPR101 were set to Pituitary adenoma 2, GH-secreting, OMIM:300943
Review for gene: GPR101 was set to GREEN
Added comment: Heterozygous or hemizygous germline variants or somatic duplications in GPR101 lead to X-linked pituitary gigantism/acrogigantism characterised by marked overgrowth in early childhood, often within the first months of life, due to excess of GH. Most patients present with concomitant hyperprolactinaemia. Histopathology shows pituitary hyperplasia or pituitary adenoma with or without associated hyperplasia. At least 30 individuals have been reported to date - mostly females harbouring germline variants, while males typically carry somatic mosaic variants although a small number of males with a germline duplication inherited from their affected mother have also been reported.
Sources: Literature
Congenital fibrosis of the extraocular muscles v2.4 ZFHX4 Nicky Cronbach gene: ZFHX4 was added
gene: ZFHX4 was added to Congenital fibrosis of the extraocular muscles. Sources: Literature
Mode of inheritance for gene: ZFHX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZFHX4 were set to PMID: 41524020; 11935336; 32962661
Phenotypes for gene: ZFHX4 were set to Isolated congenital ptosis
Penetrance for gene: ZFHX4 were set to unknown
Review for gene: ZFHX4 was set to GREEN
Added comment: Multiple unrelated cases of isolated congenital ptosis reported. Three unrelated Han-Chinese patients (PMID 41524020) and one Nepalese patient (32962661) with missense variants in ZFHX4, and one case (unspecified ethnicity) related to a translocation disrupting ZFHX4.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFH Ida Ertmanska changed review comment from: PMID: 36211394 Gouda et al., 2022
Egyptian cohort of 40 patients with LN, lupus nephritis (23) or PIGN, post-infectious glomerulonephritis (17), tested for genetic variants in CFH and CD46 genes. VUS CFH:p.F614S variant was found in 28 (70%) of patients: 17 (74%) of LN patients, and 11 (65%) of PIGN patients. 3 Pathogenic CFH mutations were detected in a heterozygous state in LN patients: c.514C>T (p.Q172*), c.2103G>A (p.W701*), and c.3288G>A (p.W1096*).

PMID: 35084692 Shears et al., 2022
Forty patients, median age 19 (range 3–62) years, were identified with terminal complement deficiencies. 2 White European patients had CFH variants and meningococcal infections and septicemia; 1 patient had non-meningococcal sepsis. Both were homozygous for CFH c.2T>C, p.Met1? variant (related?).

PMID: 32064578 Brodszki et al., 2020
"Complement deficiencies account for ~5% of PIDs." <30 patients reported with CFH variants according to the lit review.

PMID: 31440263 Sissy et al., 2019
13 patients reported with 7 different homozygous CFH variants and Factor H deficiency (primarily resulting in severe or multiple infections—mainly meningococcal infections—or severe autoimmune diseases). However, in this cohort, all 13 patients with CFH variants presented with kidney disease and no recurrent infections.

PMID: 14978182 Dragon-Durey et al., 2004
Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS. No mention of recurring infections in these patients - authors pose that previously reported susceptibility to meningococcal disease is secondary to acquired C3 or C5-C9 deficiencies.

Functional:
PMID: 12091909 Pickering et al., 2002 - mouse Cfh knockout caused membranoproliferative glomerulonephritis, seen at 8 months old.

CFH is associated with AD,AR Complement factor H deficiency, OMIM:609814 and AD, AR {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400, among others (OMIM accessed 22nd Jun 2026). The association between CFH and semidominant atypical hemolytic-uremic syndrome is Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, July 2023); CFH-related AR C3 glomerulonephritis is also Definitive (Complement-Mediated Kidney Diseases GCEP, Feb 2024).; to: PMID: 36211394 Gouda et al., 2022
Egyptian cohort of 40 patients with LN, lupus nephritis (23) or PIGN, post-infectious glomerulonephritis (17), tested for genetic variants in CFH and CD46 genes. VUS CFH:p.F614S variant was found in 28 (70%) of patients: 17 (74%) of LN patients, and 11 (65%) of PIGN patients. 3 Pathogenic CFH mutations were detected in a heterozygous state in LN patients: c.514C>T (p.Q172*), c.2103G>A (p.W701*), and c.3288G>A (p.W1096*).

PMID: 35084692 Shears et al., 2022
Forty patients, median age 19 (range 3–62) years, were identified with terminal complement deficiencies. 2 White European patients had CFH variants and meningococcal infections and septicemia; 1 of these patients also had non-meningococcal sepsis. Both were homozygous for CFH c.2T>C, p.Met1? variant (related?).

PMID: 32064578 Brodszki et al., 2020
"Complement deficiencies account for ~5% of PIDs." <30 patients reported with CFH variants according to the lit review.

PMID: 31440263 Sissy et al., 2019
13 patients reported with 7 different homozygous CFH variants and Factor H deficiency (primarily resulting in severe or multiple infections—mainly meningococcal infections—or severe autoimmune diseases). However, in this cohort, all 13 patients with CFH variants presented with kidney disease and no recurrent infections.

PMID: 14978182 Dragon-Durey et al., 2004
Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS. No mention of recurring infections in these patients - authors pose that previously reported susceptibility to meningococcal disease is secondary to acquired C3 or C5-C9 deficiencies.

Functional:
PMID: 12091909 Pickering et al., 2002 - mouse Cfh knockout caused membranoproliferative glomerulonephritis, seen at 8 months old.

CFH is associated with AD,AR Complement factor H deficiency, OMIM:609814 and AD, AR {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400, among others (OMIM accessed 22nd Jun 2026). The association between CFH and semidominant atypical hemolytic-uremic syndrome is Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, July 2023); CFH-related AR C3 glomerulonephritis is also Definitive (Complement-Mediated Kidney Diseases GCEP, Feb 2024).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFB Ida Ertmanska changed review comment from: PMID: 41663882 Bougeard et al., 2026
Report of a 14yo French girl with Neisseria meningitidis serogroup Y meningitis complicated by bacteremia and cerebral venous sinus thrombosis. She was found to be comp het for CFB: p.Gly396Arg and p.Gln713Arg.

PMID: 33165708 Gauthier et al., 2021
8yo male, Caucasian, with repeated pneumococcal infections: pneumococcal bacteriemia at 4 months, pneumococcal meningitis and bacteriemia at 11 months, empyema caused by S. pneumoniae at 8 years: pneumonia with septic shock and acute respiratory distress syndrome (intubated for 9 days + mechanical ventilation + 7 days of extracorporeal membrane oxygenation). Compound heterozygous for CFB variants c.1938dup, p.(Ile647Hisfs*6) and c.1186G>A, p.(Gly396Arg).

PMID: 24152280 Slade et al., 2018
32yo female, recurrent episodes of pneumococcal and meningococcal infections starting at age 2 yrs. She was compound heterozygous for CFB: c.766C>T, p.Gln256* (nonsense), c.1895_1898del, p.Phe632Cysfs*8 (frameshift). Factor B levels were undetectable in the patient.

PMCID: PMC3334074 Dehoorne et al., 2008
Report of a 16-y-old Caucasian girl, who presented with recurrent episodes of aseptic meningitis. She presented with a 2-week history of headache, vomiting, neck stiffness, facial palsy, equilibrium problems, diplopia, and low grade temperature. 4 months prior to admission she presented with a leucocytoclastic vasculitis. Biochemical testing showed very low levels of factor B (1mg/dl), but normal factors I and H. No genetic testing described.

CFB is associated with AR Complement factor B deficiency, MIM:615561 and AD {Hemolytic uremic syndrome, atypical, susceptibility to, 4}, MIM:612924 in OMIM (accessed 22nd Jun 2026).
The association between CFB and AD C3 glomerulonephritis was classified as Limited (Nov 2024), and CFB-related AD atypical hemolytic-uremic syndrome with B factor anomaly was classified as Moderate (July 2023) by the ClinGen Complement-Mediated Kidney Diseases GCEP.; to: PMID: 41663882 Bougeard et al., 2026
Report of a 14yo French girl with Neisseria meningitiis serogroup Y complicated by bacteremia and cerebral venous sinus thrombosis. She was found to be comp het for CFB: p.Gly396Arg and p.Gln713Arg.

PMID: 33165708 Gauthier et al., 2021
8yo male, Caucasian, with repeated pneumococcal infections: pneumococcal bacteriemia at 4 months, pneumococcal meningitis and bacteriemia at 11 months, empyema caused by S. pneumoniae at 8 years: pneumonia with septic shock and acute respiratory distress syndrome (intubated for 9 days + mechanical ventilation + 7 days of extracorporeal membrane oxygenation). Compound heterozygous for CFB variants c.1938dup, p.(Ile647Hisfs*6) and c.1186G>A, p.(Gly396Arg).

PMID: 24152280 Slade et al., 2018
32yo female, recurrent episodes of pneumococcal and meningococcal infections starting at age 2 yrs. She was compound heterozygous for CFB: c.766C>T, p.Gln256* (nonsense), c.1895_1898del, p.Phe632Cysfs*8 (frameshift). Factor B levels were undetectable in the patient.

PMCID: PMC3334074 Dehoorne et al., 2008
Report of a 16-y-old Caucasian girl, who presented with recurrent episodes of aseptic meningitis. She presented with a 2-week history of headache, vomiting, neck stiffness, facial palsy, equilibrium problems, diplopia, and low grade temperature. 4 months prior to admission she presented with a leucocytoclastic vasculitis. Biochemical testing showed very low levels of factor B (1mg/dl), but normal factors I and H. No genetic testing described.

CFB is associated with AR Complement factor B deficiency, MIM:615561 and AD {Hemolytic uremic syndrome, atypical, susceptibility to, 4}, MIM:612924 in OMIM (accessed 22nd Jun 2026).
The association between CFB and AD C3 glomerulonephritis was classified as Limited (Nov 2024), and CFB-related AD atypical hemolytic-uremic syndrome with B factor anomaly was classified as Moderate (July 2023) by the ClinGen Complement-Mediated Kidney Diseases GCEP.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFH Ida Ertmanska Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFH Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported with both monoallelic and biallelic CFH variants and renal disease (aHUS, MPGN). However, there is little evidence of patients with FH deficiency having primary immunodeficiency. Of more than 30 patients summarised below, only two were reported to have recurrent (meningococcal) infections - this is posed to be secondary to acquired deficiency of other complements (PMID: 14978182). Hence, this gene is tagged for demotion from Green to Amber, with expert review also requested.; to: Comment on list classification: There are numerous patients reported with both monoallelic and biallelic CFH variants and renal disease (aHUS, MPGN). However, there is little evidence of patients with FH deficiency having primary immunodeficiency. Of more than 30 patients summarised below, only two were reported to have recurrent (meningococcal) infections - this is posed to be secondary to acquired deficiency of other complements (PMID: 14978182). Hence, this gene will be tagged for demotion from Green to Amber, with expert review also requested.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFH Ida Ertmanska Tag Q2_26_expert_review was removed from gene: CFH.
Tag Q2_26_demote_amber was removed from gene: CFH.
Fetal anomalies v7.24 VCP Arina Puzriakova Classified gene: VCP as Amber List (moderate evidence)
Fetal anomalies v7.24 VCP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated individuals with Adams-Oliver syndrome due to heterozygous hypermorphic variants in the NTD domain of VCP.
Fetal anomalies v7.24 VCP Arina Puzriakova Gene: vcp has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.22 VCP Arina Puzriakova Classified gene: VCP as Amber List (moderate evidence)
Skeletal dysplasia v9.22 VCP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated individuals with Adams-Oliver syndrome due to heterozygous hypermorphic variants in the NTD domain of VCP.
Skeletal dysplasia v9.22 VCP Arina Puzriakova Gene: vcp has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v4.14 VCP Arina Puzriakova Classified gene: VCP as Amber List (moderate evidence)
Pulmonary arterial hypertension v4.14 VCP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated individuals with Adams-Oliver syndrome, of which 6 had pulmonary hypertension, due to heterozygous hypermorphic variants in the NTD domain of VCP.
Pulmonary arterial hypertension v4.14 VCP Arina Puzriakova Gene: vcp has been classified as Amber List (Moderate Evidence).
Limb disorders v8.16 VCP Arina Puzriakova Classified gene: VCP as Amber List (moderate evidence)
Limb disorders v8.16 VCP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated individuals with Adams-Oliver syndrome due to heterozygous hypermorphic variants in the NTD domain of VCP.
Limb disorders v8.16 VCP Arina Puzriakova Gene: vcp has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CD46 Ida Ertmanska edited their review of gene: CD46: Changed rating: AMBER; Changed publications to: 14566051, 16621965, 16762990, 29644059, 33238263, 40983966; Changed phenotypes to: {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CD46 Ida Ertmanska changed review comment from: PMID: 33238263 Bamhraz et al., 2020
Saudi Arabian aHUS cohort.
Patient 1 homozygous for CD46: c.736T>A (p.Phe246Ile) variant, as well as het for CFI c.540A>G (p.Glu180Glu) - both labelled VUS. Disease onset at 10yrs, complete recovery after eculizumab treatment.
Patient 5 - homozygous for CD46: c.769 C>A (p.Cys 256*) - LP, as well as heterozygous for CFI c.803 C>T (p.Ser268Leu) variant (LB). Disease onset at 2.5yrs, developed into ESRD and required a post-kidney transplant.
Patient 7 - homozygous for CD46: c.350-351dup AC (p.Glu11ThfsX17) - LP. Disease onset at 21 months. Patient responded to plasma therapy leading to full recovery.

PMID: 29644059 Khandelwal et al., 2018
Cohort of Indian children with aHUS.
Sibling pairs 2–3 and 7–8 with familial disease showed a homozygous c.286 + 2T > G splice-site mutation; in both families, the parents were consanguineous. Patient 9 had a homozygous c.104G > A, p.Cys35Tyr; his affected sibling had died before genetic evaluation. 3 unrelated families total.; to: BIALLELIC CASES:
PMID: 40983966 Hu et al., 2025
Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced. Other modifier mutations may affect penetrance here.

PMID: 33238263 Bamhraz et al., 2020
Saudi Arabian aHUS cohort.
Patient 1 homozygous for CD46: c.736T>A (p.Phe246Ile) variant, as well as het for CFI c.540A>G (p.Glu180Glu) - both labelled VUS. Disease onset at 10yrs, complete recovery after eculizumab treatment.
Patient 5 - homozygous for CD46: c.769 C>A (p.Cys 256*) - LP, as well as heterozygous for CFI c.803 C>T (p.Ser268Leu) variant (LB). Disease onset at 2.5yrs, developed into ESRD and required a post-kidney transplant.
Patient 7 - homozygous for CD46: c.350-351dup AC (p.Glu11ThfsX17) - LP. Disease onset at 21 months. Patient responded to plasma therapy leading to full recovery.

PMID: 29644059 Khandelwal et al., 2018
Cohort of Indian children with aHUS.
Sibling pairs 2–3 and 7–8 with familial disease showed a homozygous c.286 + 2T > G splice-site mutation; in both families, the parents were consanguineous. Patient 9 had a homozygous c.104G > A, p.Cys35Tyr; his affected sibling had died before genetic evaluation. 3 unrelated families total.

PMID: 16762990 Fremeaux-Bacchi et al., 2006
3 homozygous aHUS patients (onset at 2, 5, and 27yrs).
Patient 1 - born with Pierre Robin sequence, presented with common variable immunodeficiency. Developed aHUS at 27yrs. Homozygous for CD46 R25X. MFI on granulocytes for CD46 expression was 0.
Patient 2 was homozygous for CD46 Y214X (no CD46 expression on granulocytes; Patient 3 homozygous for IVS2+2T>G - CD46 MFI level was 46 (normal range 600-1400). No mention of immunodeficiency in Patients 2 & 3.

PMID: 16621965 Caprioli et al., 2006
Family 099 - Sardinian origin, 2 individuals homozygous for CD46 IVS1-1G > C, and 1 heterozygous affected member (4 het carriers unaffected). The homozygous sibs developed aHUS early (before age 4 yrs); adult onset seen in heterozygous family members.
Family 024 - 2 comp het sibs CD46 variants c.218C>T, p.R25Stop & c.147G>A, p.C1Y - showed almost no MCP staining by FACS. Parents were carriers of 1 mutation each, unaffected.

PMID: 14566051 Richards et al., 2003
Family 3 - recessive aHUS, CD46 c.822T>C, p.Ser206Pro. Same mutation caused aHUS in Family 2 in a heterozygous state. Demonstrated that het patients had protein expression reduced by 50%, and it was absent in homozygotes.
Pulmonary arterial hypertension v4.13 VCP Arina Puzriakova gene: VCP was added
gene: VCP was added to Pulmonary arterial hypertension. Sources: Literature
Q2_26_promote_green tags were added to gene: VCP.
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 41979051
Phenotypes for gene: VCP were set to Adams-Oliver syndrome, MONDO:0007034
Mode of pathogenicity for gene: VCP was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: VCP was set to GREEN
Added comment: Lehman et al 2026 (PMID: 41979051) report 7 unrelated families with Adams-Oliver syndrome characterised by aplasia cutis congenita and terminal limb reduction defects. Members of three families displayed features of multisystem proteinopathy, previously associated with this gene, including a parent (myopathy, lytic bone lesions and/or neuropathy in F1 and 2) or grandparent (frontotemporal dementia in F4). Pulmonary hypertension was found in 6/7 families.

Heterozygous rare missense variants in the VCP gene were identified by WGS or WES (4 de novo, 2 inherited and 1 presumed inherited). Variants clustered in the N-terminal domain (NTD), and the same amino acid residue, p.Arg89, was altered in 4/7 families. Variants were shown to exert a GoF effect, leading to overactive ATP hydrolysis and caused NTD hyperflexibility with loss of interdomain coupling.
Sources: Literature
Fetal anomalies v7.23 VCP Arina Puzriakova gene: VCP was added
gene: VCP was added to Fetal anomalies. Sources: Literature
Q2_26_promote_green tags were added to gene: VCP.
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 41979051
Phenotypes for gene: VCP were set to Adams-Oliver syndrome, MONDO:0007034
Mode of pathogenicity for gene: VCP was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: VCP was set to GREEN
Added comment: Lehman et al 2026 (PMID: 41979051) report 7 unrelated families with Adams-Oliver syndrome characterised by aplasia cutis congenita and terminal limb reduction defects. Members of three families displayed features of multisystem proteinopathy, previously associated with this gene, including a parent (myopathy, lytic bone lesions and/or neuropathy in F1 and 2) or grandparent (frontotemporal dementia in F4). Pulmonary hypertension was found in 6/7 families.

Heterozygous rare missense variants in the VCP gene were identified by WGS or WES (4 de novo, 2 inherited and 1 presumed inherited). Variants clustered in the N-terminal domain (NTD), and the same amino acid residue, p.Arg89, was altered in 4/7 families. Variants were shown to exert a GoF effect, leading to overactive ATP hydrolysis and caused NTD hyperflexibility with loss of interdomain coupling.
Sources: Literature
Skeletal dysplasia v9.21 VCP Arina Puzriakova gene: VCP was added
gene: VCP was added to Skeletal dysplasia. Sources: Literature
Q2_26_promote_green tags were added to gene: VCP.
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 41979051
Phenotypes for gene: VCP were set to Adams-Oliver syndrome, MONDO:0007034
Mode of pathogenicity for gene: VCP was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: VCP was set to GREEN
Added comment: Lehman et al 2026 (PMID: 41979051) report 7 unrelated families with Adams-Oliver syndrome characterised by aplasia cutis congenita and terminal limb reduction defects. Members of three families displayed features of multisystem proteinopathy, previously associated with this gene, including a parent (myopathy, lytic bone lesions and/or neuropathy in F1 and 2) or grandparent (frontotemporal dementia in F4). Pulmonary hypertension was found in 6/7 families.

Heterozygous rare missense variants in the VCP gene were identified by WGS or WES (4 de novo, 2 inherited and 1 presumed inherited). Variants clustered in the N-terminal domain (NTD), and the same amino acid residue, p.Arg89, was altered in 4/7 families. Variants were shown to exert a GoF effect, leading to overactive ATP hydrolysis and caused NTD hyperflexibility with loss of interdomain coupling.
Sources: Literature
Limb disorders v8.15 VCP Arina Puzriakova gene: VCP was added
gene: VCP was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: VCP.
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 41979051
Phenotypes for gene: VCP were set to Adams-Oliver syndrome, MONDO:0007034
Mode of pathogenicity for gene: VCP was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: VCP was set to GREEN
Added comment: Lehman et al 2026 (PMID: 41979051) report 7 unrelated families with Adams-Oliver syndrome characterised by aplasia cutis congenita and terminal limb reduction defects. Members of three families displayed features of multisystem proteinopathy, previously associated with this gene, including a parent (myopathy, lytic bone lesions and/or neuropathy in F1 and 2) or grandparent (frontotemporal dementia in F4). Pulmonary hypertension was found in 6/7 families.

Heterozygous rare missense variants in the VCP gene were identified by WGS or WES (4 de novo, 2 inherited and 1 presumed inherited). Variants clustered in the N-terminal domain (NTD), and the same amino acid residue, p.Arg89, was altered in 4/7 families. Variants were shown to exert a GoF effect, leading to overactive ATP hydrolysis and caused NTD hyperflexibility with loss of interdomain coupling.
Sources: Literature
Fetal anomalies v7.22 NPR2 Ida Ertmanska changed review comment from: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).

Consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as heterozygous individuals also present with skeletal features, limb disorders.; to: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).

Brachydactyly is a consistent feature in recessive NPR2-related skeletal dysplasia (Acromesomelic dysplasia 1, Maroteaux type). Heterozygous individuals also present with skeletal features, limb disorders. Hence, consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Fetal anomalies v7.22 NPR2 Ida Ertmanska changed review comment from: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement) so the TD criteria are fulfilled for at least 5 individuals (> 2 years old and height <-3SD).

Consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as heterozygous individuals also present with skeletal features, limb disorders.; to: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).

Consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as heterozygous individuals also present with skeletal features, limb disorders.
Skeletal dysplasia v9.20 GHR Ida Ertmanska Tag treatable tag was added to gene: GHR.
Monogenic short stature v2.8 GHR Ida Ertmanska Tag treatable tag was added to gene: GHR.
Skeletal dysplasia v9.20 GHR Ida Ertmanska commented on gene: GHR: NHS Clinical Commissioning Policy: Mecasermin for treatment of growth failure (April 2013): "The NHS Commissioning Board (NHS CB) will commission mecasermin for children and adolescents with growth failure due to severe primary insulin-like growth factor1 deficiency (SPIGFD)" - treatable tag has been added.
Pituitary hormone deficiency v4.10 GHR Ida Ertmanska Tag treatable tag was added to gene: GHR.
Pituitary hormone deficiency v4.10 GHR Ida Ertmanska commented on gene: GHR: NHS Clinical Commissioning Policy: Mecasermin for treatment of growth failure (April 2013): "The NHS Commissioning Board (NHS CB) will commission mecasermin for children and adolescents with growth failure due to severe primary insulin-like growth factor1 deficiency (SPIGFD)" - treatable tag has been added.
Pituitary hormone deficiency v4.10 GHR Ida Ertmanska commented on gene: GHR: NHS Clinical Commissioning Policy: Mecasermin for treatment of growth failure (April 2013): "The NHS Commissioning Board (NHS CB) will commission mecasermin for children and adolescents with growth failure due to severe primary insulin-like growth factor1 deficiency (SPIGFD)" - treatable tag has been added.
Monogenic short stature v2.8 GHR Ida Ertmanska commented on gene: GHR: NHS Clinical Commissioning Policy: Mecasermin for treatment of growth failure (April 2013): "The NHS Commissioning Board (NHS CB) will commission mecasermin for children and adolescents with growth failure due to severe primary insulin-like growth factor1 deficiency (SPIGFD)" - treatable tag has been added.
Hereditary neuropathy v1.510 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Charcot-Marie-Tooth disease, type 2Y; Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia; Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 to Charcot-Marie-Tooth disease, type 2Y, OMIM:616687
Amyotrophic lateral sclerosis/motor neuron disease v1.75 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia, 613954; Amyotrophic Lateral Sclerosis, Dominant; familial amyotrophic lateral sclerosis (ALS14) to Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, OMIM:613954
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 167320 to Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1, OMIM:167320
Arthrogryposis v10.13 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia, 613954 Inclusion body myopathy,Paget disease and frontotemporal dementia 1, 167320 ; Inclusion Body Myopathy, Dominant; Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia to nclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1, OMIM:167320
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.85 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia, 613954 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, OMIM:613954
Distal myopathies v7.5 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1, 167320 to Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1, OMIM:167320
Monogenic hearing loss v6.25 COL9A3 Ida Ertmanska Phenotypes for gene: COL9A3 were changed from Stickler syndrome, MONDO:0019354 to Stickler syndrome, MONDO:0019354; Stickler syndrome, type VI, OMIM:620022
Stickler syndrome v4.11 COL9A3 Ida Ertmanska Phenotypes for gene: COL9A3 were changed from Stickler syndrome, MONDO:0019354 to Stickler syndrome, MONDO:0019354; Stickler syndrome, type VI, OMIM:620022
Stickler syndrome v4.10 GZF1 Ida Ertmanska Phenotypes for gene: GZF1 were changed from Larsen syndrome, MONDO:0007875 to Larsen syndrome, MONDO:0007875; JOINT LAXITY, SHORT STATURE, AND MYOPIA, OMIM:617662
Intellectual disability v10.44 UBR5 Ida Ertmanska Phenotypes for gene: UBR5 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Neurodevelopmental disorder with speech delay and behavioral abnormalities, OMIM:621372
Early onset or syndromic epilepsy v9.22 UBR5 Ida Ertmanska Phenotypes for gene: UBR5 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Neurodevelopmental disorder with speech delay and behavioral abnormalities, OMIM:621372
Ataxia and cerebellar anomalies - childhood onset v9.9 TTBK2 Ida Ertmanska Phenotypes for gene: TTBK2 were changed from Spinocerebellar ataxia 11 to Spinocerebellar ataxia 11, OMIM:604432; spinocerebellar ataxia type 11, MONDO:0011464
Likely inborn error of metabolism v9.17 STS Ida Ertmanska Phenotypes for gene: STS were changed from X-linked ichthyosis (Other disorders in the metabolism of sterols); Autosomal recessive congenital ichthyosis to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269
Corneal dystrophy v4.11 STS Ida Ertmanska Phenotypes for gene: STS were changed from Ichthyosis, X-linked to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269
Palmoplantar keratodermas v4.16 STS Ida Ertmanska Phenotypes for gene: STS were changed from X linked ichthyosis to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269
Intellectual disability v10.43 STAG2 Ida Ertmanska Phenotypes for gene: STAG2 were changed from STAG2-related developmental delay with microcephaly and congenital anomalies; STAG2-related X-linked Intellectual Deficiency; cohesinopathy; Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology to Holoprosencephaly 13, X-linked, OMIM:301043; Mullegama-Klein-Martinez syndrome, OMIM:301022
Respiratory ciliopathies including non-CF bronchiectasis v5.3 SPEF2 Ida Ertmanska Phenotypes for gene: SPEF2 were changed from Spermatogenic failure 43, OMIM:618751, MONDO:0032898; Primary ciliary dyskinesia-like phenotype to Spermatogenic failure 43, OMIM:618751; Primary ciliary dyskinesia-like phenotype
Hereditary neuropathy or pain disorder v8.9 RCC1 Ida Ertmanska Phenotypes for gene: RCC1 were changed from Severe, acute-onset axonal neuropathy following infection to Infection-induced acute-onset axonal neuropathy, OMIM:621333; infection-induced acute-onset axonal neuropathy, MONDO:0979881
Pigmentary skin disorders v5.11 RAB27A Ida Ertmanska Phenotypes for gene: RAB27A were changed from GS2; GRISCELLI SYNDROME, TYPE 2; Griscelli syndrome to Griscelli syndrome, type 2, OMIM:607624; Griscelli syndrome type 2, MONDO:0011872
Hereditary spastic paraplegia, adult onset v6.12 PSEN1 Ida Ertmanska Phenotypes for gene: PSEN1 were changed from Alzheimer disease, type 3, with spastic paraparesis, apraxia and unusual plaques; Alzheimer disease, type 3, with spastic paraparesis and apraxia; Alzheimer disease, type 3, with spastic paraparesis and unusual plaques to Alzheimer disease, type 3, with or without spastic paraparesis, OMIM:607822
Retinal disorders v9.10 PLA2G5 Ida Ertmanska Phenotypes for gene: PLA2G5 were changed from Eye Disorders to [Fleck retina, familial benign], OMIM:228980
Intellectual disability v10.42 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904
Likely inborn error of metabolism v9.16 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, OMIM:618135; muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, MONDO:0029135
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.14 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8, 614830; limb girdle muscular dystrophy to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, OMIM:618135; muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, MONDO:0029135
Ataxia and cerebellar anomalies - childhood onset v9.8 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies type to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904
Arthrogryposis v10.12 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies type; Walker-Warburg syndrome to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, OMIM:618135; muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, MONDO:0029135
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 PIK3CG Ida Ertmanska Phenotypes for gene: PIK3CG were changed from Immunodeficiency 97 with autoinflammation, OMIM:619802 to Immunodeficiency 97 with autoinflammation, OMIM:619802; immunodeficiency 97 with autoinflammation, MONDO:0030717
Primary immunodeficiency or monogenic inflammatory bowel disease v9.17 PIK3CG Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.17 PIK3CG Ida Ertmanska Phenotypes for gene: PIK3CG were changed from Immune dysregulation; HLH-like; childhood-onset antibody defects; cytopenias; T lymphocytic pneumonitis and colitis to Immunodeficiency 97 with autoinflammation, OMIM:619802
Vascular skin disorders v2.7 PIK3CA Ida Ertmanska Phenotypes for gene: PIK3CA were changed from PIK3CA-related overgrowth syndromes; Vascular malformation, MONDO:0024291 to PIK3CA-related overgrowth syndromes; Vascular malformation, MONDO:0024291; CLAPO syndrome, somatic, OMIM:613089; Nevus, epidermal, somatic mosaic, OMIM:162900; CLOVE syndrome, somatic, OMIM:612918; Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, OMIM:602501
Mosaic skin disorders - Deep sequencing v3.34 PIK3CA Ida Ertmanska Phenotypes for gene: PIK3CA were changed from PIK3CA-related overgrowth syndromes; Vascular malformations to CLAPO syndrome, somatic, OMIM:613089; Nevus, epidermal, somatic mosaic, OMIM:162900; CLOVE syndrome, somatic, OMIM:612918
Malformations of cortical development v8.6 PIK3CA Ida Ertmanska Phenotypes for gene: PIK3CA were changed from Polymicrogyria, hemimegalencephaly, macrocephaly to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, OMIM:602501; Cerebral cavernous malformations 4, somatic, OMIM:619538
Pigmentary skin disorders v5.10 PIK3CA Ida Ertmanska Phenotypes for gene: PIK3CA were changed from MCAP; PIK3CA-related overgrowth syndromes; MEGALENCEPHALY-CAPILLARY MALFORMATION-POLYMICROGYRIA SYNDROME; Vascular malformations to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, OMIM:602501
Intellectual disability v10.41 TMEM63B Achchuthan Shanmugasundram Phenotypes for gene: TMEM63B were changed from Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275 to Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder; lung disorder, MONDO:0005275
Dystonia, chorea or related movement disorder, childhood onset v8.5 PDYN Ida Ertmanska Phenotypes for gene: PDYN were changed from Spinocerebellar ataxia 23, 610245 to Spinocerebellar ataxia 23, OMIM:610245; spinocerebellar ataxia type 23, MONDO:0012449
Hereditary neuropathy or pain disorder v8.8 PDYN Ida Ertmanska Phenotypes for gene: PDYN were changed from Spinocerebellar ataxia 23, 610245; Cerebellar ataxia, sensory-motor axonal neuropathy to Spinocerebellar ataxia 23, OMIM:610245; spinocerebellar ataxia type 23, MONDO:0012449
Ataxia and cerebellar anomalies - childhood onset v9.7 PDYN Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Ataxia and cerebellar anomalies - childhood onset v9.7 PDYN Ida Ertmanska Phenotypes for gene: PDYN were changed from Spinocerebellar ataxia 23 to Spinocerebellar ataxia 23, OMIM:610245; spinocerebellar ataxia type 23, MONDO:0012449
Childhood interstitial lung disease v1.6 TMEM63B Achchuthan Shanmugasundram Phenotypes for gene: TMEM63B were changed from autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275 to autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder; lung disorder, MONDO:0005275
Congenital myopathy v7.77 TUBA4A Achchuthan Shanmugasundram changed review comment from: PMID:38413182 (2024) reported the identification of a recurrent novel heterozygous de novo variant (c.679C>T/ p.Leu227Phe) in the TUBA4A gene in two unrelated Chinese patients with sporadic congenital myopathy (14-year-old and 6-year-old females). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F variant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

PMID:41678358 (2026) reported a multi-centre study in which the authors identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease, while probands from the remaining two families presented with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation.

Four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. The disease onset ranged from congenital to late adulthood.

Of the three families with homozygous variants, the disease onset/ first clinical examination was only after 10 years in two (although motor delay reported in one family) and the third was 70-year-old patient also with a VUS variant in FLNC gene.

This gene has been associated only with AD congenital myopathy in OMIM (MIM #621225) and the record was last accessed 09 June 2026.; to: PMID:38413182 (2024) reported the identification of a recurrent novel heterozygous de novo variant (c.679C>T/ p.Leu227Phe) in the TUBA4A gene in two unrelated Chinese patients with sporadic congenital myopathy (14-year-old and 6-year-old females). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F variant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

PMID:41678358 (2026) reported a multi-centre study in which the authors identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease, while probands from the remaining two families presented with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation.

Four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. The disease onset ranged from congenital to late adulthood.

Of the three families with homozygous variants, the disease onset/ first clinical examination was only after 10 years in two (although motor delay reported in one family) and the third was 60-year-old patient with a VUS variant in FLNC gene, which has since been reported as LB in ClinVar.

This gene has been associated only with AD congenital myopathy in OMIM (MIM #621225) and the record was last accessed 09 June 2026.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.13 TUBA4A Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: TUBA4A.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.13 TUBA4A Achchuthan Shanmugasundram Classified gene: TUBA4A as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.13 TUBA4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are several unrelated families reported with monoallelic TUBA4A variants and three unrelated families with biallelic TUBA4A variants. Hence, this gene can be considered for promotion to green rating with 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' MOI in the next GMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.13 TUBA4A Achchuthan Shanmugasundram Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.12 TUBA4A Achchuthan Shanmugasundram gene: TUBA4A was added
gene: TUBA4A was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature
Mode of inheritance for gene: TUBA4A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TUBA4A were set to 38413182; 41678358
Phenotypes for gene: TUBA4A were set to Congenital myopathy 26, OMIM:621225; congenital myopathy 26, MONDO:0979229
Review for gene: TUBA4A was set to GREEN
Added comment: PMID:38413182 (2024) reported the identification of a recurrent novel heterozygous de novo variant (c.679C>T/ p.Leu227Phe) in the TUBA4A gene in two unrelated Chinese patients with sporadic congenital myopathy (14-year-old and 6-year-old females). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F variant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

PMID:41678358 (2026) reported a multi-centre study in which the authors identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease, while probands from the remaining two families presented with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation.

Four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. The disease onset ranged from congenital to late adulthood. Three families with heterozygous variants and one with homozygous variant presented with myofibrillar disorganisation.

The following are details of the three patients with biallelic variants:
- Patient 26 (homozygous for c. 34G>A/ p.Ala12Thr) - myofibrillar myopathy with prominent axial muscle weakness, late-onset ataxia with cerebellar atrophy, nemaline bodies, proteinopathy. Age of onset at 60 years. The patient was also identified with a VUS variant in FLCN gene, which has since been reported as LB in ClinVar.
- Patient 21 (homozygous for c.722C>T/ p.Ser241Phe) - phenotype of myopathy / myo-tubulinopathy with fatigability and severe distal and proximal upper and lower limb weakness. Age of onset at 12 years.
- Patients 22/23 (siblings homozygous for c.1061G>A/ p.Gly354Asp) - phenotype listed as myopathy / myo-tubulinopathy with fatigability and generalised symmetrical weakness (distal and proximal). Age of onset from first year.

This gene has been associated only with AD congenital myopathy in OMIM (MIM #621225) and the record was last accessed 25 June 2026.
Sources: Literature
Childhood interstitial lung disease v1.5 TMEM63B Eleanor Williams changed review comment from: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature; to: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, doi:10.1016/j.bdcasr.2024.100043. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature
Intellectual disability v10.40 TMEM63B Eleanor Williams Phenotypes for gene: TMEM63B were changed from Developmental and epileptic encephalopathy 118, OMIM:621250 to Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275
Intellectual disability v10.39 TMEM63B Eleanor Williams Publications for gene: TMEM63B were set to 37421948; 42259295
Intellectual disability v10.38 TMEM63B Eleanor Williams Publications for gene: TMEM63B were set to 37421948
Intellectual disability v10.37 TMEM63B Eleanor Williams Added comment: Comment on mode of inheritance: There are sufficient biallelic cases with loss of function variants and phenotype that includes moderate-severe developmental delay as well as lung disease to change the mode of inheritance to BOTH monoallelic and biallelic, autosomal or pseudoautosomal subject to GMS review.
Intellectual disability v10.37 TMEM63B Eleanor Williams Mode of inheritance for gene: TMEM63B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v10.36 TMEM63B Eleanor Williams Tag Q2_26_MOI tag was added to gene: TMEM63B.
Intellectual disability v10.36 TMEM63B Eleanor Williams changed review comment from: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss.

Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants.

In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals.; to: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed.

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss.

Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals.
Intellectual disability v10.36 TMEM63B Eleanor Williams Deleted their comment
Intellectual disability v10.36 TMEM63B Eleanor Williams commented on gene: TMEM63B: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss.

Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants.

In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals.
Intellectual disability v10.36 TMEM63B Eleanor Williams reviewed gene: TMEM63B: Rating: GREEN; Mode of pathogenicity: None; Publications: 42259295; Phenotypes: autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,, lung disorder, MONDO:0005275; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood interstitial lung disease v1.5 TMEM63B Eleanor Williams Phenotypes for gene: TMEM63B were changed from autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder to autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275
Childhood interstitial lung disease v1.4 TMEM63B Eleanor Williams Classified gene: TMEM63B as Amber List (moderate evidence)
Childhood interstitial lung disease v1.4 TMEM63B Eleanor Williams Added comment: Comment on list classification: Rating amber but with a recommendation for green rating following GMS review. There are 4 families with biallelic loss of function variants in this gene and a relevant phenotype.
Childhood interstitial lung disease v1.4 TMEM63B Eleanor Williams Gene: tmem63b has been classified as Amber List (Moderate Evidence).
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams changed review comment from: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic pLoF variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature; to: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature
Intellectual disability v10.36 KCNB1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Intellectual disability v10.36 KCNB1 Ida Ertmanska Phenotypes for gene: KCNB1 were changed from EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 26 to Developmental and epileptic encephalopathy 26, OMIM:616056; developmental and epileptic encephalopathy, 26, MONDO:0014477
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams changed review comment from: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic pLoF variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature; to: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic pLoF variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature
Early onset or syndromic epilepsy v9.21 KCNB1 Ida Ertmanska Publications for gene: KCNB1 were set to Torkamani et al (2014) Ann. Neurol. 76: 529-540, 2014
Early onset or syndromic epilepsy v9.20 KCNB1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Early onset or syndromic epilepsy v9.20 KCNB1 Ida Ertmanska Phenotypes for gene: KCNB1 were changed from Epileptic encephalopathy, early infantile, 26 to Developmental and epileptic encephalopathy 26, OMIM:616056; developmental and epileptic encephalopathy, 26, MONDO:0014477
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams Tag Q2_26_promote_green tag was added to gene: TMEM63B.
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams edited their review of gene: TMEM63B: Changed rating: GREEN
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams gene: TMEM63B was added
gene: TMEM63B was added to Childhood interstitial lung disease. Sources: Literature
Mode of inheritance for gene: TMEM63B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63B were set to 42259295
Phenotypes for gene: TMEM63B were set to autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder
Review for gene: TMEM63B was set to AMBER
Added comment: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic pLoF variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature
Intellectual disability v10.35 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Intellectual disability v10.35 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699; neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Early onset or syndromic epilepsy v9.19 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Early onset or syndromic epilepsy v9.19 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027 to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027; Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Fetal anomalies v7.22 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Fetal anomalies v7.22 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Hereditary spastic paraplegia, childhood onset v9.4 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIm phenotype updated.
Hereditary spastic paraplegia, childhood onset v9.4 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092; Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Severe microcephaly v9.8 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Severe microcephaly v9.8 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149 to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149; Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Ataxia and cerebellar anomalies - childhood onset v9.6 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated on 25th Jun 2026.
Ataxia and cerebellar anomalies - childhood onset v9.6 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092; Cerebellar hypoplasia, HP:0001321 to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Bleeding and platelet disorders v4.16 IKZF5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Bleeding and platelet disorders v4.16 IKZF5 Ida Ertmanska Phenotypes for gene: IKZF5 were changed from Thrombocytopenia (HP:0001873), Reduced platelet alpha granules (HP:0012528). to Thrombocytopenia, autosomal dominant, 7, OMIM:619130
Intellectual disability v10.34 ELFN1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Intellectual disability v10.34 ELFN1 Ida Ertmanska Phenotypes for gene: ELFN1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder, MONDO:0700092; Dursun-Ozgul neurodevelopmental syndrome, OMIM:621344
Early onset or syndromic epilepsy v9.18 ELFN1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Early onset or syndromic epilepsy v9.18 ELFN1 Ida Ertmanska Phenotypes for gene: ELFN1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder, MONDO:0700092; Dursun-Ozgul neurodevelopmental syndrome, OMIM:621344
Malformations of cortical development v8.5 DPYSL5 Ida Ertmanska commented on gene: DPYSL5
Intellectual disability v10.33 DPYSL5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Intellectual disability v10.33 DPYSL5 Ida Ertmanska Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, OMIM:619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Malformations of cortical development v8.5 DPYSL5 Ida Ertmanska Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, OMIM:619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Ataxia and cerebellar anomalies - childhood onset v9.5 DPYSL5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Ataxia and cerebellar anomalies - childhood onset v9.5 DPYSL5 Ida Ertmanska Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, OMIM:619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Palmoplantar keratodermas v4.15 CYP4F22 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Palmoplantar keratodermas v4.15 CYP4F22 Ida Ertmanska Phenotypes for gene: CYP4F22 were changed from Autosomal recessive congenital ichthyosis to Ichthyosis, congenital, autosomal recessive 5, OMIM:604777
Early onset or syndromic epilepsy v9.17 SF3B1 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with 13 individuals reported to have seizures. Based on available evidence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with 13 individuals reported to have seizures. Based on available evidence, this gene can be promoted to Green at the next update.
Clefting v7.7 SF3B1 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with clefting / high-arched palate seen in 12/26 patients. Based on available evidence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with clefting / high-arched palate seen in 12/26 patients. Based on available evidence, this gene can be promoted to Green at the next update.
Likely inborn error of metabolism v9.15 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Mitochondrial disorder with complex IV deficiency v5.4 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Hereditary neuropathy or pain disorder v8.7 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Hereditary neuropathy or pain disorder v8.7 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Mitochondrial disorders v10.9 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Mitochondrial disorders v10.9 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Possible mitochondrial disorder, nuclear genes v5.8 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Possible mitochondrial disorder, nuclear genes v5.8 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Likely inborn error of metabolism v9.14 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Likely inborn error of metabolism v9.14 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Mitochondrial disorder with complex IV deficiency v5.3 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Mitochondrial disorder with complex IV deficiency v5.3 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Palmoplantar keratodermas v4.14 CAST Ida Ertmanska Phenotypes for gene: CAST were changed from Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads to Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, OMIM:616295
Likely inborn error of metabolism v9.13 ASPA Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Likely inborn error of metabolism v9.13 ASPA Ida Ertmanska Phenotypes for gene: ASPA were changed from Canavan disease to Canavan disease, OMIM:271900
White matter disorders and cerebral calcification - childhood onset v8.5 ASPA Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
White matter disorders and cerebral calcification - childhood onset v8.5 ASPA Ida Ertmanska Phenotypes for gene: ASPA were changed from General Leukodystrophy & Mitochondrial Leukoencephalopathy, 25655951 to Canavan disease, OMIM:271900
Hereditary neuropathy or pain disorder v8.6 ARHGAP19 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Hereditary neuropathy or pain disorder v8.6 ARHGAP19 Ida Ertmanska Phenotypes for gene: ARHGAP19 were changed from motor peripheral neuropathy, MONDO:0002316 to motor peripheral neuropathy, MONDO:0002316; Charcot-Marie-Tooth disease, axonal, type 2KK, OMIM:621466
Hereditary neuropathy v1.509 ARHGAP19 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Hereditary neuropathy v1.509 ARHGAP19 Ida Ertmanska Phenotypes for gene: ARHGAP19 were changed from motor peripheral neuropathy, MONDO:0002316 to motor peripheral neuropathy, MONDO:0002316; Charcot-Marie-Tooth disease, axonal, type 2KK, OMIM:621466
Ataxia and cerebellar anomalies - childhood onset v9.4 HMBS Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes updated 25th Jun 2026.
Ataxia and cerebellar anomalies - childhood onset v9.4 HMBS Ida Ertmanska Phenotypes for gene: HMBS were changed from Leukoencephalopathy, HP:0002352; cerebellar ataxia, MONDO:0000437 to Leukoencephalopathy, HP:0002352; cerebellar ataxia, MONDO:0000437; Leukoencephalopathy, porphyria-related, OMIM:620711; Encephalopathy, porphyria-related, OMIM:620704
White matter disorders and cerebral calcification - childhood onset v8.4 HMBS Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
White matter disorders and cerebral calcification - childhood onset v8.4 HMBS Ida Ertmanska Phenotypes for gene: HMBS were changed from Leukoencephalopathy, HP:0002352 to Leukoencephalopathy, HP:0002352; Leukoencephalopathy, porphyria-related, OMIM:620711
Skeletal ciliopathies v7.1 RSG1 Ida Ertmanska Tag gene-checked tag was added to gene: RSG1.
Limb disorders v8.14 RSG1 Ida Ertmanska Tag gene-checked tag was added to gene: RSG1.
Early onset or syndromic epilepsy v9.17 SNX27 Ida Ertmanska Tag gene-checked was removed from gene: SNX27.
Intellectual disability v10.32 SNX27 Ida Ertmanska Tag gene-checked was removed from gene: SNX27.
Early onset or syndromic epilepsy v9.17 SNX27 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Early onset or syndromic epilepsy v9.17 SNX27 Ida Ertmanska Phenotypes for gene: SNX27 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Damseh-Danson neurodevelopmental disorder, OMIM:621591
Intellectual disability v10.32 SNX27 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Intellectual disability v10.32 SNX27 Ida Ertmanska Phenotypes for gene: SNX27 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Damseh-Danson neurodevelopmental disorder, OMIM:621591
Retinal disorders v9.9 RNU6-9 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Retinal disorders v9.9 RNU6-9 Ida Ertmanska Phenotypes for gene: RNU6-9 were changed from retinitis pigmentosa, MONDO:0019200 to retinitis pigmentosa, MONDO:0019200; Retinitis pigmentosa 106, OMIM:621564
Retinal disorders v9.8 RNU6-8 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Retinal disorders v9.8 RNU6-8 Ida Ertmanska Phenotypes for gene: RNU6-8 were changed from retinitis pigmentosa, MONDO:0019200 to retinitis pigmentosa, MONDO:0019200; Retinitis pigmentosa 105, OMIM:621563
Retinal disorders v9.7 RNU6-2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Retinal disorders v9.7 RNU6-2 Ida Ertmanska Phenotypes for gene: RNU6-2 were changed from retinitis pigmentosa, MONDO:0019200 to retinitis pigmentosa, MONDO:0019200; Retinitis pigmentosa 104, OMIM:621562
Paediatric or syndromic cardiomyopathy v8.4 NRAP Ida Ertmanska Tag gene-checked was removed from gene: NRAP.
Dilated and arrhythmogenic cardiomyopathy v4.3 NRAP Ida Ertmanska Tag gene-checked was removed from gene: NRAP.
Dilated and arrhythmogenic cardiomyopathy v4.3 NRAP Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th June 2026.
Dilated and arrhythmogenic cardiomyopathy v4.3 NRAP Ida Ertmanska Phenotypes for gene: NRAP were changed from Dilated cardiomyopathy, MONDO:0005021 to Dilated cardiomyopathy, MONDO:0005021; Cardiomopathy, dilated, 2N, OMIM:621595
Paediatric or syndromic cardiomyopathy v8.4 NRAP Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th June 2026.
Paediatric or syndromic cardiomyopathy v8.4 NRAP Ida Ertmanska Phenotypes for gene: NRAP were changed from Dilated cardiomyopathy, MONDO:0005021 Edit to Dilated cardiomyopathy, MONDO:0005021; Cardiomopathy, dilated, 2N, OMIM:621595
DDG2P v7.7 LRRC56 Ida Ertmanska Tag gene-checked tag was added to gene: LRRC56.
Early onset or syndromic epilepsy v9.16 H3F3B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 25th June 2026.
Early onset or syndromic epilepsy v9.16 H3F3B Ida Ertmanska Phenotypes for gene: H3F3B were changed from Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies; Bryant-Li-Bhoj neurodevelopmental syndrome 2, OMIM:619721
Intellectual disability v10.31 H3F3B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th June 2026.
Intellectual disability v10.31 H3F3B Ida Ertmanska Phenotypes for gene: H3F3B were changed from Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies; Bryant-Li-Bhoj neurodevelopmental syndrome 2, OMIM:619721
Amelogenesis imperfecta v4.37 FAM83H Ida Ertmanska Tag new-gene-name tag was added to gene: FAM83H.
Congenital muscular dystrophy v7.26 MCOLN1 Eleanor Williams changed review comment from: Comment on list classification: Assigned red rating as the phenotype is suggestive of a muscle myopathy and is not confirmed dystrophy.

In addition, as this is a syndromic condition, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel. ; to: Comment on list classification: Assigned red rating as the phenotype is suggestive of a muscle myopathy and is not confirmed dystrophy.

In addition, as this is a syndromic condition, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy/dystrophy being a less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel.
Congenital myopathy v7.77 MCOLN1 Eleanor Williams changed review comment from: Comment on list classification: Rating amber based on 1 case with a confirmed myopathy and 2 further cases with elevated creatine kinase and myopathy features.

However, as this is a syndromic presentation, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel. ; to: Comment on list classification: Rating amber based on 1 case with a confirmed myopathy and 2 further cases with elevated creatine kinase and myopathy features.

In addition, as this is a syndromic condition, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel.
Congenital muscular dystrophy v7.26 MCOLN1 Eleanor Williams changed review comment from: Comment on list classification: Assigned red rating as the phenotype is suggestive of a muscle myopathy and is not confirmed dystrophy.; to: Comment on list classification: Assigned red rating as the phenotype is suggestive of a muscle myopathy and is not confirmed dystrophy.

In addition, as this is a syndromic condition, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel.
Congenital myopathy v7.77 MCOLN1 Eleanor Williams changed review comment from: Comment on list classification: Rating amber based on 1 case with a confirmed myopathy and 2 further cases with elevated creatine kinase and myopathy features.; to: Comment on list classification: Rating amber based on 1 case with a confirmed myopathy and 2 further cases with elevated creatine kinase and myopathy features.

However, as this is a syndromic presentation, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel.
Clefting v7.7 SF3B1 Ida Ertmanska Classified gene: SF3B1 as Amber List (moderate evidence)
Clefting v7.7 SF3B1 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with clefting / high-arched palate seen in 12/26 patients. Based on available evidence, this gene can be promoted to Green at the next update.
Clefting v7.7 SF3B1 Ida Ertmanska Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.15 SF3B1 Ida Ertmanska Classified gene: SF3B1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.15 SF3B1 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with 13 individuals reported to have seizures. Based on available evidence, this gene can be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.15 SF3B1 Ida Ertmanska Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Clefting v7.6 SF3B1 Ida Ertmanska gene: SF3B1 was added
gene: SF3B1 was added to Clefting. Sources: Literature
Q2_26_promote_green tags were added to gene: SF3B1.
Mode of inheritance for gene: SF3B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B1 were set to 25363760; 28135719; 41577671
Phenotypes for gene: SF3B1 were set to Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: SF3B1 was set to GREEN
Added comment: As reviewed by Karen Stals, Uguen et al. (PMID: 41577671, 2026) reported 26 patients with heterozygous SF3B1 variants. Most of them were confirmed to be de novo, with 3 cases where variant was inherited from a parent (2 parents with learning difficulties, and 1 asymptomatic father). Seq method: Trio or Solo WES. 3 patients had VUS variants in other genes.
"Almost all (23/26) affected individuals exhibited at least one neurodevelopmental abnormality, the most frequent being language delay (21/26). Motor delay was found in 18/24 individuals. Intellectual disability (ID) was present in 9/15 individuals, some cases being too young (8/26) to assess. The severity of ID was mainly mild to moderate, only two individuals presenting with severe ID. Seizures were reported in 13 individuals, with variable ages of onset and types." Other features: hypotonia (11 patients), spastic quadriplegia (2 patients without NDD), non-specific brain MRI anomalies (4 cases), cleft palate or high-arched palate (12 patients), heart defects (8/25), postnatal short stature (6), IUGR (5), microcephaly (7/22 assessed).

De novo missense variants in the SF3B1 gene have also been identified in ASD probands (PMID: 25363768 Iossifov et al., 2014 - 2 probands with ASD, harbouring SF3B1 variants c.1078A>G, p.Ile360Val & c.890C>A, p.Pro297His) and two probands with unspecified developmental disorders, with de novo SF3B1 variants c.1108C>T, p.Pro370Ser & c.1781G>A, p.Arg594Gln (PMID: 28135719 Deciphering Developmental Disorders Study 2017).

SF3B1 is not yet associated with an NDD in OMIM, and it has not been classified in ClinGen (accessed 17th Jun 2026). The gene is Green in PanelApp Australia on 'Intellectual disability syndromic and non-syndromic' panel.
Sources: Literature
Early onset or syndromic epilepsy v9.14 SF3B1 Ida Ertmanska gene: SF3B1 was added
gene: SF3B1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_26_promote_green tags were added to gene: SF3B1.
Mode of inheritance for gene: SF3B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B1 were set to 25363760; 28135719; 41577671
Phenotypes for gene: SF3B1 were set to Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: SF3B1 was set to GREEN
Added comment: As reviewed by Karen Stals, Uguen et al. (PMID: 41577671, 2026) reported 26 patients with heterozygous SF3B1 variants. Most of them were confirmed to be de novo, with 3 cases where variant was inherited from a parent (2 parents with learning difficulties, and 1 asymptomatic father). Seq method: Trio or Solo WES. 3 patients had VUS variants in other genes.
"Almost all (23/26) affected individuals exhibited at least one neurodevelopmental abnormality, the most frequent being language delay (21/26). Motor delay was found in 18/24 individuals. Intellectual disability (ID) was present in 9/15 individuals, some cases being too young (8/26) to assess. The severity of ID was mainly mild to moderate, only two individuals presenting with severe ID. Seizures were reported in 13 individuals, with variable ages of onset and types." Other features: hypotonia (11 patients), spastic quadriplegia (2 patients without NDD), non-specific brain MRI anomalies (4 cases), cleft palate or high-arched palate (12 patients), heart defects (8/25), postnatal short stature (6), IUGR (5), microcephaly (7/22 assessed).

De novo missense variants in the SF3B1 gene have also been identified in ASD probands (PMID: 25363768 Iossifov et al., 2014 - 2 probands with ASD, harbouring SF3B1 variants c.1078A>G, p.Ile360Val & c.890C>A, p.Pro297His) and two probands with unspecified developmental disorders, with de novo SF3B1 variants c.1108C>T, p.Pro370Ser & c.1781G>A, p.Arg594Gln (PMID: 28135719 Deciphering Developmental Disorders Study 2017).

SF3B1 is not yet associated with an NDD in OMIM, and it has not been classified in ClinGen (accessed 17th Jun 2026). The gene is Green in PanelApp Australia on 'Intellectual disability syndromic and non-syndromic' panel.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.11 DYSF Achchuthan Shanmugasundram changed review comment from: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second pateint, who was previolusly active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.; to: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second patient, who was previously active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.
Rhabdomyolysis and metabolic muscle disorders v6.6 DYSF Achchuthan Shanmugasundram changed review comment from: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second pateint, who was previolusly active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.; to: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second patient, who was previously active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.
Distal myopathies v7.4 DYSF Achchuthan Shanmugasundram changed review comment from: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second pateint, who was previolusly active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.; to: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second patient, who was previously active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.
Congenital muscular dystrophy v7.26 TCAP Achchuthan Shanmugasundram Phenotypes for gene: TCAP were changed from Muscular dystrophy, limb-girdle, autosomal recessive 7, OMIM:601954 to Muscular dystrophy, limb-girdle, autosomal recessive 7, OMIM:601954; autosomal recessive limb-girdle muscular dystrophy type 2G, MONDO:0011170
Congenital muscular dystrophy v7.25 TCAP Achchuthan Shanmugasundram Publications for gene: TCAP were set to 23479141; 21530252; 18948002; 25055047; 29797799; 29935994; 32761539; 36463458; 37216648; 39015008
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Anna Sarkozy, there are at least ten peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decade of life. Although there are several patients reported with early/ childhood-onset, there is only patient from PMID:21530252 (2011) reported with onset in infancy and identified with biallelic TCAP variant. This gene is already green in R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Hence, this gene should remain amber on this panel with the current evidence.; to: Comment on list classification: There are at least ten peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decades of life. Although there are several patients reported with early/ childhood-onset muscular dystrophy, there is only patient from PMID:21530252 (2011) reported with onset in infancy and identified with biallelic TCAP variant.

This gene is already green on 'R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies' panel. As reviewed by Anna Sarkozy, this gene should remain amber on this panel with the current evidence.
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Anna Sarkozy, there are at least eight peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decade of life. Although there are several patients reported with childhood-onset, there is only patient from PMID:36463458 (2023) reported with onset in infancy. This gene is already green in R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Hence, this gebne should remina amber with current evidnece.; to: Comment on list classification: As reviewed by Anna Sarkozy, there are at least ten peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decade of life. Although there are several patients reported with early/ childhood-onset, there is only patient from PMID:21530252 (2011) reported with onset in infancy and identified with biallelic TCAP variant. This gene is already green in R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Hence, this gene should remain amber on this panel with the current evidence.
Early onset or syndromic epilepsy v9.13 MED17 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated families where affected individuals harboured biallelic MED17 variants and presented with seizures (among other syndromic symptoms). Based on available evidence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are 3 unrelated families (Jewish families with potential founder variant counted as one) where affected individuals harboured biallelic MED17 variants and presented with seizures (among other syndromic symptoms). Based on available evidence, this gene can be promoted to Green at the next update.
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram edited their review of gene: TCAP: Changed publications to: 18948002, 21530252, 23479141, 25055047, 29797799, 29935994, 32761539, 36463458, 37216648, 39015008
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram edited their review of gene: TCAP: Changed publications to: 18948002, 21530252, 25055047, 29797799, 29935994, 32761539, 36463458, 37216648, 39015008
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram Publications for gene: TCAP were set to 23479141; 21530252
Congenital muscular dystrophy v7.23 TCAP Achchuthan Shanmugasundram Classified gene: TCAP as Amber List (moderate evidence)
Congenital muscular dystrophy v7.23 TCAP Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Anna Sarkozy, there are at least eight peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decade of life. Although there are several patients reported with childhood-onset, there is only patient from PMID:36463458 (2023) reported with onset in infancy. This gene is already green in R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Hence, this gebne should remina amber with current evidnece.
Congenital muscular dystrophy v7.23 TCAP Achchuthan Shanmugasundram Gene: tcap has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v7.22 TCAP Achchuthan Shanmugasundram reviewed gene: TCAP: Rating: AMBER; Mode of pathogenicity: None; Publications: 18948002, 25055047, 29797799, 29935994, 32761539, 36463458, 37216648, 39015008; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 7, OMIM:601954, autosomal recessive limb-girdle muscular dystrophy type 2G, MONDO:0011170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.30 GIGYF1 Jana Jezkova reviewed gene: GIGYF1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35917186, 36924980, 36189799, 31439631; Phenotypes: ASD, NDD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Amelogenesis imperfecta v4.37 FAM83H Ida Ertmanska commented on gene: FAM83H
Adult solid tumours cancer susceptibility v2.40 CHEK2 Arina Puzriakova Publications for gene: CHEK2 were set to 40335619
Inherited predisposition to acute myeloid leukaemia (AML) v3.10 CHEK2 Arina Puzriakova Publications for gene: CHEK2 were set to 29902706
Inherited predisposition to acute myeloid leukaemia (AML) v3.9 CHEK2 Arina Puzriakova Phenotypes for gene: CHEK2 were changed from 609265 Li-Fraumeni syndrome; 609265 (OMIM phenotype description ID) to Hematologic malignancy predisposition; Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265
Rhabdomyolysis and metabolic muscle disorders v6.6 DYSF Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least 6 unrelated families with heterozygous carrier individuals presenting with a limb-girdle muscular dystrophy/ distal myopathy phenotype despite it being milder and later-onset than individuals with biallelic variants. There is also evidence of some heterozygous carriers from two of the families not displaying phenotype suggesting reduced penetrance.

As there are six unrelated families with monoalellic phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.
Rhabdomyolysis and metabolic muscle disorders v6.6 DYSF Achchuthan Shanmugasundram Mode of inheritance for gene: DYSF was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v6.5 DYSF Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: DYSF.
Rhabdomyolysis and metabolic muscle disorders v6.5 DYSF Achchuthan Shanmugasundram commented on gene: DYSF: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second pateint, who was previolusly active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.
Rhabdomyolysis and metabolic muscle disorders v6.5 DYSF Achchuthan Shanmugasundram Publications for gene: DYSF were set to 25929793
Rhabdomyolysis and metabolic muscle disorders v6.4 DYSF Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Biallelic variants in DYSF gene are associated with relevant phenotypes in OMIM (MIMs #253601, #254130 & #606768) and the records were last accessed 25 June 2026.

Biallelic DYSF variants are also associated with AR limb-girdle muscular dystrophy with 'Definitive' rating by the Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004715).
Rhabdomyolysis and metabolic muscle disorders v6.4 DYSF Achchuthan Shanmugasundram Phenotypes for gene: DYSF were changed from Miyoshi muscular dystrophy 1, OMIM:254130; Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601; Myopathy, distal, with anterior tibial onset, OMIM:606768 to Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601; Miyoshi muscular dystrophy 1, OMIM:254130; Myopathy, distal, with anterior tibial onset, OMIM:606768
Rhabdomyolysis and metabolic muscle disorders v6.3 DYSF Achchuthan Shanmugasundram reviewed gene: DYSF: Rating: GREEN; Mode of pathogenicity: None; Publications: 17287450, 21658164, 29879922, 35962550; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601, Miyoshi muscular dystrophy 1, OMIM:254130, Myopathy, distal, with anterior tibial onset, OMIM:606768; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Distal myopathies v7.4 DYSF Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least 6 unrelated families with heterozygous carrier individuals presenting with a limb-girdle muscular dystrophy/ distal myopathy phenotype despite it being milder and later-onset than individuals with biallelic variants. There is also evidence of some heterozygous carriers from two of the families not displaying phenotype suggesting reduced penetrance.

As there are six unrelated families with monoalellic phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.
Distal myopathies v7.4 DYSF Achchuthan Shanmugasundram Mode of inheritance for gene: DYSF was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.11 DYSF Achchuthan Shanmugasundram Publications for gene: DYSF were set to http://www.ncbi.nlm.nih.gov/books/NBK1408/
Distal myopathies v7.3 DYSF Achchuthan Shanmugasundram Publications for gene: DYSF were set to 20301480
Distal myopathies v7.2 DYSF Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: DYSF.
Distal myopathies v7.2 DYSF Achchuthan Shanmugasundram edited their review of gene: DYSF: Added comment: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second pateint, who was previolusly active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.; Changed rating: GREEN; Changed publications to: 17287450, 21658164, 29879922, 35962550; Changed phenotypes to: Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601, Miyoshi muscular dystrophy 1, OMIM:254130, Myopathy, distal, with anterior tibial onset, OMIM:606768; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Distal myopathies v7.2 DYSF Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Biallelic variants in DYSF gene are associated with relevant phenotypes in OMIM (MIMs #253601, #254130 & #606768) and the records were last accessed 25 June 2026. Biallelic DYSF variants are also associated with AR limb-girdle muscular dystrophy with 'Definitive' rating by the Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004715).
Distal myopathies v7.2 DYSF Achchuthan Shanmugasundram Phenotypes for gene: DYSF were changed from Miyoshi muscular dystrophy 1, 254130 to Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601; Miyoshi muscular dystrophy 1, OMIM:254130; Myopathy, distal, with anterior tibial onset, OMIM:606768
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.10 DYSF Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least 6 unrelated families with heterozygous carrier individuals presenting with a limb-girdle muscular dystrophy/ myopathy phenotype despite it being milder and later-onset than individuals with biallelic variants. There is also evidence of some heterozygous carriers from two of the families not displaying phenotype suggesting reduced penetrance.

As there are six unrelated families with monoalellic phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.10 DYSF Achchuthan Shanmugasundram Mode of inheritance for gene: DYSF was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.9 DYSF Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: DYSF.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.9 DYSF Achchuthan Shanmugasundram edited their review of gene: DYSF: Added comment: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second pateint, who was previolusly active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.; Changed publications to: 17287450, 21658164, 29879922, 35962550; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.9 DYSF Achchuthan Shanmugasundram Deleted their comment
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen.; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen or Gene2Phenotype.
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026).; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen.
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly variant specific phenotype?; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly a variant-specific phenotype.
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - variant specific phenotype?; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly variant specific phenotype?
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188).; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - variant specific phenotype?
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected. ; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026).
Optic neuropathy v6.43 PPIB Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: PPIB.
Tag Q2_26_expert_review tag was added to gene: PPIB.
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.
However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188).; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188).
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. As 8/9 families are of European (Austrian) origins, a founder variant effect cannot be excluded.
Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188). Based on the available evidence, this gene-disease association is ambiguous and should be rated as Amber.; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.
However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188).
Optic neuropathy v6.43 PPIB Ida Ertmanska edited their review of gene: PPIB: Changed rating: GREEN
Blepharophimosis ptosis and epicanthus inversus v1.5 Achchuthan Shanmugasundram List of related panels changed from R43; GT841; TP355 to R43; GT688; TP68
Non-acute porphyrias v1.42 HMBS Arina Puzriakova changed review comment from: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.; to: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
DDG2P v7.7 GNAS Arina Puzriakova Deleted their comment
DDG2P v7.7 GNAS Arina Puzriakova Deleted their comment
DDG2P v7.7 GNAS Arina Puzriakova Deleted their comment
Renal tubulopathies v6.7 GNAS Arina Puzriakova Deleted their comment
Renal tubulopathies v6.7 GNAS Arina Puzriakova Deleted their comment
Renal tubulopathies v6.7 GNAS Arina Puzriakova Deleted their comment
Skeletal dysplasia v9.20 GNAS Arina Puzriakova Deleted their comment
Skeletal dysplasia v9.20 GNAS Arina Puzriakova Deleted their comment
Skeletal dysplasia v9.20 GNAS Arina Puzriakova Deleted their comment
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 GNAS Arina Puzriakova Deleted their comment
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 GNAS Arina Puzriakova Deleted their comment
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 GNAS Arina Puzriakova Deleted their comment
Osteogenesis imperfecta v6.7 GNAS Arina Puzriakova Deleted their comment
Osteogenesis imperfecta v6.7 GNAS Arina Puzriakova Deleted their comment
Osteogenesis imperfecta v6.7 GNAS Arina Puzriakova Deleted their comment
Limb disorders v8.14 GNAS Arina Puzriakova Deleted their comment
Limb disorders v8.14 GNAS Arina Puzriakova Deleted their comment
Limb disorders v8.14 GNAS Arina Puzriakova Deleted their comment
Cholestasis v4.11 GNAS Arina Puzriakova Deleted their comment
Cholestasis v4.11 GNAS Arina Puzriakova Deleted their comment
Cholestasis v4.11 GNAS Arina Puzriakova Deleted their comment
Fetal anomalies v7.21 GNAS Arina Puzriakova Deleted their comment
Fetal anomalies v7.21 GNAS Arina Puzriakova Deleted their comment
Fetal anomalies v7.21 GNAS Arina Puzriakova Deleted their comment
Severe early-onset obesity v6.7 GNAS Arina Puzriakova Deleted their comment
Severe early-onset obesity v6.7 GNAS Arina Puzriakova Deleted their comment
Severe early-onset obesity v6.7 GNAS Arina Puzriakova Deleted their comment
Congenital hypothyroidism v3.10 GNAS Arina Puzriakova Deleted their comment
Congenital hypothyroidism v3.10 GNAS Arina Puzriakova Deleted their comment
Congenital hypothyroidism v3.10 GNAS Arina Puzriakova Deleted their comment
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.16 GNAS Arina Puzriakova Deleted their comment
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.16 GNAS Arina Puzriakova Deleted their comment
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.16 GNAS Arina Puzriakova Deleted their comment
Intellectual disability v10.30 GNAS Arina Puzriakova Deleted their comment
Intellectual disability v10.30 GNAS Arina Puzriakova Deleted their comment
Intellectual disability v10.30 GNAS Arina Puzriakova Deleted their comment
Pigmentary skin disorders v5.9 GNAS Arina Puzriakova Deleted their comment
Pigmentary skin disorders v5.9 GNAS Arina Puzriakova Deleted their comment
Pigmentary skin disorders v5.9 GNAS Arina Puzriakova Deleted their comment
Mosaic skin disorders - Deep sequencing v3.33 GNAS Arina Puzriakova Deleted their comment
Mosaic skin disorders - Deep sequencing v3.33 GNAS Arina Puzriakova Deleted their comment
Mosaic skin disorders - Deep sequencing v3.33 GNAS Arina Puzriakova Deleted their comment
Non-acute porphyrias v1.42 HMBS Arina Puzriakova Tag Q2_26_MOI was removed from gene: HMBS.
Non-acute porphyrias v1.42 HMBS Arina Puzriakova Deleted their comment
Non-acute porphyrias v1.42 HMBS Arina Puzriakova Deleted their comment
Non-acute porphyrias v1.42 HMBS Arina Puzriakova Deleted their comment
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova Tag Q2_26_demote_red was removed from gene: DNMT3A.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova Deleted their comment
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova Deleted their comment
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova Deleted their comment
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova Tag Q2_26_demote_red was removed from gene: AMPD1.
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova Deleted their comment
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova Deleted their comment
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova Deleted their comment
DDG2P v7.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Renal tubulopathies v6.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Skeletal dysplasia v9.20 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Osteogenesis imperfecta v6.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Limb disorders v8.14 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Cholestasis v4.11 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Fetal anomalies v7.21 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Severe early-onset obesity v6.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Congenital hypothyroidism v3.10 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.16 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Intellectual disability v10.30 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Pigmentary skin disorders v5.9 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Mosaic skin disorders - Deep sequencing v3.33 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Non-acute porphyrias v1.42 HMBS Arina Puzriakova commented on gene: HMBS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova commented on gene: DNMT3A: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova commented on gene: AMPD1: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
DDG2P v7.6 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Renal tubulopathies v6.6 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Skeletal dysplasia v9.19 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.10 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Osteogenesis imperfecta v6.6 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Limb disorders v8.13 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Cholestasis v4.10 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Fetal anomalies v7.20 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Severe early-onset obesity v6.6 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Congenital hypothyroidism v3.9 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.15 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Intellectual disability v10.29 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Pigmentary skin disorders v5.8 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Mosaic skin disorders - Deep sequencing v3.32 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Non-acute porphyrias v1.41 HMBS Arina Puzriakova commented on gene: HMBS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.7 DNMT3A Arina Puzriakova commented on gene: DNMT3A: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
Acute rhabdomyolysis v2.15 AMPD1 Arina Puzriakova commented on gene: AMPD1: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
DDG2P v7.5 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Renal tubulopathies v6.5 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Skeletal dysplasia v9.18 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.9 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Osteogenesis imperfecta v6.5 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Limb disorders v8.12 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Cholestasis v4.9 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Fetal anomalies v7.19 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Severe early-onset obesity v6.5 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Congenital hypothyroidism v3.8 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.14 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Intellectual disability v10.28 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Pigmentary skin disorders v5.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Mosaic skin disorders - Deep sequencing v3.31 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Non-acute porphyrias v1.40 HMBS Arina Puzriakova commented on gene: HMBS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.6 DNMT3A Arina Puzriakova commented on gene: DNMT3A: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
Acute rhabdomyolysis v2.14 AMPD1 Arina Puzriakova commented on gene: AMPD1: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
DDG2P v7.4 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Renal tubulopathies v6.4 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Skeletal dysplasia v9.17 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.8 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Osteogenesis imperfecta v6.4 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Limb disorders v8.11 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Cholestasis v4.8 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Fetal anomalies v7.18 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Severe early-onset obesity v6.4 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Congenital hypothyroidism v3.7 GNAS Arina Puzriakova edited their review of gene: GNAS: Added comment: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.; Changed mode of inheritance: Unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.13 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Intellectual disability v10.27 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Pigmentary skin disorders v5.6 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Mosaic skin disorders - Deep sequencing v3.30 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Non-acute porphyrias v1.39 HMBS Arina Puzriakova edited their review of gene: HMBS: Added comment: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.5 DNMT3A Arina Puzriakova edited their review of gene: DNMT3A: Added comment: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.; Changed rating: RED
Acute rhabdomyolysis v2.13 AMPD1 Arina Puzriakova commented on gene: AMPD1: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
DDG2P v7.3 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Renal tubulopathies v6.3 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to Unknown
Skeletal dysplasia v9.16 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.7 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) to Unknown
Osteogenesis imperfecta v6.3 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from to Unknown
Limb disorders v8.10 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Cholestasis v4.7 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Unknown
Fetal anomalies v7.17 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Severe early-onset obesity v6.3 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Congenital hypothyroidism v3.6 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.12 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Intellectual disability v10.26 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Pigmentary skin disorders v5.5 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Mosaic skin disorders - Deep sequencing v3.29 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Non-acute porphyrias v1.38 HMBS Arina Puzriakova Mode of inheritance for gene HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.4 DNMT3A Arina Puzriakova Source Expert Review Red was added to DNMT3A.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Acute rhabdomyolysis v2.12 AMPD1 Arina Puzriakova Source Expert Review Red was added to AMPD1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.16 BIRC3 Boaz Palterer gene: BIRC3 was added
gene: BIRC3 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: BIRC3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: BIRC3 were set to Inflammatory bowel disease; IBD; Crohn's disease
Penetrance for gene: BIRC3 were set to unknown
Review for gene: BIRC3 was set to GREEN
Added comment: Qi Li et al. described 14 patients from 10 unrelated families with monoallelic and biallelic variants in BIRC3 presenting with CD. Biallelic variants present more severe and earlier. Extensive funtional validation including zebrafish and mice models, recapitulating phenotype
https://www.gastrojournal.org/article/S0016-5085(26)06946-5/fulltext
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v5.2 Eleanor Williams List of related panels changed from R189 to R189; GT67; TP149
Pulmonary Fibrosis, Familial v1.11 Eleanor Williams List of related panels changed from R421 to R421; GT1047; TP235
Pulmonary arterial hypertension v4.12 Eleanor Williams List of related panels changed from PAH; R188 to PAH; R188; GT412; TP299
Pulmonary alveolar microlithiasis v1.4 Eleanor Williams List of related panels changed from R426 to R426; GT1005; TP491
Pneumothorax - familial v3.7 Eleanor Williams List of related panels changed from Familial Pneumothorax; Familial Primary Spontaneous Pneumothorax; R190 to Familial Pneumothorax; Familial Primary Spontaneous Pneumothorax; R190; GT843; TP219
Laterality disorders and isomerism v5.2 Eleanor Williams List of related panels changed from R139 to R139; GT588; TP531
Hereditary haemorrhagic telangiectasia v3.8 Eleanor Williams List of related panels changed from Familial and multiple pulmonary arteriovenous malformations; R186 to Familial and multiple pulmonary arteriovenous malformations; R186; GT336; TP252
Cystic fibrosis - Diagnostic v1.4 Eleanor Williams List of related panels changed from R184 to R184; GT219; TP46
Childhood interstitial lung disease v1.2 Eleanor Williams List of related panels changed from R462 to R462; GT1438; TP109
Central congenital hypoventilation v1.8 Eleanor Williams List of related panels changed from R333 to R333; GT163; TP470
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.9 Eleanor Williams List of related panels changed from R330 to R330; GT755; TP42
Unexplained young onset end-stage renal disease v13.15 Eleanor Williams List of related panels changed from Unexplained paediatric onset end-stage renal disease; R257 to Unexplained paediatric onset end-stage renal disease; R257; GT608; GT787; TP574
Tubulointerstitial kidney disease v3.34 Eleanor Williams List of related panels changed from R202 to R202; GT827; TP233
Renal tubulopathies v6.2 Eleanor Williams List of related panels changed from Renal tubular acidosis; R198 to Renal tubular acidosis; R198; GT1245; TP408
Proteinuric renal disease v6.2 Eleanor Williams List of related panels changed from R195 to R195; GT785; TP484
Nephrocalcinosis or nephrolithiasis v6.2 Eleanor Williams List of related panels changed from Renal tract calcification (or Nephrolithiasis or nephrocalcinosis); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis); R256 to Renal tract calcification (or Nephrolithiasis or nephrocalcinosis); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis); R256; GT28; TP136
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.14 Eleanor Williams List of related panels changed from PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; Primary membranoproliferative glomerulonephritis; Membranoproliferative glomerulonephritis; R197 to PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; Primary membranoproliferative glomerulonephritis; Membranoproliferative glomerulonephritis; R197; GT704; TP82
Hereditary systemic amyloidosis v1.30 Eleanor Williams List of related panels changed from Amyloidosis; R204 to Amyloidosis; R204; GT199; TP394
Haematuria v2.19 Eleanor Williams List of related panels changed from Alport syndrome; Familial haematuria; R194 to Alport syndrome; Familial haematuria; R194; GT846; TP94
Cystic renal disease v13.4 Eleanor Williams List of related panels changed from Cystic renal disease - PKD1; R193 to Cystic renal disease - PKD1; R193; GT497; TP171
Atypical haemolytic uraemic syndrome v3.10 Eleanor Williams List of related panels changed from R201 to R201; GT997; TP209
Structural eye disease v5.7 Eleanor Williams List of related panels changed from R36 to R36; GT692; TP458
Stickler syndrome v4.9 Eleanor Williams List of related panels changed from R45 to R45; GT654; TP572
Sporadic aniridia v3.7 Eleanor Williams List of related panels changed from Aniridia; R38 to Aniridia; R38; GT663; TP329
Skeletal dysplasia v9.15 Achchuthan Shanmugasundram List of related panels changed from Unexplained skeletal dysplasia; Skeletal dysplasia; R104 to Unexplained skeletal dysplasia; Skeletal dysplasia; R104; GT245; TP399
Short stature - SHOX deficiency v1.4 Achchuthan Shanmugasundram List of related panels changed from R52 to R52; GT920; TP319
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.6 Achchuthan Shanmugasundram List of related panels changed from Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis; Craniosynostosis; R100 to Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis; Craniosynostosis; R100; GT241; TP474
Osteopetrosis v2.2 Achchuthan Shanmugasundram List of related panels changed from R104.4 to R104.4; GT167; TP399
Osteogenesis imperfecta v6.2 Achchuthan Shanmugasundram List of related panels changed from Osteogenesis Imperfecta; R102 to Osteogenesis Imperfecta; R102; GT1068; TP505
Retinal disorders v9.6 Eleanor Williams List of related panels changed from Posterior segment abnormalities; Cone Dysfunction Syndrome; Developmental macular and foveal dystrophy; Inherited macular dystrophy; Leber Congenital Amaurosis Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy; Rod Dysfunction Syndrome; Rod-cone dystrophy; Familial exudative vitreoretinopathy; Familial exudative retinopathy; Sorsby retinal dystrophy; Doyne retinal dystrophy; R32 to Posterior segment abnormalities; Cone Dysfunction Syndrome; Developmental macular and foveal dystrophy; Inherited macular dystrophy; Leber Congenital Amaurosis Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy; Rod Dysfunction Syndrome; Rod-cone dystrophy; Familial exudative vitreoretinopathy; Familial exudative retinopathy; Sorsby retinal dystrophy; Doyne retinal dystrophy; R32; GT1235; TP381
Pseudoxanthoma elasticum v1.5 Eleanor Williams List of related panels changed from R420 to R420; GT375; TP462
Retinal disorders v9.5 Chr17q22 Katie Cox reviewed Region: Chr17q22: Rating: ; Mode of pathogenicity: None; Publications: PMID: 33022222; Phenotypes: RETINITIS PIGMENTOSA 17 (OMIM #600852); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Multiple exostoses v1.5 Achchuthan Shanmugasundram List of related panels changed from R390 to R390; GT1204; TP487
Intestinal failure or congenital diarrhoea v3.13 Arina Puzriakova List of related panels changed from R331; Intestinal failure; GT1311; TP348 to Intestinal failure; R331; GT1311; TP348
Optic neuropathy v6.43 Eleanor Williams List of related panels changed from Inherited optic neuropathies; R41 to Inherited optic neuropathies; R41; GT487; TP247
Ehlers Danlos syndrome with a likely monogenic cause v4.14 Achchuthan Shanmugasundram List of related panels changed from Classical Ehlers Danlos Syndrome; Classical Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome (unusual phenotypes e.g. absent pain sense); Ehlers-Danlos syndrome type 3; Kyphoscoliotic Ehlers-Danlos syndrome; EDS; Ehlers-Danlos syndromes; Ehlers Danlos syndromes; R101 to Classical Ehlers Danlos Syndrome; Classical Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome (unusual phenotypes e.g. absent pain sense); Ehlers-Danlos syndrome type 3; Kyphoscoliotic Ehlers-Danlos syndrome; EDS; Ehlers-Danlos syndromes; Ehlers Danlos syndromes; R101; GT525; TP509
Corneal dystrophy v4.10 Eleanor Williams List of related panels changed from Corneal dystrophies; R262 to Corneal dystrophies; R262; GT1218; TP489
Common craniosynostosis syndromes v1.18 Achchuthan Shanmugasundram List of related panels changed from R99 to R99; GT322; TP134
Congenital fibrosis of the extraocular muscles v2.4 Eleanor Williams List of related panels changed from R46 to R46; GT216; TP77
Amelogenesis imperfecta v4.37 Achchuthan Shanmugasundram List of related panels changed from Amelogenesis Imperfecta; R340 to Amelogenesis Imperfecta; R340; GT464; TP321
Thiamine metabolism dysfunction syndrome 2 v1.4 Achchuthan Shanmugasundram List of related panels changed from R395 to R395; GT285; TP463
Fetal anomalies v7.16 Arina Puzriakova List of related panels changed from R21; Fetal anomalies with a likely genetic cause; Fetal anomalies with a likely genetic cause - non urgent; R412; GT520; TP260; TP416 to Fetal anomalies with a likely genetic cause; R21; Fetal anomalies with a likely genetic cause - non urgent; R412; GT520; TP260; TP416
Ataxia and cerebellar anomalies - childhood onset v9.3 ATP2B2 Christopher Burke gene: ATP2B2 was added
gene: ATP2B2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review
Mode of inheritance for gene: ATP2B2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743
Phenotypes for gene: ATP2B2 were set to Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities
Penetrance for gene: ATP2B2 were set to unknown
Review for gene: ATP2B2 was set to GREEN
gene: ATP2B2 was marked as current diagnostic
Added comment: ATP2B2 is associated with Deafness, autosomal dominant 82 (OMIM 619804) in OMIM. Emerging evidence suggests that heterozygous pathogenic variants in ATP2B2 can cause a neurodevelopmental phenotype.

Recent papers have outlined and extended neurodevelopmental phenotype (PMID: 39367743, PMID: 37675773, PMID: 29655659) not documented in OMIM or G2P. Summarised phenotypes from 14 reported individuals (13 unrelated individuals) - Global developmental delay (12/14), delayed motor development (12/14), ataxia (9/14), impaired speech (13/14), intellectual disability (13/14), cerebellar atrophy (4/14), behavioural issues (9/14), seizures (9/14), hypotonia (6/14), dysmorphic features (4/14), hearing abnormalities (3/14), and ophthalmological abnormalities (6/14).

PMID: 29655659 - Heterozygous missense. Targeted NGS, unknown inheritance.

PMID: 37675773 - Trio exome sequencing for families 1-6, confirmed de novo status for all 6 families. Seventh family could not be confirmed. 5 missense variants, 2 frameshift variants.

PMID: 39367743 - Trio exome sequencing for families 1-4, confirmed de novo in all 4 families. One case paternally inherited, one unknown. 4 missense variants, 1 frameshift variant (2 individuals in the same family).

ATP2B2 is plasma membrane Ca2+ ATPase involved in Ca2+ homeostasis. Ca2+ deregulation in humans and mice can cause cognitive, behavioural, sensory, and movement disorders. Discussed in detail in PMID: 37675773.

Request addition to R27, R29, R55, R59, R69, R84, Ataxia and Cerebellar Anomalies - Narrow Panel.
Sources: Expert Review
Pyruvate dehydrogenase (PDH) deficiency v1.41 Achchuthan Shanmugasundram List of related panels changed from R316 to R316; GT767; TP9
Blepharophimosis ptosis and epicanthus inversus v1.4 Eleanor Williams List of related panels changed from R43 to R43; GT841; TP355
Retinal disorders v9.5 Chr17q22 Katie Cox Deleted their review
Possible mitochondrial disorder, nuclear genes v5.7 Achchuthan Shanmugasundram List of related panels changed from R63 to R63; GT759; TP627
Early onset or syndromic epilepsy v9.13 ATP2B2 Christopher Burke gene: ATP2B2 was added
gene: ATP2B2 was added to Early onset or syndromic epilepsy. Sources: Expert Review
Mode of inheritance for gene: ATP2B2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743
Phenotypes for gene: ATP2B2 were set to Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities
Penetrance for gene: ATP2B2 were set to unknown
Review for gene: ATP2B2 was set to GREEN
gene: ATP2B2 was marked as current diagnostic
Added comment: ATP2B2 is associated with Deafness, autosomal dominant 82 (OMIM 619804) in OMIM. Emerging evidence suggests that heterozygous pathogenic variants in ATP2B2 can cause a neurodevelopmental phenotype.

Recent papers have outlined and extended neurodevelopmental phenotype (PMID: 39367743, PMID: 37675773, PMID: 29655659) not documented in OMIM or G2P. Summarised phenotypes from 14 reported individuals (13 unrelated individuals) - Global developmental delay (12/14), delayed motor development (12/14), ataxia (9/14), impaired speech (13/14), intellectual disability (13/14), cerebellar atrophy (4/14), behavioural issues (9/14), seizures (9/14), hypotonia (6/14), dysmorphic features (4/14), hearing abnormalities (3/14), and ophthalmological abnormalities (6/14).

PMID: 29655659 - Heterozygous missense. Targeted NGS, unknown inheritance.

PMID: 37675773 - Trio exome sequencing for families 1-6, confirmed de novo status for all 6 families. Seventh family could not be confirmed. 5 missense variants, 2 frameshift variants.

PMID: 39367743 - Trio exome sequencing for families 1-4, confirmed de novo in all 4 families. One case paternally inherited, one unknown. 4 missense variants, 1 frameshift variant (2 individuals in the same family).

ATP2B2 is plasma membrane Ca2+ ATPase involved in Ca2+ homeostasis. Ca2+ deregulation in humans and mice can cause cognitive, behavioural, sensory, and movement disorders. Discussed in detail in PMID: 37675773.

Request addition to R27, R29, R55, R59, R69, R84, Ataxia and Cerebellar Anomalies - Narrow Panel.
Sources: Expert Review
Bilateral congenital or childhood onset cataracts v8.5 Eleanor Williams List of related panels changed from Cataracts; R31 to Cataracts; R31; GT841; TP355
POLG-related disorder v1.4 Achchuthan Shanmugasundram List of related panels changed from R315 to R315; GT281; TP294
NARP syndrome or maternally inherited Leigh syndrome v2.3 Achchuthan Shanmugasundram List of related panels changed from R351 to R351; GT87; TP207
Bardet Biedl syndrome v2.18 Eleanor Williams List of related panels changed from R107 to R107; GT286; TP326
Intellectual disability v10.25 ATP2B2 Christopher Burke gene: ATP2B2 was added
gene: ATP2B2 was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: ATP2B2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743
Phenotypes for gene: ATP2B2 were set to Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities
Penetrance for gene: ATP2B2 were set to unknown
Review for gene: ATP2B2 was set to GREEN
gene: ATP2B2 was marked as current diagnostic
Added comment: ATP2B2 is associated with Deafness, autosomal dominant 82 (OMIM 619804) in OMIM. Emerging evidence suggests that heterozygous pathogenic variants in ATP2B2 can cause a neurodevelopmental phenotype.

Recent papers have outlined and extended neurodevelopmental phenotype (PMID: 39367743, PMID: 37675773, PMID: 29655659) not documented in OMIM or G2P. Summarised phenotypes from 14 reported individuals (13 unrelated individuals) - Global developmental delay (12/14), delayed motor development (12/14), ataxia (9/14), impaired speech (13/14), intellectual disability (13/14), cerebellar atrophy (4/14), behavioural issues (9/14), seizures (9/14), hypotonia (6/14), dysmorphic features (4/14), hearing abnormalities (3/14), and ophthalmological abnormalities (6/14).

PMID: 29655659 - Heterozygous missense. Targeted NGS, unknown inheritance.

PMID: 37675773 - Trio exome sequencing for families 1-6, confirmed de novo status for all 6 families. Seventh family could not be confirmed. 5 missense variants, 2 frameshift variants.

PMID: 39367743 - Trio exome sequencing for families 1-4, confirmed de novo in all 4 families. One case paternally inherited, one unknown. 4 missense variants, 1 frameshift variant (2 individuals in the same family).

ATP2B2 is plasma membrane Ca2+ ATPase involved in Ca2+ homeostasis. Ca2+ deregulation in humans and mice can cause cognitive, behavioural, sensory, and movement disorders. Discussed in detail in PMID: 37675773.

Request addition to R27, R29, R55, R59, R69, R84, Ataxia and Cerebellar Anomalies - Narrow Panel.
Sources: Expert Review
Mitochondrial neurogastrointestinal encephalopathy v1.4 Achchuthan Shanmugasundram List of related panels changed from R394 to R394; GT1179; TP267
Albinism or congenital nystagmus v4.12 Eleanor Williams List of related panels changed from R39 to R39; GT1287; TP208
Mitochondrial liver disease v1.15 Achchuthan Shanmugasundram List of related panels changed from Mitochondrial liver disease; R317 to Mitochondrial liver disease; R317; GT766; TP167
Mitochondrial DNA maintenance disorder v3.10 Achchuthan Shanmugasundram List of related panels changed from R352 to R352; GT1167; TP138
Tuberous sclerosis v1.5 Eleanor Williams List of related panels changed from R228 to R228; GT686; GT257; TP17
Mitochondrial disorder with complex V deficiency v3.6 Achchuthan Shanmugasundram List of related panels changed from R357 to R357; GT640; TP221
Spinal muscular atrophy - Diagnostic v1.4 Eleanor Williams List of related panels changed from R71 to R71; GT571; TP137
Mitochondrial disorder with complex IV deficiency v5.2 Achchuthan Shanmugasundram List of related panels changed from R356 to R356; GT631; TP461
Pituitary hormone deficiency v4.10 Arina Puzriakova List of related panels changed from R159 to R159; GT1249; TP259
Skeletal muscle channelopathy v3.9 Eleanor Williams List of related panels changed from R76; Myotonia congenita to Myotonia congenita; R76; GT367; TP384
Neonatal diabetes - small panel v1.7 Arina Puzriakova List of related panels changed from R143.1; Neonatal diabetes to Neonatal diabetes; R143.1; GT1019; TP437
Mitochondrial disorder with complex III deficiency v2.8 Achchuthan Shanmugasundram List of related panels changed from R355 to R355; GT891; TP272
Retinal disorders v9.5 Chr17q22 Katie Cox changed review comment from: Structural variants in the RP17 locus (Chr17q22) have been associated with retinitis pigmentosa 17, breakpoints within the genomic region spanning YPEL2 to LINC01476.
Sources: Literature; to: Structural variants in the RP17 locus (Chr17q22) have been associated with retinitis pigmentosa 17, breakpoints within the genomic region spanning YPEL2 to LINC01476.
Sources: Literature
Neonatal diabetes v6.2 Arina Puzriakova List of related panels changed from Neonatal diabetes (diagnosed less than 6 months); Neonatal diabetes diagnosed <6 months; Diabetes - neonatal onset; R143 to Neonatal diabetes (diagnosed less than 6 months); Neonatal diabetes diagnosed <6 months; Diabetes - neonatal onset; R143; GT346; TP437
Mitochondrial disorder with complex II deficiency v2.12 Achchuthan Shanmugasundram List of related panels changed from R354 to R354; GT446; TP472
Multiple endocrine neoplasia type 2 v1.4 Arina Puzriakova List of related panels changed from R218 to R218; GT1254; TP376
Multi Locus Imprinting Disorder (MLID) v2.2 Arina Puzriakova List of related panels changed from R417.2 to R417.2; GT377; TP270
Severe microcephaly v9.7 Eleanor Williams List of related panels changed from Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly; R88 to Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly; R88; GT370; TP54
Monogenic short stature v2.8 Arina Puzriakova List of related panels changed from R453 to R453; GT193; TP365
Mitochondrial disorder with complex I deficiency v4.2 Achchuthan Shanmugasundram List of related panels changed from R353 to R353; GT349; TP318
Retinal disorders v9.5 Chr17q22 Katie Cox Region: Chr17q22 was added
Region: Chr17q22 was added to Retinal disorders. Sources: Literature
Mode of inheritance for Region: Chr17q22 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for Region: Chr17q22 were set to PMID: 33022222
Phenotypes for Region: Chr17q22 were set to Retinitis pigmentosa
Penetrance for Region: Chr17q22 were set to Complete
Review for Region: Chr17q22 was set to GREEN
Region: Chr17q22 was marked as current diagnostic
Added comment: Structural variants in the RP17 locus (Chr17q22) have been associated with retinitis pigmentosa 17, breakpoints within the genomic region spanning YPEL2 to LINC01476.
Sources: Literature
Monogenic diabetes v3.26 Arina Puzriakova List of related panels changed from R141 to R141; GT362; TP258
Segmental or atypical neurofibromatosis type 1 testing v1.4 Eleanor Williams List of related panels changed from R376 to R376; GT1270; TP251
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v1.4 Arina Puzriakova List of related panels changed from R157 to R157; GT590; TP317
Mitochondrial Complex V deficiency, TMEM70 type v1.4 Achchuthan Shanmugasundram List of related panels changed from R396 to R396; GT970; TP303
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.3 Arina Puzriakova List of related panels changed from R223 to R223; GT968; TP432
Paroxysmal central nervous system disorders v4.4 Eleanor Williams List of related panels changed from Paroxysmal neurological disorders; pain disorders and sleep disorders; R66 to Paroxysmal neurological disorders; pain disorders and sleep disorders; R66; GT801; TP74
Inherited parathyroid cancer v1.4 Arina Puzriakova List of related panels changed from R226 to R226; GT938; TP31
Tay-Sachs disease v1.4 Achchuthan Shanmugasundram List of related panels changed from R286 to R286; GT848; TP367
Hypophosphataemia or rickets v4.4 Arina Puzriakova List of related panels changed from R154 to R154; GT753; TP239
Hypogonadotropic hypogonadism (GMS) v5.3 Arina Puzriakova List of related panels changed from Hypogonadotropic hypogonadism idiopathic; R148 to Hypogonadotropic hypogonadism idiopathic; R148; GT626; TP508
Other rare neuromuscular disorders v31.113 Eleanor Williams List of related panels changed from Neuromuscular disorders; R381 to Neuromuscular disorders; R381; GT1059; TP350
Hyperthyroidism v3.7 Arina Puzriakova List of related panels changed from Resistance to thyroid hormone; R182 to Resistance to thyroid hormone; R182; GT966; TP60
Hereditary isolated diabetes insipidus v2.3 Arina Puzriakova List of related panels changed from Neuropophyseal diabetes insipidus; R440 to Neuropophyseal diabetes insipidus; R440; GT150; TP551
Neurofibromatosis type 1 (GMS) v1.5 Eleanor Williams List of related panels changed from R222 to R222; GT867; TP251
Glucokinase-related fasting hyperglycaemia v1.4 Arina Puzriakova List of related panels changed from R142 to R142; GT899; TP471
Malignant hyperthermia v1.6 Eleanor Williams List of related panels changed from R371 to R371; GT1075; TP405
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.9 Eleanor Williams List of related panels changed from Limb girdle muscular dystrophy; R82 to Limb girdle muscular dystrophy; R82; GT1037; TP111
Familial tumoral calcinosis v1.12 Arina Puzriakova List of related panels changed from R162 to R162; GT240; TP481
Hydrocephalus v5.13 Eleanor Williams List of related panels changed from Hydrocephalus; R86 to Hydrocephalus; R86; GT719; TP187
Holoprosencephaly v6.2 Eleanor Williams List of related panels changed from Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85 to Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85; GT142; TP125
Familial hypoparathyroidism v3.6 Arina Puzriakova List of related panels changed from Familial or syndromic hypoparathyroidism; R153 to Familial or syndromic hypoparathyroidism; R153; GT990; TP359
Hereditary neuropathy or pain disorder v8.5 Eleanor Williams List of related panels changed from Hereditary neuropathy NOT PMP22 copy number; Hereditary neuropathy or pain disorder - NOT PMP22 copy number; R78 to Hereditary neuropathy NOT PMP22 copy number; Hereditary neuropathy or pain disorder - NOT PMP22 copy number; R78; GT1108; TP632
Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v3.9 Arina Puzriakova List of related panels changed from Familial hyperparathyroidism; Hypocalciuric hypercalcaemia; R151 to Familial hyperparathyroidism; Hypocalciuric hypercalcaemia; R151; GT1100; TP492
Familial dysalbuminaemic hyperthyroxinaemia v1.4 Arina Puzriakova List of related panels changed from R329 to R329; GT18; TP364
Endocrine neoplasia v3.6 Arina Puzriakova List of related panels changed from Endocrine neoplasms; R217 to Endocrine neoplasms; R217; GT127; TP59
Inherited predisposition to GIST v1.17 Ida Ertmanska List of related panels changed from R363 to R363; GT971; TP129
Differences in sex development v4.22 Arina Puzriakova List of related panels changed from R146; Disorders of sex development to Disorders of sex development; R146; GT771; TP322
Hereditary ataxia and cerebellar anomalies, childhood onset v23.5 Eleanor Williams List of related panels changed from Hereditary ataxia with onset in childhood; Cerebellar anomalies; R55; R84 to Hereditary ataxia with onset in childhood; Cerebellar anomalies; R55; R84; GT936; TP356; TP411
Inherited polyposis and early onset colorectal cancer - germline testing v4.2 Ida Ertmanska List of related panels changed from Inherited polyposis; R211 to Inherited polyposis; R211; GT1289; TP447
Congenital hypothyroidism v3.5 Arina Puzriakova List of related panels changed from Congenital hypothyroidism or thyroid agenesis; R145 to Congenital hypothyroidism or thyroid agenesis; R145; GT229; TP433
Inherited pancreatic cancer v3.4 Ida Ertmanska List of related panels changed from R367 to R367; GT297; TP108
Congenital hyperinsulinism v3.9 Arina Puzriakova List of related panels changed from Hyperinsulinism; R144 to Hyperinsulinism; R144; GT544; TP368
Inherited ovarian cancer (without breast cancer) v5.2 Ida Ertmanska List of related panels changed from Familial ovarian cancer; R207 to Familial ovarian cancer; R207; GT904; TP174
Inherited MMR deficiency (Lynch syndrome) v1.15 Ida Ertmanska List of related panels changed from R210 to R210; GT768; TP168
Inherited breast cancer and ovarian cancer v3.2 Ida Ertmanska List of related panels changed from R208 to R208; GT324; TP547
Congenital adrenal hypoplasia v5.5 Arina Puzriakova List of related panels changed from R150 to R150; GT1284; TP371
Hereditary diffuse gastric cancer v2.6 Ida Ertmanska List of related panels changed from CDH1-related cancer syndrome; R215 to CDH1-related cancer syndrome; R215; GT689; TP404
Congenital adrenal hyperplasia v1.4 Arina Puzriakova List of related panels changed from R180 to R180; GT724; TP41
Carney complex v1.4 Arina Puzriakova List of related panels changed from R156 to R156; GT2; TP454
Fumarate hydratase-related tumour syndromes v1.4 Ida Ertmanska List of related panels changed from R365 to R365; GT558; TP263
Calcium-sensing receptor phenotypes v1.4 Arina Puzriakova List of related panels changed from R319 to R319; GT780; TP548
Familial melanoma v2.15 Ida Ertmanska List of related panels changed from R254 to R254; GT402; TP483
Embryonal tumour of possible germline origin v1.2 Ida Ertmanska List of related panels changed from R456 to R456; GT1441; TP170
DICER1-related cancer predisposition v1.4 Ida Ertmanska List of related panels changed from R364 to R364; GT182; TP265
BAP1 associated tumour predisposition syndrome v1.4 Ida Ertmanska List of related panels changed from R422 to R422; GT648; TP372
APC associated Polyposis v1.4 Ida Ertmanska List of related panels changed from R414 to R414; GT650; TP55
Wiskott-Aldrich syndrome v1.5 Ida Ertmanska List of related panels changed from R20 to R20; GT365; TP342
Severe combined immunodeficiency with PNP deficiency v1.4 Ida Ertmanska List of related panels changed from R234 to R234; GT396; TP254
Severe combined immunodeficiency with adenosine deaminase deficiency v1.6 Ida Ertmanska List of related panels changed from R16 to R16; GT43; TP558
Smith-Lemli-Opitz syndrome v1.4 Achchuthan Shanmugasundram List of related panels changed from R270 to R270; GT659; TP201
SCID with features of gamma chain deficiency v1.4 Ida Ertmanska List of related panels changed from R235 to R235; GT572; TP388
Beckwith-Wiedemann syndrome v1.4 Arina Puzriakova List of related panels changed from R49.3 to R49.3; GT758; TP566
Primary immunodeficiency or monogenic inflammatory bowel disease v9.16 Ida Ertmanska List of related panels changed from Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; Primary immunodeficiency; R15 to Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; Primary immunodeficiency; R15; GT1295; GT837; TP223
Sitosterolaemia v1.5 Achchuthan Shanmugasundram List of related panels changed from R323 to R323; GT569; TP87
Lymphoproliferative syndrome with absent SAP expression v1.4 Ida Ertmanska List of related panels changed from R17 to R17; GT392; TP296
Hereditary angioedema types I and II v1.4 Ida Ertmanska List of related panels changed from R341 to R341; GT603; TP10
Sandhoff disease v1.4 Achchuthan Shanmugasundram List of related panels changed from R285 to R285; GT378; TP39
Haemophagocytic syndrome with absent XIAP expression v1.5 Ida Ertmanska List of related panels changed from R18 to R18; GT390; TP581
Haemophagocytic syndrome with absent perforin expression v1.5 Ida Ertmanska List of related panels changed from R232 to R232; GT553; TP366
Autoinflammatory disorders v3.10 Ida Ertmanska List of related panels changed from R413 to R413; GT1098; TP52
Phenylketonuria v1.4 Achchuthan Shanmugasundram List of related panels changed from R283 to R283; GT124; TP565
Autoimmune Polyendocrine Syndrome v1.5 Ida Ertmanska List of related panels changed from R155 to R155; GT628; TP276
Niemann-Pick disease type A or B v1.4 Achchuthan Shanmugasundram List of related panels changed from R282 to R282; GT364; TP279
Familial tumours of the nervous system v3.2 Eleanor Williams List of related panels changed from R221 to R221; GT735; TP166
Autoimmune lymphoproliferative syndrome with defective apoptosis v1.4 Ida Ertmanska List of related panels changed from R19 to R19; GT651; TP156
Niemann Pick disease type C v1.5 Achchuthan Shanmugasundram List of related panels changed from R380 to R380; GT179; TP519
Agammaglobulinaemia with absent BTK expression v1.4 Ida Ertmanska List of related panels changed from R233 to R233; GT141; TP47
Facioscapulohumeral muscular dystrophy - extended testing v1.4 Eleanor Williams List of related panels changed from R345 to R345; GT722; TP629
Neuronal ceroid lipofuscinosis type 2 v1.4 Achchuthan Shanmugasundram List of related panels changed from R271 to R271; GT1244; TP327
Duchenne or Becker muscular dystrophy v1.4 Eleanor Williams List of related panels changed from R73 to R73; GT1251; TP122
von Willebrand disease v1.5 Ida Ertmanska List of related panels changed from R121 to R121; GT470; TP14
Alstrom syndrome v1.4 Arina Puzriakova List of related panels changed from R106 to R106; GT610; TP155
Thrombophilia with a likely monogenic cause v3.2 Ida Ertmanska List of related panels changed from Thrombophilia; R97 to Thrombophilia; R97; GT116; TP120
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.11 Arina Puzriakova List of related panels changed from R293 to R293; GT582; TP386
Thrombocythaemia v2.2 Ida Ertmanska List of related panels changed from R406 to R406; GT1176; TP417
Neuronal ceroid lipofuscinosis v3.3 Achchuthan Shanmugasundram List of related panels changed from R231 to R231; GT310; TP210
Congenital myopathy v7.77 Eleanor Williams List of related panels changed from R81 to R81; GT988; TP240
Sickle cell, thalassaemia and other haemoglobinopathies v2.10 Ida Ertmanska List of related panels changed from R93; Thalassaemia and other haemoglobinopathies to R93; Thalassaemia and other haemoglobinopathies; GT713; TP199; TP473
Paediatric disorders v75.113 Arina Puzriakova List of related panels changed from Congenital malformation and dysmorphism syndromes - microarray and sequencing; Congenital malformation and dysmorphism syndromes; R27 to Congenital malformation and dysmorphism syndromes - microarray and sequencing; Congenital malformation and dysmorphism syndromes; R27; GT1095; TP459
Congenital myaesthenic syndrome v6.2 Eleanor Williams List of related panels changed from Congenital myaesthenia; Congenital myasthenia; R80 to Congenital myaesthenia; Congenital myasthenia; R80; GT950; TP61
Mucopolysaccharidosis type VI v1.4 Achchuthan Shanmugasundram List of related panels changed from R290 to R290; GT826; TP440
Rare anaemia v4.7 Ida Ertmanska List of related panels changed from R92 to R92; GT455; TP301
Congenital muscular dystrophy v7.22 Eleanor Williams List of related panels changed from R79 to R79; GT273; TP80
Nijmegen breakage syndrome v1.4 Ida Ertmanska List of related panels changed from R259.2 to R259.2; GT132; TP216
Mucopolysaccharidosis type IVA v1.4 Achchuthan Shanmugasundram List of related panels changed from R287 to R287; GT1119; TP385
Hypotonic infant v46.145 Arina Puzriakova List of related panels changed from Floppy infant with a likely central cause; Hypotonic infant with a likely central cause; R69 to Floppy infant with a likely central cause; Hypotonic infant with a likely central cause; R69; GT46; TP383
Leukodystrophy, childhood onset v31.49 Eleanor Williams List of related panels changed from White matter disorders - childhood onset; R109 to White matter disorders - childhood onset; R109; GT207; TP419
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.8 Arina Puzriakova List of related panels changed from Cockayne and Xeroderma Pigmentosum-like disorders; Cockayne syndrome; Xeroderma Pigmentosum-like disorders; XP-like disorders; R227 to Cockayne and Xeroderma Pigmentosum-like disorders; Cockayne syndrome; Xeroderma Pigmentosum-like disorders; XP-like disorders; R227; GT1099; TP332
Neutropaenia consistent with ELANE variants v1.4 Ida Ertmanska List of related panels changed from R313 to R313; GT502; TP76
Mucopolysaccharidosis type IIIB v1.4 Achchuthan Shanmugasundram List of related panels changed from R292 to R292; GT893; TP143
Monitoring for G(M)CSF escape variants v1.4 Ida Ertmanska List of related panels changed from R338 to R338; GT188; TP539
Iron metabolism disorders - NOT common HFE mutations v4.3 Ida Ertmanska List of related panels changed from Iron metabolism disorders; R96 to Iron metabolism disorders; R96; GT715; TP630
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.5 Ida Ertmanska List of related panels changed from R366 to R366; GT540; TP396
Mucopolysaccharidosis type IIIA v1.4 Achchuthan Shanmugasundram List of related panels changed from R291 to R291; GT1256; TP536
Inherited predisposition to acute myeloid leukaemia (AML) v3.8 Ida Ertmanska List of related panels changed from R347 to R347; GT204; TP464
Hereditary Erythrocytosis v3.2 Ida Ertmanska List of related panels changed from R405 to R405; GT1006; TP337
Factor XIII deficiency v1.5 Ida Ertmanska List of related panels changed from R122 to R122; GT906; TP162
Mucopolysaccharidosis type II v1.4 Achchuthan Shanmugasundram List of related panels changed from R278 to R278; GT536; TP152
Hereditary spastic paraplegia, childhood onset v9.3 Eleanor Williams List of related panels changed from Hereditary spastic paraplegia - childhood onset; R61 to Hereditary spastic paraplegia - childhood onset; R61; GT34; TP579
Dystonia, chorea or related movement disorder, childhood onset v8.4 Eleanor Williams List of related panels changed from Childhood onset dystonia or chorea or related movement disorder; R57 to Childhood onset dystonia or chorea or related movement disorder; R57; GT25; TP173
Factor XI deficiency v1.4 Ida Ertmanska List of related panels changed from R120 to R120; GT498; TP429
Vascular skin disorders v2.6 Arina Puzriakova List of related panels changed from R326 to R326; GT92; TP501
Cerebral vascular malformations v5.2 Eleanor Williams List of related panels changed from Cerebrovascular disorders; Vein of Galen malformation; Cerebral arteriovenous malformations; Moyamoya disease; R336 to Cerebrovascular disorders; Vein of Galen malformation; Cerebral arteriovenous malformations; Moyamoya disease; R336; GT922; TP113
Mucopolysaccharidosis type IH or S v1.4 Achchuthan Shanmugasundram List of related panels changed from R277; Mucopolysaccharidosis type IH/S to Mucopolysaccharidosis type IH/S; R277; GT1130; TP206
Factor X deficiency v1.4 Ida Ertmanska List of related panels changed from R119 to R119; GT960; TP571
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v1.4 Arina Puzriakova List of related panels changed from R424 to R424; GT298; TP309
Factor VIII deficiency v1.4 Ida Ertmanska List of related panels changed from R117 to R117; GT1283; TP268
Cerebral malformation v16.7 Eleanor Williams List of related panels changed from Cerebral malformations; R87 to Cerebral malformations; R87; GT458; TP23
Segmental overgrowth disorders - Deep sequencing v5.2 Arina Puzriakova List of related panels changed from Regional overgrowth disorders; Segmental overgrowth disorders; R110 to Regional overgrowth disorders; Segmental overgrowth disorders; R110; GT1057; TP498
Factor VII deficiency v1.4 Ida Ertmanska List of related panels changed from R116 to R116; GT993; TP75
Rare genetic inflammatory skin disorders v4.20 Arina Puzriakova List of related panels changed from R332 to R332; GT1269; TP373
Pigmentary skin disorders v5.4 Arina Puzriakova List of related panels changed from R236 to R236; GT1115; TP79
Factor V deficiency v1.4 Ida Ertmanska List of related panels changed from R115 to R115; GT1159; TP369
Mucolipidosis II and III Alpha or Beta v1.4 Achchuthan Shanmugasundram List of related panels changed from R289; Mucolipidosis II and III Alpha/Beta to Mucolipidosis II and III Alpha/Beta; R289; GT835; TP556
Palmoplantar keratodermas v4.13 Arina Puzriakova List of related panels changed from R166 to R166; GT255; TP328
Factor IX deficiency v1.4 Ida Ertmanska List of related panels changed from R118 to R118; GT77; TP50
Multiple monogenic benign skin tumours v2.7 Arina Puzriakova List of related panels changed from R230 to R230; GT811; TP538
CADASIL v1.8 Eleanor Williams List of related panels changed from R337 to R337; GT1061; TP4
Factor II deficiency v1.4 Ida Ertmanska List of related panels changed from R112 to R112; GT64; TP53
Mosaic skin disorders - Deep sequencing v3.28 Arina Puzriakova List of related panels changed from R327 to R327; GT878; TP169
Lysosomal storage disorder v3.10 Achchuthan Shanmugasundram List of related panels changed from R276 to R276; GT798; TP95
Cytopenia - NOT Fanconi anaemia v5.7 Ida Ertmanska List of related panels changed from R91 to R91; GT424; TP549
Incontinentia pigmenti v1.5 Arina Puzriakova List of related panels changed from R239 to R239; GT877; TP285
Ataxia telangiectasia - mutation testing v1.4 Eleanor Williams List of related panels changed from R295 to R295; GT65; TP621
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 ITGAL Boaz Palterer gene: ITGAL was added
gene: ITGAL was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ITGAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITGAL were set to 41758928
Phenotypes for gene: ITGAL were set to epidermodysplasia verruciformis
Penetrance for gene: ITGAL were set to unknown
Review for gene: ITGAL was set to GREEN
Added comment: Yatim et al. described 6 subjects from 4 kindreds with biallelic variants in ITGAL presenting with EV, accounting for 10% of unexplained EV cohort. The EV cohort was therefore highly enriched in individuals homozygous for predicted deleterious ITGAL variants (10%, 4 of 40), compared with patients with other infectious diseases (0 of 25,329) and with the general population (0 of 807,162). Follows extensive ex-vivo and in vitro functional validation.
Sources: Literature
Ichthyosis and erythrokeratoderma v4.15 Arina Puzriakova List of related panels changed from R165 to R165; GT388; TP217
Fanconi anaemia or Bloom syndrome v2.16 Ida Ertmanska List of related panels changed from R229; R258; Confirmed Fanconi anaemia or Bloom syndrome - mutation testing; Cytopenia - Fanconi breakage testing indicated to R229; R258; Confirmed Fanconi anaemia or Bloom syndrome - mutation testing; Cytopenia - Fanconi breakage testing indicated; GT566; TP191
Lysosomal acid lipase deficiency v1.4 Achchuthan Shanmugasundram List of related panels changed from R325 to R325; GT371; TP104
Epidermolysis bullosa and congenital skin fragility v2.16 Arina Puzriakova List of related panels changed from R164 to R164; GT805; TP262
Epidermodysplasia verruciformis v1.8 Arina Puzriakova List of related panels changed from R255 to R255; GT107; TP78
Combined vitamin K-dependent clotting factor deficiency v1.5 Ida Ertmanska List of related panels changed from R123 to R123; GT948; TP425
Arthrogryposis v10.11 Eleanor Williams List of related panels changed from R83 to R83; GT413; TP577
Likely inborn error of metabolism v9.12 Achchuthan Shanmugasundram List of related panels changed from Likely inborn error of metabolism - targeted testing not possible; Inborn errors of metabolism; R98 to Likely inborn error of metabolism - targeted testing not possible; Inborn errors of metabolism; R98; GT317; GT1144; TP229
Ectodermal dysplasia v5.2 Arina Puzriakova List of related panels changed from R163 to R163; GT1125; TP314
Combined factor V and VIII deficiency v1.12 Ida Ertmanska List of related panels changed from R124 to R124; GT1020; TP90
Cutaneous photosensitivity with a likely genetic cause v3.17 Arina Puzriakova List of related panels changed from R237 to R237; GT1088; TP479
Bleeding and platelet disorders v4.15 Ida Ertmanska List of related panels changed from R90 to R90; GT575; TP360
Autosomal recessive primary hypertrophic osteoarthropathy v2.2 Arina Puzriakova List of related panels changed from R167 to R167; GT1026; TP158
Wilson disease v1.4 Ida Ertmanska List of related panels changed from R172 to R172; GT1170; TP497
Unexplained death in infancy and sudden unexplained death in childhood v23.41 Arina Puzriakova List of related panels changed from R441 to R441; GT1045; TP424
Adult-onset neurological disorders v9.6 Eleanor Williams List of related panels changed from R54; R56; R60; R458; R459; R460; R461; Hereditary ataxia with onset in adulthood; Adult onset dystonia; chorea or related movement disorder; Adult onset hereditary spastic paraplegia; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy to R54; R56; R60; R458; R459; R460; R461; Hereditary ataxia with onset in adulthood; Adult onset dystonia; chorea or related movement disorder; Adult onset hereditary spastic paraplegia; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy; GT1442; TP69; TP114; TP213; TP133; TP142; TP123; TP146
Krabbe disease - Saposin A deficiency v1.4 Achchuthan Shanmugasundram List of related panels changed from R281 to R281; GT1141; TP25
Thoracic aortic aneurysm or dissection (GMS) v5.5 Arina Puzriakova List of related panels changed from Thoracic aortic aneurysm and dissection; R125 to Thoracic aortic aneurysm and dissection; R125; GT797; TP516
Krabbe disease - GALC deficiency v1.4 Achchuthan Shanmugasundram List of related panels changed from R280 to R280; GT1241; TP49
Leukodystrophy, adult onset v7.3 Eleanor Williams List of related panels changed from White matter disorders - adult onset; R62 to White matter disorders - adult onset; R62; GT117; TP85
Sudden unexplained death or survivors of a cardiac event v23.17 Arina Puzriakova List of related panels changed from Molecular autopsy; Sudden cardiac death; R138 to Molecular autopsy; Sudden cardiac death; R138; GT666; TP119
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 LY9 Boaz Palterer gene: LY9 was added
gene: LY9 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: LY9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY9 were set to 40446017
Phenotypes for gene: LY9 were set to Tubercolosis
Penetrance for gene: LY9 were set to unknown
Review for gene: LY9 was set to GREEN
Added comment: Ogishi et al. described 3 subjects from 3 kindreds with homozygous LOF mutations in LY9 presenting with tuberculosis in a large TB cohort, notably no homozygous LOF was found in a large control cohort. Extensive ex-vivo and in vivo functional validation.
Sources: Literature
Short QT syndrome v3.23 Arina Puzriakova List of related panels changed from R130 to R130; GT1219; TP334
Progressive cardiac conduction disease v2.17 Arina Puzriakova List of related panels changed from R328 to R328; GT1286; TP110
Acute rhabdomyolysis v2.11 Eleanor Williams List of related panels changed from R419 to R419; GT782; TP164
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v1.4 Achchuthan Shanmugasundram List of related panels changed from R288 to R288; GT130; TP293
Primary lymphoedema v5.2 Arina Puzriakova List of related panels changed from Lymphatic Disorders; Meiges disease; Meige disease; Milroy disease; Lymphoedema distichiasis; Lipoedema disease; R136 to Lymphatic Disorders; Meiges disease; Meige disease; Milroy disease; Lymphoedema distichiasis; Lipoedema disease; R136; GT750; TP261
Paediatric or syndromic cardiomyopathy v8.3 Arina Puzriakova List of related panels changed from Cardiomyopathies - including childhood onset; R135 to Cardiomyopathies - including childhood onset; R135; GT490; GT1273; TP159
Long QT syndrome v3.14 Arina Puzriakova List of related panels changed from Long QT; R127 to Long QT; R127; GT611; TP323
Glycogen storage disease V v1.5 Achchuthan Shanmugasundram List of related panels changed from R273 to R273; GT1054; TP1
Hypertrophic cardiomyopathy v6.3 Arina Puzriakova List of related panels changed from Hypertrophic cardiomyopathy - teen and adult; HCM; R131 to Hypertrophic cardiomyopathy - teen and adult; HCM; R131; GT1132; TP145
Thanatophoric dysplasia v1.4 Eleanor Williams List of related panels changed from R25 to R25; GT300; TP186
Generalised arterial calcification in infancy v1.5 Arina Puzriakova List of related panels changed from R384 to R384; GT62; TP423
Elastin-related phenotypes v1.4 Arina Puzriakova List of related panels changed from R140 to R140; GT249; TP521
Glycogen storage disease v2.8 Achchuthan Shanmugasundram List of related panels changed from R274 to R274; GT710; TP1
Dilated and arrhythmogenic cardiomyopathy v4.2 Arina Puzriakova List of related panels changed from Dilated cardiomyopathy - adult and teen; R132 to Dilated cardiomyopathy - adult and teen; R132; GT11; TP357
Syndromic and non syndromic craniosynostosis involving midline sutures v1.4 Eleanor Williams List of related panels changed from R416 to R416; GT896; TP562
Variegate porphyria v1.5 Ida Ertmanska List of related panels changed from R170 to R170; GT283; TP430
Catecholaminergic polymorphic VT v5.5 Arina Puzriakova List of related panels changed from Catecholaminergic Polymorphic Ventricular Tachycardia; R129 to Catecholaminergic Polymorphic Ventricular Tachycardia; R129; GT1136; TP436
Gaucher disease v1.4 Achchuthan Shanmugasundram List of related panels changed from R272 to R272; GT1172; TP160
Brugada syndrome and cardiac sodium channel disease v3.17 Arina Puzriakova List of related panels changed from Brugada syndrome; R128 to Brugada syndrome; R128; GT683; TP230
Polycystic liver disease v1.33 Ida Ertmanska List of related panels changed from Polycystic liver disease interim; R173 to Polycystic liver disease interim; R173; GT915; TP414
Fabry disease v1.4 Achchuthan Shanmugasundram List of related panels changed from R335 to R335; GT435; TP71
Pancreatitis v3.6 Ida Ertmanska List of related panels changed from R175 to R175; GT947; TP35
Barth syndrome v1.5 Arina Puzriakova List of related panels changed from R391 to R391; GT423; TP135
Paediatric pseudo-obstruction syndrome v2.7 Ida Ertmanska List of related panels changed from R438 to R438; GT201; TP38
Arrhythmogenic right ventricular cardiomyopathy v3.17 Arina Puzriakova List of related panels changed from Arrhythmogenic cardiomyopathy; R133 to Arrhythmogenic cardiomyopathy; R133; GT1053; TP338
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Diagnostic v1.3 Achchuthan Shanmugasundram List of related panels changed from R451 to R451; GT1105; TP378
Non-acute porphyrias v1.37 Ida Ertmanska List of related panels changed from R168 to R168; GT530; TP528
Isovaleric acidaemia - Diagnostic v1.3 Achchuthan Shanmugasundram List of related panels changed from R450 to R450; GT1229; TP67