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Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Tag watchlist tag was added to gene: PAK2.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 unrelated individuals reported in literature with retinal detachment associated with PAK2‐related Knobloch syndrome.; to: Comment on list classification: Rating Amber as only 2 cases have been reported with epilepsy to date. PAK2 has mostly been linked to Knobloch syndrome which is primarily characterised by ocular manifestations and prenatal/neonatal pulmonary features. Neurodevelopmental abnormalities are variable but not a defining feature in most cases. However, given there is a case without cardinal features of Knobloch syndrome, where epilepsy was the primary phenotype, this gene has been included on the panel as Amber in case additional evidence emerges that supports promotion to Green in the future.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Deleted their comment
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova changed review comment from: Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.


Other PAK2 cases not reporting ocular abnormalities:

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.; to: Antonarakis et al., 2021 (PMID: 33693784) reported two affected siblings from a non-consanguineous New Zealand family. Both had retinal detachment and interstitial parenchymal pulmonary changes on chest X-rays, but only one child had additional significant features such as cataract, posterior encephalocele, severe DD/ID with ASD, and epilepsy. WES revealed a heterozygous PAK2 variant (c.1303 G>A, p.Glu435Lys) in both individuals that apparently occurred de novo indicating parental germ-line mosaicism; however, mosaicism could not be detected by deep sequencing of blood parental DNA. Functional studies showed that the variant, located in the kinase domain, results in a partial loss of the kinase activity.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.


Other PAK2 cases not reporting epilepsy:

Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Tag Q1_26_promote_green was removed from gene: PAK2.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Entity copied from Retinal disorders v8.82
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova gene: PAK2 was added
gene: PAK2 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
Q1_26_promote_green tags were added to gene: PAK2.
Mode of inheritance for gene: PAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAK2 were set to 33693784; 38894571; 39876536; 39994693; 40262506; 40247748
Phenotypes for gene: PAK2 were set to Knobloch 2 syndrome, OMIM:618458
Retinal disorders v8.82 PAK2 Arina Puzriakova changed review comment from: Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.; to: Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.


Other PAK2 cases not reporting ocular abnormalities:

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.
Retinal disorders v8.82 PAK2 Arina Puzriakova Classified gene: PAK2 as Amber List (moderate evidence)
Retinal disorders v8.82 PAK2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 unrelated individuals reported in literature with retinal detachment associated with PAK2‐related Knobloch syndrome.
Retinal disorders v8.82 PAK2 Arina Puzriakova Gene: pak2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.81 PAK2 Arina Puzriakova Publications for gene: PAK2 were set to 33693784
Retinal disorders v8.80 PAK2 Arina Puzriakova Tag Q1_26_promote_green tag was added to gene: PAK2.
Retinal disorders v8.80 PAK2 Arina Puzriakova edited their review of gene: PAK2: Added comment: Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.; Changed rating: GREEN; Changed publications to: 33693784, 38894571, 39876536, 39994693, 40262506, 40247748; Changed phenotypes to: Knobloch 2 syndrome, OMIM:618458
Retinal disorders v8.80 PAK2 Arina Puzriakova Phenotypes for gene: PAK2 were changed from Knobloch 2 syndrome to Knobloch 2 syndrome, OMIM:618458
Likely inborn error of metabolism v8.91 PAICS Arina Puzriakova Classified gene: PAICS as Amber List (moderate evidence)
Likely inborn error of metabolism v8.91 PAICS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green - three unrelated cases with phosphoribosylaminoimidazole carboxylase deficiency, an inborn error of de novo purine synthesis caused by biallelic variants in the PAICS gene (PMID: 31600779; 39604553; 39726239)

Inclusion on this panel would also ensure inclusion on the Paediatric disorders super panel which is relevant to the polymalformative syndrome or neurodevelopmental disorder displayed by affected individuals.
Likely inborn error of metabolism v8.91 PAICS Arina Puzriakova Gene: paics has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.90 PAICS Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype (?Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859) accessed on 27-01-2026
Likely inborn error of metabolism v8.90 PAICS Arina Puzriakova Phenotypes for gene: PAICS were changed from Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859 to ?Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859
Likely inborn error of metabolism v8.89 PAICS Arina Puzriakova gene: PAICS was added
gene: PAICS was added to Likely inborn error of metabolism. Sources: Literature
Q1_26_promote_green tags were added to gene: PAICS.
Mode of inheritance for gene: PAICS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAICS were set to 31600779; 39604553; 39726239
Phenotypes for gene: PAICS were set to Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859
Review for gene: PAICS was set to GREEN
Added comment: Pelet et al. 2019 (PMID: 31600779) report an AR inborn error of de novo purine synthesis due to homozygous missense variant in PAICS (c.158A>G; p.Lys53Arg) in 2 siblings from the Faroe islands. Catalytic activity of the mutant protein in patient skin fibroblasts was approx 10% of wild type levels. The siblings had multiple malformations resulting in early neonatal death.

Weng et al. 2024 (PMID: 39604553) identified two Taiwanese siblings with compound heterozygous variants, c.535T>C (p.Ser179Pro) and c.1207C>T (p.Arg403Ter). They presented a markedly different clinical course, with both being born at term following uncomplicated pregnancies. However, clinical manifestations did start to emerge from infancy and manifested as progressive cerebral atrophy, epileptic encephalopathy, psychomotor retardation, and retinopathy. Phenotypic variability could be attributed to residual enzyme activities where the Ser179Pro and Arg403Ter proteins had residual activities decreased to 76 and 21%, respectively, compared to 10% of the Lys35Arg protein of Faroe Island patients.

Boussion et al. 2025 (PMID: 39726239) reported a 7-year-old boy homozygous for the same p.Lys53Arg mutation as the Faroe cases. This individual presented with a multiple malformations including complex congenital heart disease, skeletal and esophageal defects but normal neurodevelopment. There was a similarly affected sibling with suspected PAICS deficiency, but this was not molecularly confirmed.
Sources: Literature
Fetal anomalies v6.137 PAICS Arina Puzriakova Publications for gene: PAICS were set to 31178128; 31600779; 3965093; 38179855; 30758658
Adult-onset neurological disorders v8.0 Achchuthan Shanmugasundram Added Panel Adult-onset neurological disorders
Set list of related panels 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
Set child panels to: Hereditary ataxia with onset in adulthood; Adult onset neurodegenerative disorder; Adult onset hereditary spastic paraplegia; Adult onset dystonia, chorea or related movement disorder
Set panel types to: GMS Rare Disease Virtual; Super Panel
Childhood interstitial lung disease v0.6 RAB5B Achchuthan Shanmugasundram Classified gene: RAB5B as Amber List (moderate evidence)
Childhood interstitial lung disease v0.6 RAB5B Achchuthan Shanmugasundram Added comment: Comment on list classification: The rating of this gene will remain amber on this panel as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.6 RAB5B Achchuthan Shanmugasundram Gene: rab5b has been classified as Amber List (Moderate Evidence).
Childhood interstitial lung disease v0.5 MARS Achchuthan Shanmugasundram changed review comment from: Added new-gene-name tag, new approved HGNC gene symbol for MARS is MARS1; to: Added new-gene-name tag, new approved HGNC gene symbol for MARS is MARS1.
Childhood interstitial lung disease v0.5 TMEM173 Achchuthan Shanmugasundram commented on gene: TMEM173: TMEM173 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 TINF2 Achchuthan Shanmugasundram commented on gene: TINF2: TINF2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 TERT Achchuthan Shanmugasundram commented on gene: TERT: TERT has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 TERC Achchuthan Shanmugasundram commented on gene: TERC: TERC has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 TBX4 Achchuthan Shanmugasundram commented on gene: TBX4: TBX4 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 STAT5B Achchuthan Shanmugasundram commented on gene: STAT5B: STAT5B has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 STAT1 Achchuthan Shanmugasundram commented on gene: STAT1: STAT1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SLC7A7 Achchuthan Shanmugasundram commented on gene: SLC7A7: SLC7A7 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SLC34A2 Achchuthan Shanmugasundram commented on gene: SLC34A2: SLC34A2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SFTPC Achchuthan Shanmugasundram commented on gene: SFTPC: SFTPC has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SFTPB Achchuthan Shanmugasundram commented on gene: SFTPB: SFTPB has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SFTPA2 Achchuthan Shanmugasundram commented on gene: SFTPA2: SFTPA2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 SFTPA1 Achchuthan Shanmugasundram commented on gene: SFTPA1: SFTPA1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 RTEL1 Achchuthan Shanmugasundram commented on gene: RTEL1: RTEL1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 PSMB9 Achchuthan Shanmugasundram commented on gene: PSMB9: PSMB9 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 PSMB8 Achchuthan Shanmugasundram commented on gene: PSMB8: PSMB8 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 PSMB4 Achchuthan Shanmugasundram commented on gene: PSMB4: PSMB4 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 PARN Achchuthan Shanmugasundram commented on gene: PARN: PARN has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 OAS1 Achchuthan Shanmugasundram commented on gene: OAS1: OAS1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 NKX2-1 Achchuthan Shanmugasundram commented on gene: NKX2-1: NKX2-1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 NAF1 Achchuthan Shanmugasundram commented on gene: NAF1: NAF1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 MARS Achchuthan Shanmugasundram commented on gene: MARS: MARS has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 LRBA Achchuthan Shanmugasundram commented on gene: LRBA: LRBA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 ITGA3 Achchuthan Shanmugasundram commented on gene: ITGA3: ITGA3 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 GATA2 Achchuthan Shanmugasundram commented on gene: GATA2: GATA2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 FOXF1 Achchuthan Shanmugasundram commented on gene: FOXF1: FOXF1 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 FLNA Achchuthan Shanmugasundram commented on gene: FLNA: FLNA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 FARSB Achchuthan Shanmugasundram commented on gene: FARSB: FARSB has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 FARSA Achchuthan Shanmugasundram commented on gene: FARSA: FARSA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 CSF2RB Achchuthan Shanmugasundram commented on gene: CSF2RB: CSF2RB has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 CSF2RA Achchuthan Shanmugasundram commented on gene: CSF2RA: CSF2RA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 COPA Achchuthan Shanmugasundram commented on gene: COPA: COPA has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 BMPR2 Achchuthan Shanmugasundram commented on gene: BMPR2: BMPR2 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Childhood interstitial lung disease v0.5 ABCA3 Achchuthan Shanmugasundram commented on gene: ABCA3: ABCA3 has been added to the panel for the clinical indication 'R462 Childhood interstitial lung disease' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 WRN Achchuthan Shanmugasundram commented on gene: WRN: WRN has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 TP53 Achchuthan Shanmugasundram commented on gene: TP53: TP53 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 T Achchuthan Shanmugasundram commented on gene: T: T has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 RECQL4 Achchuthan Shanmugasundram commented on gene: RECQL4: RECQL4 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 RB1 Achchuthan Shanmugasundram commented on gene: RB1: RB1 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 PTPN11 Achchuthan Shanmugasundram commented on gene: PTPN11: PTPN11 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 NF1 Achchuthan Shanmugasundram commented on gene: NF1: NF1 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 NBN Achchuthan Shanmugasundram commented on gene: NBN: NBN has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 KRAS Achchuthan Shanmugasundram commented on gene: KRAS: KRAS has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 HRAS Achchuthan Shanmugasundram commented on gene: HRAS: HRAS has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 DICER1 Achchuthan Shanmugasundram commented on gene: DICER1: DICER1 has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 CBL Achchuthan Shanmugasundram commented on gene: CBL: CBL has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Sarcoma of possible germline origin v0.4 BUB1B Achchuthan Shanmugasundram commented on gene: BUB1B: BUB1B has been added to the panel for the clinical indication 'R457 Sarcoma of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 WT1 Achchuthan Shanmugasundram commented on gene: WT1: WT1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 TRIP13 Achchuthan Shanmugasundram commented on gene: TRIP13: TRIP13 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 TRIM37 Achchuthan Shanmugasundram commented on gene: TRIM37: TRIM37 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 TRIM28 Achchuthan Shanmugasundram commented on gene: TRIM28: TRIM28 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 TP53 Achchuthan Shanmugasundram commented on gene: TP53: TP53 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 SUFU Achchuthan Shanmugasundram commented on gene: SUFU: SUFU has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 SOS1 Achchuthan Shanmugasundram commented on gene: SOS1: SOS1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 SMARCB1 Achchuthan Shanmugasundram commented on gene: SMARCB1: SMARCB1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 SMARCA4 Achchuthan Shanmugasundram commented on gene: SMARCA4: SMARCA4 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 REST Achchuthan Shanmugasundram commented on gene: REST: REST has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 PTPN11 Achchuthan Shanmugasundram commented on gene: PTPN11: PTPN11 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 PTCH1 Achchuthan Shanmugasundram commented on gene: PTCH1: PTCH1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 PHOX2B Achchuthan Shanmugasundram commented on gene: PHOX2B: PHOX2B has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 KRAS Achchuthan Shanmugasundram commented on gene: KRAS: KRAS has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 HRAS Achchuthan Shanmugasundram commented on gene: HRAS: HRAS has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 GPR161 Achchuthan Shanmugasundram commented on gene: GPR161: GPR161 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 GPC3 Achchuthan Shanmugasundram commented on gene: GPC3: GPC3 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 EZH2 Achchuthan Shanmugasundram commented on gene: EZH2: EZH2 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 ELP1 Achchuthan Shanmugasundram commented on gene: ELP1: ELP1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 DIS3L2 Achchuthan Shanmugasundram commented on gene: DIS3L2: DIS3L2 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 DICER1 Achchuthan Shanmugasundram commented on gene: DICER1: DICER1 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 CTR9 Achchuthan Shanmugasundram commented on gene: CTR9: CTR9 has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 CDKN1C Achchuthan Shanmugasundram commented on gene: CDKN1C: CDKN1C has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 CBL Achchuthan Shanmugasundram commented on gene: CBL: CBL has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 BUB1B Achchuthan Shanmugasundram commented on gene: BUB1B: BUB1B has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Embryonal tumour of possible germline origin v0.7 ALK Achchuthan Shanmugasundram commented on gene: ALK: ALK has been added to the panel for the clinical indication 'R456 Embryonal tumour of possible germline origin' with a green rating as agreed with the NHS Genomic Medicine Service.
Adult onset hereditary spastic paraplegia v6.6 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Adult onset neurodegenerative disorder v8.10 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Childhood onset dystonia, chorea or related movement disorder v7.13 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Hereditary neuropathy or pain disorder v7.33 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Hereditary ataxia with onset in adulthood v8.21 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Adult onset dystonia, chorea or related movement disorder v5.3 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Cystic kidney disease v8.2 CYP24A1 Eleanor Williams reviewed gene: CYP24A1: Rating: ; Mode of pathogenicity: None; Publications: 21675912, 22337913, 24235083, 26214117, 2712945, 34307984, 38504242, 33249478; Phenotypes: ; Mode of inheritance: None
Pulmonary fibrosis familial v1.8 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Pyruvate dehydrogenase (PDH) deficiency v1.38 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Rhabdomyolysis and metabolic muscle disorders v5.14 Eleanor Williams Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Segmental overgrowth disorders - Deep sequencing v4.5 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Structural eye disease v4.37 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Thoracic aortic aneurysm or dissection (GMS) v4.5 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Tubulointerstitial kidney disease v3.15 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
White matter disorders and cerebral calcification - narrow panel v7.9 Eleanor Williams Panel types changed to Component Of Super Panel; GMS signed-off
Progressive cardiac conduction disease v2.13 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Primary lymphoedema v4.21 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Primary immunodeficiency or monogenic inflammatory bowel disease v8.76 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Pituitary hormone deficiency v4.4 Eleanor Williams Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex V deficiency v3.3 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex IV deficiency v4.14 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex III deficiency v2.7 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial liver disease, including transient infantile liver failure v1.14 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial DNA maintenance disorder v3.9 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex I deficiency v3.19 Ida Ertmanska Panel types changed to GMS Rare Disease; GMS signed-off
Paediatric pseudo-obstruction syndrome v2.5 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Paediatric motor neuronopathies v3.12 Ida Ertmanska Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Paediatric disorders - additional genes v7.29 Ida Ertmanska Panel types changed to Component Of Super Panel; GMS signed-off
Osteopetrosis v1.38 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Multi locus imprinting disorders v1.18 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease; GMS signed-off
Mosaic skin disorders - deep sequencing v3.27 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease; GMS signed-off
Intellectual disability v9.240 AIMP2 Eleanor Williams Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; leukodystrophy, hypomyelinating, 17, MONDO:0054817; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17,OMIM:618006; leukodystrophy, hypomyelinating, 17, MONDO:0054817; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Intellectual disability v9.239 AIMP2 Eleanor Williams Publications for gene: AIMP2 were set to 29215095
Intellectual disability v9.238 AIMP2 Eleanor Williams Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17, 618006; leukodystrophy, hypomyelinating, 17, MONDO:0054817; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Early onset or syndromic epilepsy v8.97 AIMP2 Eleanor Williams Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, OMIM:618006 to Leukodystrophy, hypomyelinating, 17, OMIM:618006; eukodystrophy, hypomyelinating, 17, MONDO:0054817
Cholestasis v3.18 SCYL1 Eleanor Williams Classified gene: SCYL1 as Amber List (moderate evidence)
Cholestasis v3.18 SCYL1 Eleanor Williams Gene: scyl1 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.17 SCYL1 Eleanor Williams Tag Q1_26_NHS_review tag was added to gene: SCYL1.
Neurological segmental overgrowth v3.3 Ida Ertmanska Panel types changed to Component Of Super Panel; GMS signed-off
Multiple monogenic benign skin tumours v2.5 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited renal cancer v1.28 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Multi locus imprinting disorders v1.17 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Paediatric or syndromic cardiomyopathy v7.92 BRAF Eleanor Williams Tag Q1_26_NHS_review tag was added to gene: BRAF.
Inherited prostate cancer v1.5 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited predisposition to GIST v1.15 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited predisposition to acute myeloid leukaemia (AML) v3.5 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited polyposis and early onset colorectal cancer - germline testing v3.11 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Fetal anomalies v6.136 CYP11A1 Eleanor Williams Tag Q1_26_MOI tag was added to gene: CYP11A1.
Mosaic skin disorders - deep sequencing v3.26 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.10 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Monogenic diabetes v3.8 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited pancreatic cancer v3.2 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited ovarian cancer (without breast cancer) v4.9 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited MMR deficiency (Lynch syndrome) v1.13 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial liver disease, including transient infantile liver failure v1.13 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Inherited breast cancer and ovarian cancer v2.18 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial DNA maintenance disorder v3.8 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hypophosphataemia or rickets v4.2 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hypogonadotropic hypogonadism (GMS) v4.5 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hyperthyroidism v3.5 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hereditary Erythrocytosis v2.17 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Glycogen storage disease v2.6 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex V deficiency v3.2 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex IV deficiency v4.13 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex III deficiency v2.6 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Mitochondrial disorder with complex I deficiency v3.18 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Familial tumours of the nervous system v2.14 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v3.7 Arina Puzriakova Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Malformations of cortical development v7.19 Ida Ertmanska Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Lysosomal storage disorder v3.5 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Long QT syndrome v3.12 Ida Ertmanska Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Severe insulin resistance and lipodystrophy syndromes v4.67 Ida Ertmanska Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.29 Ida Ertmanska Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Endocrine neoplasia v3.4 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Congenital adrenal hypoplasia v4.11 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Differences in sex development v4.14 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
DDG2P v6.15 Achchuthan Shanmugasundram Panel types changed to Component Of Super Panel; GMS signed-off
Cystic kidney disease v8.2 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Congenital myopathy v6.45 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Congenital myaesthenic syndrome v5.7 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Congenital muscular dystrophy v6.8 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Congenital hypothyroidism v3.3 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Congenital hyperinsulinism v3.6 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Congenital disorders of glycosylation v7.12 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Common craniosynostosis syndromes v1.16 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Skeletal dysplasia v8.32 FGFR3 Eleanor Williams Phenotypes for gene: FGFR3 were changed from Thanatophoric dysplasia, type I 187600; Muenke syndrome 602849; CATSHL syndrome 610474; SADDAN 616482; Thanatophoric dysplasia, type II 187601; Achondroplasia 100800; LADD syndrome 149730; Hypochondroplasia 146000; Crouzon syndrome with acanthosis nigricans 612247 to CATSHL syndrome, OMIM:610474; camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504
Skeletal dysplasia v8.31 FGFR3 Eleanor Williams Publications for gene: FGFR3 were set to
Ataxia and cerebellar anomalies - narrow panel v8.51 GRID2 Eleanor Williams Publications for gene: GRID2 were set to 9285588; 21460832; 25841024; 35882834; 37944084
Ataxia and cerebellar anomalies - narrow panel v8.50 GRID2 Eleanor Williams edited their review of gene: GRID2: Changed publications to: 23611888, 24078737
Ataxia and cerebellar anomalies - narrow panel v8.50 GRID2 Eleanor Williams commented on gene: GRID2
Cerebral vascular malformations v4.10 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Hereditary ataxia with onset in adulthood v8.20 GRID2 Eleanor Williams Phenotypes for gene: GRID2 were changed from Progressive cerebellar ataxia, HP:0002073; Spinocerebellar ataxia, autosomal recessive 18, OMIM:616204 to Progressive cerebellar ataxia, HP:0002073; Spinocerebellar ataxia, autosomal recessive 18, OMIM:616204; autosomal recessive spinocerebellar ataxia 18, MONDO:0014530
Hereditary ataxia with onset in adulthood v8.19 GRID2 Eleanor Williams Mode of pathogenicity for gene: GRID2 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
Catecholaminergic polymorphic VT v5.3 Achchuthan Shanmugasundram Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Ataxia and cerebellar anomalies - narrow panel v8.50 GRID2 Eleanor Williams Phenotypes for gene: GRID2 were changed from Spinocerebellar ataxia, autosomal recessive 18, 616204 to Spinocerebellar ataxia, autosomal recessive 18, 616204; Progressive cerebellar ataxia, HP:0002073; autosomal recessive spinocerebellar ataxia 18, MONDO:0014530
Ataxia and cerebellar anomalies - narrow panel v8.49 GRID2 Eleanor Williams Mode of pathogenicity for gene: GRID2 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
Ataxia and cerebellar anomalies - narrow panel v8.48 GRID2 Eleanor Williams Publications for gene: GRID2 were set to 25841024
Bardet Biedl syndrome v2.9 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Autoinflammatory disorders v2.35 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Ataxia and cerebellar anomalies - narrow panel v8.47 Achchuthan Shanmugasundram Panel types changed to Component Of Super Panel; GMS signed-off
Adult onset leukodystrophy v6.8 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Rare anaemia v3.17 PPOX Sharon Whatley Deleted their review
Rare anaemia v3.17 PPOX Sharon Whatley Deleted their comment
Congenital hyperinsulinism v3.5 HK1 Sarah Flanagan reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 40033430, PMID: 36333503; Phenotypes: Congenital Hyperinsulinism, hyperinsulinaemic hypoglycaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Polycystic liver disease v1.31 PKHD1 Florentina Sava reviewed gene: PKHD1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 28375157, PMID: 21945273, PMID: 30600684, PMID: 33554127, Internal Sheffield data, KDIGO guidelines, ClinGen PKHD1 gene; Phenotypes: Ductal plate malformation, Polycystic liver disease, Congenital hepatic fibrosis, Caroli's disease, Biliary dysplasia; Mode of inheritance: Other; Current diagnostic: yes
Cholestasis v3.16 SCYL1 Ida Ertmanska commented on gene: SCYL1: Comment on list classification: As reviewed by Karen Stals, biallelic mutations in SCYL1 were reported in at least 7 pedigrees where affected individuals presented with acute liver failure with onset in infancy / early childhood. Based on available evidence, this gene should be promoted to Green for Cholestasis.
Cholestasis v3.16 SCYL1 Ida Ertmanska Phenotypes for gene: SCYL1 were changed from Liver failure; cholestasis; ataxia; peripheral neuropathy; cerebellar atrophy to cholestasis, MONDO:0001751; acute liver failure, MONDO:0019542; Spinocerebellar ataxia, autosomal recessive 21, OMIM:616719
Cholestasis v3.15 SCYL1 Ida Ertmanska Publications for gene: SCYL1 were set to PMID: 30842961; PMID: 33442927; PMID: 30842961; PMID: 29419818
Cholestasis v3.14 SCYL1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: SCYL1.
Cholestasis v3.14 SCYL1 Ida Ertmanska reviewed gene: SCYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29419818, 30842961, 33442927; Phenotypes: cholestasis, MONDO:0001751, acute liver failure, MONDO:0019542, Spinocerebellar ataxia, autosomal recessive 21, OMIM:616719; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v7.92 BRAF Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: BRAF.
Paediatric or syndromic cardiomyopathy v7.92 BRAF Ida Ertmanska reviewed gene: BRAF: Rating: GREEN; Mode of pathogenicity: None; Publications: 19206169; Phenotypes: Cardiofaciocutaneous syndrome, OMIM:115150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v6.135 CYP11A1 Ida Ertmanska reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11502818, 29995203, 30620006, 35418949, 39457196; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital adrenal hypoplasia v4.10 CYP11A1 Ida Ertmanska Publications for gene: CYP11A1 were set to 11502818; 29995203; 31671693; 12161514; 15507506; 16705068; 18182448; 19116240
Congenital adrenal hypoplasia v4.9 CYP11A1 Ida Ertmanska Phenotypes for gene: CYP11A1 were changed from Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743 to drenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743; Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400
Differences in sex development v4.13 CYP11A1 Ida Ertmanska Phenotypes for gene: CYP11A1 were changed from Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743 to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743; Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400
Differences in sex development v4.12 CYP11A1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: CYP11A1.
Differences in sex development v4.12 CYP11A1 Ida Ertmanska edited their review of gene: CYP11A1: Added comment: Comment on mode of inheritance: There are only two potentially plausible reports of heterozygous CYP11A1 variants and adrenal insufficiency / differences in sex development (PMIDs: 29995203, 11502818). In contrast, there are at least 44 biallelic CYP11A1 cases with adrenal insufficiency and/or differences in sex development. Studies have shown that severe CYP11A1 LOF variants in conjunction with common, 'likely benign' variants (e.g., rs6161 in European populations) may underlie unsolved cases of PAI (PMID:30620006). Hence, the mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal, for Differences in sex development.; Changed rating: GREEN; Changed publications to: 11502818, 29995203, 30620006, 35418949, 39457196; Changed phenotypes to: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences in sex development v4.12 CYP11A1 Ida Ertmanska commented on gene: CYP11A1
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: CYP11A1.
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska edited their review of gene: CYP11A1: Changed publications to: 11502818, 29995203, 30620006, 35418949, 39457196
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska changed review comment from: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic?

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).; to: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 biallelic cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic?

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska commented on gene: CYP11A1: Comment on mode of inheritance: There are only two potentially plausible reports of heterozygous CYP11A1 variants and adrenal insufficiency (PMIDs: 29995203, 11502818). In contrast, there are at least 44 biallelic CYP11A1 cases with adrenal insufficiency and/or differences in sex development. Studies have shown that severe CYP11A1 LOF variants in conjunction with common, 'likely benign' variants (e.g., rs6161 in European populations) may underlie unsolved cases of PAI (PMID:30620006). Hence, the mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal, for Congenital adrenal hypoplasia.
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska changed review comment from: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).; to: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic?

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska changed review comment from: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).; to: PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 homozygous cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).
Congenital adrenal hypoplasia v4.8 CYP11A1 Ida Ertmanska reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11502818, 29995203, 35418949, 39457196; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.236 SLITRK2 Mike Spiller gene: SLITRK2 was added
gene: SLITRK2 was added to Intellectual disability. Sources: NHS GMS,Literature
Mode of inheritance for gene: SLITRK2 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: SLITRK2 were set to PMID: 35840571
Review for gene: SLITRK2 was set to GREEN
Added comment: Gene is associated with Intellectual developmental disorder, X-linked 111 (OMIM 301107).
Association based on PMID: 35840571 - 7 probands, 6 male one female. Female de novo, males mix of de novo and maternally inherited. ID levels range from borderline-severe, 5 patients moderate-severe.
One LOF, others missenses distributed through the gene. Missenses well supported by mouse data including inability to rescue KO phenotypes, as well as HEK293 transcfection studies..

Also 2 hemizygous LOF on CVA with consistent phenotypes (NHS GMS).
Sources: NHS GMS, Literature
Skeletal dysplasia v8.30 FGFR3 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FGFR3.
Skeletal dysplasia v8.30 FGFR3 Ida Ertmanska edited their review of gene: FGFR3: Added comment: Comment on mode of inheritance: FGFR3 variants are associated with several dominant conditions that include skeletal dysplasia. However, evidence of recessive inheritance is lacking. To date, one family has been reported with autosomal recessive Camptodactyly-Tall Stature-Scoliosis-Hearing Loss (CATSHL) syndrome. 3 other families were reported with a dominantly inherited CATSHL syndrome. All dominant cases involve a missense change at the same residue (621), while recessive disease was cause by a missense variant p.Thr546Lys. The mode of inheritance for FGFR3 should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted for Skeletal dysplasia, until more cases emerge in support of recessive inheritance.; Changed publications to: 17033969, 24864036, 27139183, 37990933; Changed phenotypes to: CATSHL syndrome, OMIM:610474, camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504
Skeletal dysplasia v8.30 FGFR3 Ida Ertmanska reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arthrogryposis v9.18 FGFR3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 20th Jan 2026.
Arthrogryposis v9.18 FGFR3 Ida Ertmanska Phenotypes for gene: FGFR3 were changed from CATSHL syndrome, OMIM:610474; camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504 to CATSHL syndrome, OMIM:610474; camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504
Arthrogryposis v9.17 FGFR3 Ida Ertmanska Phenotypes for gene: FGFR3 were changed from CATSHL syndrome 610474 to CATSHL syndrome, OMIM:610474; camptodactyly-tall stature-scoliosis-hearing loss syndrome, MONDO:0012504
Arthrogryposis v9.16 FGFR3 Ida Ertmanska Publications for gene: FGFR3 were set to 17033969
Arthrogryposis v9.15 FGFR3 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FGFR3.
Arthrogryposis v9.15 FGFR3 Ida Ertmanska commented on gene: FGFR3: Comment on mode of inheritance: Mutations in FGFR3 may rarely cause Camptodactyly-Tall Stature-Scoliosis-Hearing Loss (CATSHL) syndrome. To date, 3 families with dominant and 1 with recessive CATSHL syndrome have been reported. All dominant cases involve a missense change at the same residue (621), while recessive disease was cause by a missense variant p.Thr546Lys. The mode of inheritance for FGFR3 should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted for Arthrogryposis, until more cases emerge in support of recessive inheritance.
Arthrogryposis v9.15 FGFR3 Ida Ertmanska reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17033969, 24864036, 27139183, 37990933; Phenotypes: CATSHL syndrome, OMIM:610474; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Non-acute porphyrias v1.34 HMBS Ida Ertmanska Tag to_be_confirmed_NHSE was removed from gene: HMBS.
Non-acute porphyrias v1.34 HMBS Ida Ertmanska Added comment: Comment on mode of inheritance: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Green. GMS reviewers note that this panel is used for biochemically undiagnosed porphyria - acute and non-acute. The MOI was updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as suggested by the NHS Genomic Medicine Service.
Non-acute porphyrias v1.34 HMBS Ida Ertmanska Mode of inheritance for gene: HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic short stature v1.30 SHOX Achchuthan Shanmugasundram Tag technical-limitations tag was added to gene: SHOX.
Possible mitochondrial disorder - nuclear genes v4.19 BTD Ida Ertmanska changed review comment from: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains green.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains green. ClinGen mitochondrial gene curation expert panel classified the association between BTD and Leigh syndrome as Moderate. Biotinidase deficiency leads to deficiency of a number of carboxylases including pyruvate carboxylase (PC) and PC is also a green gene on this panel.
Cytopenia - NOT Fanconi anaemia v4.31 RPL17 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotype in OMIM (MIM #621262) and this OMIM record was last accessed on 20 January 2026.
Cytopenia - NOT Fanconi anaemia v4.31 RPL17 Achchuthan Shanmugasundram Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia, MONDO:0015253 to Diamond-Blackfan anemia 22, OMIM:621262; Diamond-Blackfan anemia 22, MONDO:0979244
Cytopenia - NOT Fanconi anaemia v4.30 RPL17 Achchuthan Shanmugasundram edited their review of gene: RPL17: Changed phenotypes to: Diamond-Blackfan anemia 22, OMIM:621262, Diamond-Blackfan anemia 22, MONDO:0979244
Rare anaemia v3.17 RPL17 Achchuthan Shanmugasundram commented on gene: RPL17: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

The GMS reviewers noted that it would be appropriate to add this gene with green rating to R92 Rare anaemia in addition to R91 Cytopenia - NOT Fanconi anaemia.
Rare anaemia v3.17 RPL17 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #621262) and this OMIM record was last accessed on 20 January 2026.
Rare anaemia v3.17 RPL17 Achchuthan Shanmugasundram Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia, MONDO:0015253 to Diamond-Blackfan anemia 22, OMIM:621262; Diamond-Blackfan anemia 22, MONDO:0979244
Rare anaemia v3.16 RPL17 Achchuthan Shanmugasundram edited their review of gene: RPL17: Changed phenotypes to: Diamond-Blackfan anemia 22, OMIM:621262, Diamond-Blackfan anemia 22, MONDO:0979244
Rare anaemia v3.16 RPL17 Achchuthan Shanmugasundram Deleted their comment
Rare anaemia v3.16 RPL17 Achchuthan Shanmugasundram Entity copied from Cytopenia - NOT Fanconi anaemia v4.30
Rare anaemia v3.16 RPL17 Achchuthan Shanmugasundram gene: RPL17 was added
gene: RPL17 was added to Rare anaemia. Sources: Expert Review Green,NHS GMS,Literature
Mode of inheritance for gene: RPL17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL17 were set to 39088281
Phenotypes for gene: RPL17 were set to Diamond-Blackfan anemia, MONDO:0015253
Penetrance for gene: RPL17 were set to Incomplete
Monogenic short stature v1.30 SHOX Achchuthan Shanmugasundram Classified gene: SHOX as Amber List (moderate evidence)
Monogenic short stature v1.30 SHOX Achchuthan Shanmugasundram Gene: shox has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.29 SHOX Achchuthan Shanmugasundram reviewed gene: SHOX: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hypogonadotropic hypogonadism (GMS) v4.4 PROKR2 Ida Ertmanska Phenotypes for gene: PROKR2 were changed from Hypogonadotropic hypogonadism type 3 (OMIM 244200) to Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200
Early onset or syndromic epilepsy v8.95 AIMP2 Ida Ertmanska Tag watchlist was removed from gene: AIMP2.
Tag Q1_26_promote_green tag was added to gene: AIMP2.
Intellectual disability v9.236 AIMP2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: AIMP2.
Intellectual disability v9.236 AIMP2 Ida Ertmanska edited their review of gene: AIMP2: Added comment: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic AIMP2 variants and a complex neurodevelopmental phenotype. 5/6 presentations included syndromic ID/DD. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.; Changed rating: GREEN; Changed publications to: 26795593, 35140751, 35568357, 38374194; Changed phenotypes to: Leukodystrophy, hypomyelinating, 17, OMIM:618006; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.236 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.

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 2025). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025).
Intellectual disability v9.236 AIMP2 Ida Ertmanska commented on gene: AIMP2
Early onset or syndromic epilepsy v8.95 AIMP2 Ida Ertmanska Phenotypes for gene: AIMP2 were changed from Epileptic Encephalopathy; Infantile Spasms; Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17, OMIM:618006
Early onset or syndromic epilepsy v8.94 AIMP2 Ida Ertmanska Publications for gene: AIMP2 were set to 29215095; 26795593
Early onset or syndromic epilepsy v8.93 AIMP2 Ida Ertmanska edited their review of gene: AIMP2: Changed phenotypes to: Leukodystrophy, hypomyelinating, 17, OMIM:618006
Early onset or syndromic epilepsy v8.93 AIMP2 Ida Ertmanska edited their review of gene: AIMP2: Added comment: Comment on list classification: There are at least 6 unrelated individuals reported with biallelic variants in AIMP2, of which 5 presented with seizures / epilepsy. Based on available evidence, this gene should be promoted to Green at the next GMS update.; Changed publications to: 35140751, 35568357, 38374194; Changed phenotypes to: eukodystrophy, hypomyelinating, 17, OMIM:618006
Early onset or syndromic epilepsy v8.93 AIMP2 Ida Ertmanska reviewed gene: AIMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.78 AIPL1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: AIPL1.
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: Comment on list classification: There is limited evidence for the association of AIPL1 and autosomal dominant cone-rod dystrophy. The overwhelming majority of reported patients has biallelic AIPL1 variants, with heterozygous carriers being unaffected. Variant AIPL1 (p.Ala352_Pro355del) has the most supporting evidence for pathogenicity. However, the allele frequency in control populations is too high to cause dominant disease. In addition, the gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen. Based on available evidence, the MOI should be changed to BIALLELIC.; to: Comment on list classification: There is limited evidence for the association of AIPL1 and autosomal dominant cone-rod dystrophy. An overwhelming majority of reported patients harbour biallelic AIPL1 variants, with heterozygous carriers being unaffected. Variant p.Ala352_Pro355del in AIPL1 has the most supporting evidence for pathogenicity. However, the allele frequency in control populations is too high to cause dominant disease (MAF = 0.01129). In addition, the gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen. Based on available evidence, the MOI should be changed to BIALLELIC.
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported. Method: WES in proband, Sanger seq in family members.
The same mutation (p.W278X) was found in homozygosity in 5 Italian families and in compound het state with another AIPL1 mutation in 3 other families with recessive LCA (PMID: 21474771). Unlikely to be pathogenic dominant.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease.

Supporting functional evidence:
PMID: 33067476 Sacristan-Reviriego et al., 2020 - poses that this deletion has an alternative pathogenicity mechanism: PRD-mediated dominant negative effect causing cone-rod dystrophy
PMID: 25274777 Ku et al., 2015 - mouse model where p.A352_P355del human AIPL1 transgene was expressed in an Aipl1 null background. In single transgenic mice, the mutant transgene led to a cone-rod dystrophy phenotype, predominantly leading to a slow and progressive cone degeneration.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

PMID: 21900377 Pennesi et al., 2011
Family 1: patient was found to have a homozygous Trp278 stop mutation in AIPL1; family 2: two siblings were compound heterozygous for AIPL1 (Leu17Pro and Lys214Asn). Variants confirmed in trans, het parents and sister unaffected. Sequenced 14 LCA-causing genes.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.; to: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported. Method: WES in proband, Sanger seq in family members.
The same mutation (p.W278X) was found in homozygosity in 5 Italian families and in compound het state with another AIPL1 mutation in 3 other families with recessive LCA (PMID: 21474771). Unlikely to be pathogenic dominant.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease.

Supporting functional evidence:
PMID: 33067476 Sacristan-Reviriego et al., 2020 - poses that this deletion has an alternative pathogenicity mechanism: PRD-mediated dominant negative effect causing cone-rod dystrophy
PMID: 25274777 Ku et al., 2015 - mouse model where p.A352_P355del human AIPL1 transgene was expressed in an Aipl1 null background. In single transgenic mice, the mutant transgene led to a cone-rod dystrophy phenotype, predominantly leading to a slow and progressive cone degeneration.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

PMID: 21900377 Pennesi et al., 2011
Family 1: patient was found to have a homozygous Trp278 stop mutation in AIPL1; family 2: two siblings were compound heterozygous for AIPL1 (Leu17Pro and Lys214Asn). Variants confirmed in trans, het parents and sister unaffected. Sequenced 14 LCA-causing genes.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.
Retinal disorders v8.78 AIPL1 Ida Ertmanska edited their review of gene: AIPL1: Added comment: Comment on list classification: There is limited evidence for the association of AIPL1 and autosomal dominant cone-rod dystrophy. The overwhelming majority of reported patients has biallelic AIPL1 variants, with heterozygous carriers being unaffected. Variant AIPL1 (p.Ala352_Pro355del) has the most supporting evidence for pathogenicity. However, the allele frequency in control populations is too high to cause dominant disease. In addition, the gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen. Based on available evidence, the MOI should be changed to BIALLELIC.; Changed publications to: 10873396, 15249368, 21474771, 21900377, 24426771, 25274777, 31576779, 33067476, 38880373; Changed phenotypes to: Leber congenital amaurosis 4, OMIM:604393, Leber congenital amaurosis, MONDO:0018998
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025 (no PMID?)
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported.

PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

PMID: 21900377 Pennesi et al., 2011
The first patient was found to have a homozygous Trp278 stop mutation in AIPL1, whereas the siblings were each found to have novel heterozygous mutations in AIPL1 (Leu17Pro and Lys214Asn). Sequenced 14 LCA-causing genes.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.; to: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported. Method: WES in proband, Sanger seq in family members.
The same mutation (p.W278X) was found in homozygosity in 5 Italian families and in compound het state with another AIPL1 mutation in 3 other families with recessive LCA (PMID: 21474771). Unlikely to be pathogenic dominant.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease.

Supporting functional evidence:
PMID: 33067476 Sacristan-Reviriego et al., 2020 - poses that this deletion has an alternative pathogenicity mechanism: PRD-mediated dominant negative effect causing cone-rod dystrophy
PMID: 25274777 Ku et al., 2015 - mouse model where p.A352_P355del human AIPL1 transgene was expressed in an Aipl1 null background. In single transgenic mice, the mutant transgene led to a cone-rod dystrophy phenotype, predominantly leading to a slow and progressive cone degeneration.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

PMID: 21900377 Pennesi et al., 2011
Family 1: patient was found to have a homozygous Trp278 stop mutation in AIPL1; family 2: two siblings were compound heterozygous for AIPL1 (Leu17Pro and Lys214Asn). Variants confirmed in trans, het parents and sister unaffected. Sequenced 14 LCA-causing genes.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025 (no PMID?)
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported.

PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).; to: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025 (no PMID?)
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported.

PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

PMID: 21900377 Pennesi et al., 2011
The first patient was found to have a homozygous Trp278 stop mutation in AIPL1, whereas the siblings were each found to have novel heterozygous mutations in AIPL1 (Leu17Pro and Lys214Asn). Sequenced 14 LCA-causing genes.

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

PMID: 15249368 Dharmaraj et al., 2004
Cohort of 303 LCA patients. Identified seventeen homozygotes and 9 compound heterozygotes. The ERG of a parent heterozygote carrier (het for W88X) revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025). AIPL1-related Leber congenital amaurosis (biallelic_autosomal) is ranked Definitive in Gene2Phenotype.
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).; to: Monoallelic cases:
https://doi.org/10.1016/j.humgen.2025.201413 Ghavidel et al., 2025 (no PMID?)
1 yo Iranian boy, heterozygous for AIPL1: c.834G>A, p.Trp278*. Consanguineous parents. Diagnosed with Leber's congenital amaurosis at 6 months old. Variant has max AF = 0.0004415 in gnomAD v4 (European pop) with 1 homozygote reported.

PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

PMID: 10873396 Sohocki, et al., 2000
Identified 11 individuals with biallelic AIPL1 variants, as well as 2 apparently dominant pedigree, with affected individuals heterozygous (AIPL1):c.1053_1064del (p.Ala352_Pro355del). Heterozygous individuals presented with juvenile RP or dominant cone-rod dystrophy. Method: sequenced 6 exons of AIPL1 only. The pedigrees are small, dominant segregation not well established.

Biallelic cases:
PMID: 38880373 Zhang et al., 2024
Cohort of 51 Chinese patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD); identified 28 disease-causing AIPL1 variants - biallelic cases only. Most common variant in the cohort was c.421C>T, p.Gln141* (18 patients homozygous, 6 heterozygous + another LoF variant).

PMID: 31576779 Wan et al., 2019
2 sibs with Leber congenital amaurosis, homozygous for AIPL1 p.Gln81* variant. Parents both heterozygous for the variant, unaffected.

PMID: 24426771 Li et al., 2014
Report of autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Homozygous AIPL1: c.773G>C (p.Arg258Pro) variant detected in family 61032, and a homozygous AIPL1: c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Heterozygous carriers had no signs of retinitis pigmentosa.

https://doi.org/10.1007/s13258-016-0467-6 Moghadam, Vallian & Vallian, 2017
Same homozygous AIPL1 p.W278* identified in 3 Iranian individuals with LCA with no known consanguinity - likely Iranian founder variant.

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).
Hereditary ataxia with onset in adulthood v8.18 GRID2 Ida Ertmanska changed review comment from: Comment on list classification: While most reported GRID2-related SCA cases show autosomal recessive inheritance, there are at least 3 unrelated pedigrees described with missense variants in GRID2 M3S2 pore domain, causing dominant / semidominant cerebellar ataxia. One childhood onset case was reported, with a homozygous missense variant in the M3 domain. The heterozygous individuals had first ataxia symptoms in adulthood, which is in the scope of this panel. Hence, the mode of inheritance should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for this panel.; to: Comment on list classification: While most reported GRID2-related SCA cases show autosomal recessive inheritance, there are at least 3 unrelated pedigrees described with missense variants in GRID2 M3S2 pore domain, causing dominant / semidominant cerebellar ataxia. One childhood onset case was reported, with a homozygous missense variant in the M3 domain. The heterozygous individuals had first ataxia symptoms in adulthood, which is in the scope of this panel. Functional evidence in mouse models supports this mechanism of disease. Hence, the mode of inheritance should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for this panel.
Hereditary ataxia with onset in adulthood v8.18 GRID2 Ida Ertmanska commented on gene: GRID2: Comment on list classification: While most reported GRID2-related SCA cases show autosomal recessive inheritance, there are at least 3 unrelated pedigrees described with missense variants in GRID2 M3S2 pore domain, causing dominant / semidominant cerebellar ataxia. One childhood onset case was reported, with a homozygous missense variant in the M3 domain. The heterozygous individuals had first ataxia symptoms in adulthood, which is in the scope of this panel. Hence, the mode of inheritance should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for this panel.
Hereditary ataxia with onset in adulthood v8.18 GRID2 Ida Ertmanska Phenotypes for gene: GRID2 were changed from Spinocerebellar ataxia, autosomal recessive 18, 616204 to Progressive cerebellar ataxia, HP:0002073; Spinocerebellar ataxia, autosomal recessive 18, OMIM:616204
Hereditary ataxia with onset in adulthood v8.17 GRID2 Ida Ertmanska Publications for gene: GRID2 were set to 25841024
Hereditary ataxia with onset in adulthood v8.16 GRID2 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: GRID2.
Hereditary ataxia with onset in adulthood v8.16 GRID2 Ida Ertmanska reviewed gene: GRID2: 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: 9285588, 21460832, 25841024, 35882834, 37944084; Phenotypes: Progressive cerebellar ataxia, HP:0002073, Spinocerebellar ataxia, autosomal recessive 18, OMIM:616204; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 GRID2 Ida Ertmanska edited their review of gene: GRID2: Added comment: Comment on list classification: While most reported GRID2-related SCA cases show autosomal recessive inheritance, there are 3 unrelated pedigrees described with missense variants in GRID2 M3S2 pore domain, causing dominant / semidominant cerebellar ataxia. One childhood onset case was reported, with a homozygous missense variant in the M3 domain. The heterozygous individuals had first ataxia symptoms in adulthood, which is not in the scope of this panel. Hence, GRID2 should remain Green with a BIALLELIC mode of inheritance, until more evidence emerges.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 GRID2 Ida Ertmanska reviewed gene: GRID2: 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: 9285588, 21460832, 25841024, 35882834, 37944084; Phenotypes: Progressive cerebellar ataxia, HP:0002073; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.93 DHDDS Ida Ertmanska reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 38451541; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v8.46 SCN8A Ida Ertmanska reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v8.78 MORC2 Siying Lin gene: MORC2 was added
gene: MORC2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to PMID: 36791574, 32693025
Phenotypes for gene: MORC2 were set to Retinal dystrophy
Penetrance for gene: MORC2 were set to unknown
Mode of pathogenicity for gene: MORC2 was set to Other
Review for gene: MORC2 was set to GREEN
Added comment: PMID 32693025 - 5 out of 6 affected individuals who had dilated eye exams had retinal pigmentary abnormalities
PMID 36791574 - retinopathy seen in at least 3 out of 7 affected individuals
Sources: Literature
Early onset or syndromic epilepsy v8.93 CRNKL1 John Taylor reviewed gene: CRNKL1: 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: 40857589; Phenotypes: microcephaly, pontocerebellar hypoplasia, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.93 C12orf66 John Taylor reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: None; Publications: 39824192; Phenotypes: Seizure, Intellectual disability, delayed speech.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.93 BRSK1 John Taylor reviewed gene: BRSK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 41035394; Phenotypes: Epilepsy, global developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).; to: PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: PMID: 33067476 Sacristan-Reviriego A, et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).; to: PMID: 33067476 Sacristan-Reviriego et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).
Retinal disorders v8.78 AIPL1 Ida Ertmanska changed review comment from: PMID: 33067476 Sacristan-Reviriego A, et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported; to: PMID: 33067476 Sacristan-Reviriego A, et al., 2020
Mutation NM_014336.5(AIPL1):c.1053_1064del (p.Ala352_Pro355del) has MAF of 0.01129 (Ashkenazi Jewish population) in gnomAD v4.1.0, and 3 total homozygotes reported - too high to cause dominant disease

The gene-disease relationship between AIPL1 and autosomal dominant retinal dystrophy has been classified as Disputed in ClinGen (Retina GCEP, April 2025).
Retinal disorders v8.78 AIPL1 Ida Ertmanska reviewed gene: AIPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33067476; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.236 WASHC5 Ida Ertmanska changed review comment from: Comment on list classification: There are two unrelated families reported in literature with biallelic variants in WASHC5 and Ritscher-Schinzel syndrome, including intellectual disability. In addition, washc5 knockout studies in zebrafish recapitulated the human phenotype and showed disrupted nervous development. Based on available evidence, this gene should be promoted to Green for Intellectual disability.; to: Comment on list classification: Evidence for this gene disease association includes a Caucasian family with four affected siblings, eight individuals from a first nations Canadian cohort, and a functional animal model. Individuals reported in literature with biallelic variants in WASHC5 were diagnosed with Ritscher-Schinzel syndrome, which includes intellectual disability. In addition, washc5 knockout studies in zebrafish recapitulated the human phenotype and showed disrupted nervous development. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.236 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025). Ritscher-Schinzel syndrome is associated with biallelic LoF variants, while Spastic paraplegia arises from GoF monoallelic variants in WASHC5.; to: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5 (KIAA0196). 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025). Ritscher-Schinzel syndrome is associated with biallelic LoF variants, while Spastic paraplegia arises from GoF monoallelic variants in WASHC5.
Paediatric or syndromic cardiomyopathy v7.92 GATA6 Ida Ertmanska commented on gene: GATA6
Dilated and arrhythmogenic cardiomyopathy v3.10 GATA6 Ida Ertmanska commented on gene: GATA6
Dilated and arrhythmogenic cardiomyopathy v3.10 SGCD Ida Ertmanska Tag disputed was removed from gene: SGCD.
Paediatric or syndromic cardiomyopathy v7.92 SGCD Ida Ertmanska commented on gene: SGCD
Dilated and arrhythmogenic cardiomyopathy v3.10 SGCD Ida Ertmanska commented on gene: SGCD
Dilated and arrhythmogenic cardiomyopathy v3.10 SGCD Ida Ertmanska Tag disputed tag was added to gene: SGCD.
Early onset or syndromic epilepsy v8.93 CELSR3 Achchuthan Shanmugasundram Classified gene: CELSR3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.93 CELSR3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in CELSR3 gene with epilepsy/ seizures (five families with each MOI). Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.93 CELSR3 Achchuthan Shanmugasundram Gene: celsr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.92 CELSR3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: CELSR3.
Early onset or syndromic epilepsy v8.92 CELSR3 Achchuthan Shanmugasundram gene: CELSR3 was added
gene: CELSR3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CELSR3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to 34951123; 38429302
Phenotypes for gene: CELSR3 were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: CELSR3 was set to GREEN
Added comment: PMID:34951123 (2022) reported trio-based whole-exome sequencing in a cohort of 462 cases with febrile seizures (FS)/ epilepsy with antecedent FS (EFS+), where five heterozygous missense variants in CELSR3 gene were identified in eight individuals from five unrelated families. All affected individuals were diagnosed with FS/EFS+, including six patients with FS and two patients with EFS+. All cases presented favorable outcomes without neurodevelopmental disorders.

PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Seizures were reported in six patients from five unrelated families.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 13 January 2026) or ClinGen, but biallelic CELSR3 variants have been associated with 'limited' rating on the DD panel of Gene2Phenotype.
Sources: Literature
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram changed review comment from: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Individuals with predominant CNS or combined CNS and CAKUT phenotypes presented with intellectual disability and/or developmental delay (ID/DD), hypotonia, seizures, brain malformations, NTDs, macro- or microcephaly. ID was present in five patients, GDD in one and DD alone in 2 patients.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.
Sources: Literature; to: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Individuals with predominant CNS or combined CNS and CAKUT phenotypes presented with intellectual disability and/or developmental delay (ID/DD), hypotonia, seizures, brain malformations, NTDs, macro- or microcephaly. ID was present in five patients, GDD in one and DD alone in 2 patients.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 13 January 2026) or ClinGen, but biallelic CELSR3 variants have been associated with 'limited' rating on the DD panel of Gene2Phenotype.
Sources: Literature
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram Classified gene: CELSR3 as Amber List (moderate evidence)
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight patients with ID/DD) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.236 CELSR3 Achchuthan Shanmugasundram Gene: celsr3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.235 CELSR3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: CELSR3.
Intellectual disability v9.235 CELSR3 Achchuthan Shanmugasundram gene: CELSR3 was added
gene: CELSR3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CELSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to 38429302
Phenotypes for gene: CELSR3 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CELSR3 was set to GREEN
Added comment: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Individuals with predominant CNS or combined CNS and CAKUT phenotypes presented with intellectual disability and/or developmental delay (ID/DD), hypotonia, seizures, brain malformations, NTDs, macro- or microcephaly. ID was present in five patients, GDD in one and DD alone in 2 patients.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.
Sources: Literature
Intellectual disability v9.234 PHF12 Sophie Ellis gene: PHF12 was added
gene: PHF12 was added to Intellectual disability. Sources: ClinGen
Mode of inheritance for gene: PHF12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Penetrance for gene: PHF12 were set to unknown
Mode of pathogenicity for gene: PHF12 was set to Other
Review for gene: PHF12 was set to GREEN
gene: PHF12 was marked as current diagnostic
Added comment: ClinGen Definitive Classification - 02/19/2025
Sources: ClinGen
Adult onset hereditary spastic paraplegia v6.5 GJC2 Ida Ertmanska commented on gene: GJC2: Comment on list classification: There are at least 3 families reported in literature with individuals affected by late-onset spastic paraplegia harbouring biallelic missense variants in GJC2. In one family, 3 siblings with the same homozygous GJC2 variant presented with a variable phenotype (1 sibling diagnosed with spastic paraplegia, and 2 sibs with hypomyelinating leukodystrophy), which may indicate the two disease entities are part of a spectrum. All individuals presented with lower limb spasticity and pyramidal disturbances. Based on available evidence, this gene should be promoted to Green for Adult onset hereditary spastic paraplegia.
Childhood onset hereditary spastic paraplegia v8.26 GJC2 Ida Ertmanska Phenotypes for gene: GJC2 were changed from Spastic paraplegia 44, autosomal recessive; Leukodystrophy, hypomyelinating,2, 608804, AR; Spastic paraplegia 44, autosomal recessive, 613206, AR; Lymphatic malformation 3, 613480, AD to ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Leukodystrophy, hypomyelinating, 2, OMIM:608804
Adult onset hereditary spastic paraplegia v6.5 GJC2 Ida Ertmanska Phenotypes for gene: GJC2 were changed from Spastic paraplegia 44, autosomal recessive; Spastic paraplegia 44, autosomal recessive 613206, AR; Leukodystrophy, hypomyelinating, 2, 608804, AR to ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Leukodystrophy, hypomyelinating, 2, OMIM:608804
Adult onset hereditary spastic paraplegia v6.4 GJC2 Ida Ertmanska Publications for gene: GJC2 were set to Orthmann-Murphy et al. (2009); 19056803
Adult onset hereditary spastic paraplegia v6.3 GJC2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: GJC2.
Adult onset hereditary spastic paraplegia v6.3 GJC2 Ida Ertmanska reviewed gene: GJC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19056803, 22833003, 31431325, 37915394; Phenotypes: ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.25 GJC2 Ida Ertmanska Publications for gene: GJC2 were set to Orthmann-Murphy et al. (2009); 19056803
Childhood onset hereditary spastic paraplegia v8.24 GJC2 Ida Ertmanska reviewed gene: GJC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 19056803, 22833003, 31431325, 37915394; Phenotypes: ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.25 ALPL Claire Smith gene: ALPL was added
gene: ALPL was added to Amelogenesis imperfecta. Sources: Literature,Expert Review
Mode of inheritance for gene: ALPL was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Penetrance for gene: ALPL were set to Complete
Review for gene: ALPL was set to GREEN
Added comment: According to the review of ALPL literature, PMID: 39872235
"78.8% of adults with pediatric-onset HPP have dental involvement vs 42.6% of those with adult-onset HPP."
"clinical observations can include enamel hypoplasia and discoloration (possibly contributing to increased caries prevalence), delayed tooth eruption, tooth mobility, and malocclusion (misalignment of upper and lower teeth due to incorrect positions along the dental arches)"

(Note that enamel hypoplasia, although it can mean just specific teeth being affected, is also a term often used to reflect amelogenesis imperfecta in the presence of diseases affecting other organ systems, this is because the original definition of amelogenesis imperfecta excluded it being part of syndromic diseases, this is now changing)

According to Chavez et al.'s ALPL review PMID: 32758526
"Ameloblasts, odontoblasts, cementoblasts, osteoblasts, and periodontal ligament (PDL) cells express TNAP (encoded by ALPL) ( (Bowden and Foster, 2019, Zweifler et al., 2015), indicating the enzyme may function in all aspects of dental and periodontal mineralization."

ALPL is also included on the panel used by Fulgent genetics to screen patients with amelogenesis imperfecta
https://fulgentgenetics.com/Amelogenesis-Imperfecta
Sources: Literature, Expert Review
Optic neuropathy v5.43 SDHA Ida Ertmanska Phenotypes for gene: SDHA were changed from Leigh syndrome, 256000; mitochondrial respiratory chain complex II deficiency 252011 to Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Cardiomyopathy, dilated, 1GG, OMIM:613642; Pheochromocytoma/paraganglioma syndrome 5, OMIM:614165
Optic neuropathy v5.42 SDHA Ida Ertmanska Publications for gene: SDHA were set to 27683074
Optic neuropathy v5.41 SDHA Ida Ertmanska Mode of inheritance for gene: SDHA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v5.40 SDHA Ida Ertmanska Classified gene: SDHA as Amber List (moderate evidence)
Optic neuropathy v5.40 SDHA Ida Ertmanska Gene: sdha has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.39 SDHA Ida Ertmanska reviewed gene: SDHA: Rating: AMBER; Mode of pathogenicity: None; Publications: 27683074, 33471299; Phenotypes: Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cholestasis v3.14 SCYL1 Karen Stals changed review comment from: Multiple patients reported with biallelic variants in SCYL1, early presentation of liver failure and cholestasis in infancy(episodes may resolve), with later development of a neurological phenotype.
Sources: Literature; to: Multiple patients reported with biallelic variants in SCYL1, early presentation of liver failure and cholestasis in infancy (episodes may resolve), with later development of a neurological phenotype.
Sources: Literature
Cholestasis v3.14 SCYL1 Karen Stals gene: SCYL1 was added
gene: SCYL1 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: SCYL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCYL1 were set to PMID: 30842961; PMID: 33442927; PMID: 30842961; PMID: 29419818
Phenotypes for gene: SCYL1 were set to Liver failure; cholestasis; ataxia; peripheral neuropathy; cerebellar atrophy
Penetrance for gene: SCYL1 were set to Complete
Review for gene: SCYL1 was set to GREEN
gene: SCYL1 was marked as current diagnostic
Added comment: Multiple patients reported with biallelic variants in SCYL1, early presentation of liver failure and cholestasis in infancy(episodes may resolve), with later development of a neurological phenotype.
Sources: Literature
Confirmed Fanconi anaemia or Bloom syndrome v2.9 RAD51C Achchuthan Shanmugasundram Mode of inheritance for gene: RAD51C was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.234 WASHC4 Ida Ertmanska Phenotypes for gene: WASHC4 were changed from Mental retardation, autosomal recessive 43, 615817 to Intellectual developmental disorder, autosomal recessive 43, OMIM:615817
Intellectual disability v9.233 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).; to: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025). Ritscher-Schinzel syndrome is associated with biallelic LoF variants, while Spastic paraplegia arises from GoF monoallelic variants in WASHC5.
Intellectual disability v9.233 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355
8 patients with Ritscher-Schinzel syndromefrom a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).
; to: PMID: 24065355 Elliot et al., 2013
8 patients with Ritscher-Schinzel syndrome from a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).
Intellectual disability v9.233 WASHC5 Ida Ertmanska commented on gene: WASHC5: Comment on list classification: There are two unrelated families reported in literature with biallelic variants in WASHC5 and Ritscher-Schinzel syndrome, including intellectual disability. In addition, washc5 knockout studies in zebrafish recapitulated the human phenotype and showed disrupted nervous development. Based on available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.233 WASHC5 Ida Ertmanska edited their review of gene: WASHC5: Changed publications to: 24065355, 36130690, 39988189
Intellectual disability v9.233 WASHC5 Ida Ertmanska changed review comment from: PMID: 24065355
8 patients with Ritscher-Schinzel syndromefrom a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.; to: PMID: 24065355
8 patients with Ritscher-Schinzel syndromefrom a first nations cohort in Canada. All homozygous for a novel splice site mutation c.3335+2T>A in WASHC5. 60% reduction in protein levels was shown in affected patients - demonstrated LoF effect.

PMID: 36130690 Neri et al., 2022
4 siblings carried compound heterozygous variants in WASHC5: c.232C>T, p.Gln78* & c.2489G>A, p.Arg830Gln. Patient 1, a 5yo live born female, and 3 fetal cases (terminated early based on elevated nuchal transluscency). Parents were confirmed as heterozygous for a variant each. All individuals presented with craniofacial dysmorphism, ID/DD, ataxic gait. Family 1: Patient 1 had severe intellectual disability. Cerebellar hypoplasia was noted on brain MRI.

Functional: PMID: 39988189 Wei et al., 2025 - washc5 knockout zebrafish showed disrupted maxillofacial, cardiovascular, and nervous development.

WASHC5 is associated with AR Ritscher-Schinzel syndrome 1, MIM:220210 and Spastic paraplegia 8, autosomal dominant, MIM:603563 (OMIM accessed 9th Jan 2025).
Intellectual disability v9.233 WASHC5 Ida Ertmanska Phenotypes for gene: WASHC5 were changed from Spastic paraplegia 8, autosomal dominant, 603563; Ritscher-Schinzel syndrome, 220210 to Ritscher-Schinzel syndrome, OMIM:220210, Ritscher-Schinzel syndrome, MONDO:0019078
Intellectual disability v9.232 WASHC4 Ida Ertmanska changed review comment from: Comment on list classification: Based on new guidance from our clinical team, syndromic intellectual disability cases should be included on this panel. There are 3 unrelated families with individuals affected by syndromic ID, harbouring biallelic variants in WASHC4. Hence, WASHC4 should be promoted to Green for Intellectual disability at the next GMS update.; to: Comment on list classification: Based on new guidance from our clinical team, syndromic intellectual disability cases should be included on this panel - regardless of severity. There are 3 unrelated families with individuals affected by syndromic ID, harbouring biallelic variants in WASHC4. Hence, WASHC4 should be promoted to Green for Intellectual disability at the next GMS update.
Intellectual disability v9.232 WASHC4 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: WASHC4.
Intellectual disability v9.232 WASHC5 Ida Ertmanska Publications for gene: WASHC5 were set to 24065355; 24916641
Intellectual disability v9.231 WASHC5 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: WASHC5.
Intellectual disability v9.231 WASHC5 Ida Ertmanska edited their review of gene: WASHC5: Changed publications to: 24065355, 36130690; Changed phenotypes to: Ritscher-Schinzel syndrome, OMIM:220210, Ritscher-Schinzel syndrome, MONDO:0019078
Intellectual disability v9.231 WASHC5 Ida Ertmanska reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 36130690; Phenotypes: Ritscher-Schinzel syndrome, OMIM:220210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.231 WASHC4 Ida Ertmanska reviewed gene: WASHC4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 43, OMIM:615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Confirmed Fanconi anaemia or Bloom syndrome v2.8 RAD51C Ida Ertmanska changed review comment from: Comment on list classification: There are two biallelic and two monoallelic cases reported with Fanconi anemia (or FA-like disorder). RAD51C should remain Amber for Confirmed Fanconi anaemia or Bloom syndrome, until more evidence emerges.; to: Comment on list classification: There are two biallelic and two monoallelic cases reported with Fanconi anemia (or FA-like disorder). RAD51C should remain Amber for Confirmed Fanconi anaemia or Bloom syndrome, until more evidence emerges. The MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Confirmed Fanconi anaemia or Bloom syndrome v2.8 RAD51C Ida Ertmanska changed review comment from: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

Functional evidence:
PMID: 36906610 Tomaszowski et al., 2023 - 'Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress' - interestingly, single gene knockouts of either Brca2 or Rad51c did not result in a Fanconi anemia phenotype in the mice.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.; to: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

Functional evidence:
PMID: 36906610 Tomaszowski et al., 2023 - 'Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress' - interestingly, single gene knockouts of either Brca2 or Rad51c did not result in a Fanconi anemia phenotype in the mice.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.
Confirmed Fanconi anaemia or Bloom syndrome v2.8 RAD51C Ida Ertmanska edited their review of gene: RAD51C: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Confirmed Fanconi anaemia or Bloom syndrome v2.8 RAD51C Achchuthan Shanmugasundram Phenotypes for gene: RAD51C were changed from Fanconi anemia, complementation group O, 613390; 613390 Fanconi anemia, complementation group O to Fanconi anemia, complementation group O, OMIM:613390; Fanconi anemia complementation group O, MONDO:0013248
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (5 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (5 unrelated patients) for the association of KDM2A gene with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram changed review comment from: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

The other reported phenotypes include microcephaly (six individuals including the foetus - none of them had OFC beyond -3 SD), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve). Seizure types included focal and generalized seizures as well as epileptic spasms. At the last assessment, two individuals continued to experience seizures, while three achieved seizure freedom. In the latter three, the anti-seizure medication was subsequently weaned off without relapse.

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

The other reported phenotypes include microcephaly (six individuals including the foetus - none of them had OFC beyond -3 SD), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve). Seizure types included focal and generalized seizures as well as epileptic spasms. At the last assessment, two individuals continued to experience seizures, while three achieved seizure freedom. In the latter three, the anti-seizure medication was subsequently weaned off without relapse.

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (17 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (5 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve). Seizure types included focal and generalized seizures as well as epileptic spasms. At the last assessment, two individuals continued to experience seizures, while three achieved seizure freedom. In the latter three, the anti-seizure medication was subsequently weaned off without relapse.

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram Entity copied from Intellectual disability v9.231
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram gene: KDM2A was added
gene: KDM2A was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q1_26_promote_green tags were added to gene: KDM2A.
Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2A were set to 41468891
Phenotypes for gene: KDM2A were set to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram Classified gene: KDM2A as Amber List (moderate evidence)
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.231 KDM2A Achchuthan Shanmugasundram Gene: kdm2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.230 KDM2A Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: KDM2A.
Intellectual disability v9.230 KDM2A Achchuthan Shanmugasundram gene: KDM2A was added
gene: KDM2A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2A were set to 41468891
Phenotypes for gene: KDM2A were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: KDM2A was set to GREEN
Added comment: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Confirmed Fanconi anaemia or Bloom syndrome v2.7 RAD51C Ida Ertmanska commented on gene: RAD51C: Comment on list classification: There are two biallelic and two monoallelic cases reported with Fanconi anemia (or FA-like disorder). RAD51C should remain Amber for Confirmed Fanconi anaemia or Bloom syndrome, until more evidence emerges.
Confirmed Fanconi anaemia or Bloom syndrome v2.7 RAD51C Ida Ertmanska changed review comment from: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.; to: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

Functional evidence:
PMID: 36906610 Tomaszowski et al., 2023 - 'Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress' - interestingly, single gene knockouts of either Brca2 or Rad51c did not result in a Fanconi anemia phenotype in the mice.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.
Early onset or syndromic epilepsy v8.90 PRMT9 Achchuthan Shanmugasundram Classified gene: PRMT9 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.90 PRMT9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>10 unrelated families) for the association of biallelic PRMT9 variants with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.90 PRMT9 Achchuthan Shanmugasundram Gene: prmt9 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.89 PRMT9 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: PRMT9.
Early onset or syndromic epilepsy v8.89 PRMT9 Achchuthan Shanmugasundram gene: PRMT9 was added
gene: PRMT9 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: PRMT9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRMT9 were set to 41260215
Phenotypes for gene: PRMT9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PRMT9 was set to GREEN
Added comment: PMID:41260215 (2025) reported the identification of biallelic loss-of-function variants in PRMT9 gene in 35 individuals from 26 unrelated families primarily presenting with a neurodevelopmental disorder characterised by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia.

There were 26 different variants identified in total which included frameshifting indels, nonsense variants, missense variants, and two copy-number variants.

Clinical examinations revealed that 14 individuals developed epilepsy, which was suspected in one other individual.

Functional evidence available from skin fibroblasts derived from affected individuals showed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), but has been associated with 'Limited' rating on the DD panel in Gene2Phenotype.
Sources: Literature
Confirmed Fanconi anaemia or Bloom syndrome v2.7 RAD51C Ida Ertmanska changed review comment from: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025).; to: PMID: 29278735 Jacquinet et al., 2018
Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth.
Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis.

PMID: 26681308 Ameziane et al., 2015
Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs.

PMID: 26253028 Wang et al., 2015
1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C.

PMID: 20400963 Vaz et al., 2010
Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C.

This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.
Confirmed Fanconi anaemia or Bloom syndrome v2.7 RAD51C Ida Ertmanska Publications for gene: RAD51C were set to 20400963; 22232082
Confirmed Fanconi anaemia or Bloom syndrome v2.6 RAD51C Ida Ertmanska reviewed gene: RAD51C: Rating: AMBER; Mode of pathogenicity: None; Publications: 20400963, 26681308, 29278735, 37031326; Phenotypes: Fanconi anemia, complementation group O, OMIM:613390, Fanconi anemia complementation group O, MONDO:0013248; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. In addition, there is also functional evidence available in support of the association of this gene with the neurodevelopmental disorder. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. In addition, there is also functional evidence available in support of the association of this gene with the neurodevelopmental disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. In addition, there is also functional evidence available in support of the association of this gene with the neurodevelopmental disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram edited their review of gene: WSB2: Changed rating: GREEN
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram edited their review of gene: WSB2: Changed rating: RED
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram changed review comment from: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Seizures were reported in three of five patients including one of two patients from the Ashkenazi Jew family. One of the patients is now free of seizures and not on medication, while the other two patients responded to treatments.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Seizures were reported in three of five patients including one of two patients from the Ashkenazi Jew family (child without seizures is aged 9 years old, while the onset of seizure on the other child was at 10 years of age). One of the patients is now free of seizures and not on medication, while the other two patients responded to treatments.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram Tag watchlist was removed from gene: WSB2.
Tag Q1_26_promote_green tag was added to gene: WSB2.
Intellectual disability v9.229 PRMT9 Achchuthan Shanmugasundram Classified gene: PRMT9 as Amber List (moderate evidence)
Intellectual disability v9.229 PRMT9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of PRMT9 with syndromic intellectual disability (>20 unrelated families). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.229 PRMT9 Achchuthan Shanmugasundram Gene: prmt9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.228 PRMT9 Achchuthan Shanmugasundram Publications for gene: PRMT9 were set to 21937992; 38561334
Intellectual disability v9.227 PRMT9 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: PRMT9.
Intellectual disability v9.227 PRMT9 Achchuthan Shanmugasundram edited their review of gene: PRMT9: Changed rating: GREEN
Intellectual disability v9.227 PRMT9 Achchuthan Shanmugasundram edited their review of gene: PRMT9: Added comment: PMID:41260215 (2025) reported the identification of biallelic loss-of-function variants in PRMT9 gene in 35 individuals from 26 unrelated families primarily presenting with a neurodevelopmental disorder characterised by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia.

There were 26 different variants identified in total which included frameshifting indels, nonsense variants, missense variants, and two copy-number variants.

Global developmental delay was present un 33 individuals and mild - severe intellectual disability was present in 29 individuals (moderate and above in 11 patients, where ID was mild-moderate or severity not reported in others).

Functional evidence available from skin fibroblasts derived from affected individuals showed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), but has been associated with 'Limited' rating on the DD panel in Gene2Phenotype.; Changed publications to: 21937992, 38561334, 41260215
Optic neuropathy v5.39 SPG7 Achchuthan Shanmugasundram Phenotypes for gene: SPG7 were changed from SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE, OMIM:607259; autosomal dominant optic atroph, MONDO:0020250 to Spastic paraplegia 7, autosomal recessive, OMIM:607259; hereditary spastic paraplegia 7, MONDO:0011803
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska changed review comment from: Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska edited their review of gene: SPG7: Changed publications to: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Changed phenotypes to: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska Deleted their comment
Optic neuropathy v5.38 SPG7 Ida Ertmanska edited their review of gene: SPG7: Changed publications to: 23065789, 24466038, 24727571, 32548275, 33841295, 37983191
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: PMID: 37983191 Bell et al., 2024
5 cases with heterozygous SPG7 variants and progressive vision loss, several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Seq method: WES (1 case) or optic atrophy panel (4 cases).
Variants identified: p.Ala759Thr, p.Gln447Ter, p.Ala510Val (3 cases). Age of onset range: 8-48 yrs old.

PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.; to: PMID: 37983191 Bell et al., 2024
5 cases with heterozygous SPG7 variants and progressive vision loss, several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Seq method: WES (1 case) or optic atrophy panel (4 cases).
Variants identified: p.Ala759Thr, p.Gln447Ter, p.Ala510Val (3 cases). Age of onset range: 8-48 yrs old.
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.2275G>A, p.Ala759Thr has MAF = 0.0009866 in gnomAD v4 (European), no homozygotes reported.
SPG7 c.1339C>T, p.Gln447Ter has 1 allele recorded in gnomAD v4.

PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.; to: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748; recurring variants are too common in the population to be associated with dominant disease). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.; to: PMID: 37983191 Bell et al., 2024
5 cases with heterozygous SPG7 variants and progressive vision loss, several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Seq method: WES (1 case) or optic atrophy panel (4 cases).
Variants identified: p.Ala759Thr, p.Gln447Ter, p.Ala510Val (3 cases). Age of onset range: 8-48 yrs old.

PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.; to: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.
Optic neuropathy v5.38 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Optic neuropathy v5.38 SPG7 Ida Ertmanska edited their review of gene: SPG7: Added comment: Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update.; Changed rating: GREEN; Changed publications to: 23065789, 24466038, 24727571, 32548275, 33841295; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v5.38 SPG7 Ida Ertmanska changed review comment from: PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.


SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.; to: PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases. All individuals with SPG7 were noted to have features of optic atrophy.
Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Possible mitochondrial disorder - nuclear genes v4.19 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Possible mitochondrial disorder - nuclear genes v4.19 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Possible mitochondrial disorder - nuclear genes v4.19 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v5.38 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: None
Mitochondrial disorders v9.40 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Mitochondrial disorders v9.40 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Mitochondrial disorders v9.40 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial DNA maintenance disorder v3.7 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Mitochondrial DNA maintenance disorder v3.7 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: An overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Mitochondrial DNA maintenance disorder v3.7 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.87 SPG7 Ida Ertmanska Publications for gene: SPG7 were set to 27604308; 9635427; 16534102; 17646629; 18200586; 20186691; 22571692
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska edited their review of gene: SPG7: Changed publications to: 24466038, 24767997, 26539208, 30252181, 33045469, 39978794
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia / optic atrophy have biallelic SPG7 variants. While several monoallelic cases have been described to date, the evidence for dominant inheritance is controversial (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska changed review comment from: PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.; to: PMID: 39978794 Jimoh et al., 2025
Reported 7 patients with mitochondrial dysfunction associated with ragged blue fibers in their muscle biopsies: P4 and P11C with homozygous SPG7 variant p.Leu78Ter, P32 and P46 with heterozygous p.Ala510Val, P38 with heterozygous p.Ser645Thr, P48 with heterozygous p.Val540Met, and P49 with heterozygous c.1552 + 1G>T. Authors pose that dominant / semi-dominant inheritance is likely for SPG7, as they have not found additional pathogenic AFG3L2 variants in the monoallelic cases - though the phenotype is notably milder.

PMID: 30252181 Magri et al., 2018
Proband: 25-year-old woman, presented at 5yo with severe vision impairment and signs of primary optic atrophy. At 6yo, manifested a slowly progressive motor impairment characterized by bradykinesia, internal rotation of right foot, and gait and balance instability. Mild ID, WISC-R IQ = 62 (assessed at 10yo). Compound het (digenic): de novo variant in AFG3L2 NM_006796.2:c.1402C>T, p.R468C & SPG7 variant NM_003119.3:c.(376+1_377-1)_(861+1_862-1)del, p.Glu127SerfsTer2. Mother and twin brothers carried heterozygous SPG7 deletion alone and were unaffected.
In PMID: 26539208 Charif et al., 2015, authors described the same AFG3L2 c.1402C>T mutation segregating in a family with optic atrophy and mild ID in an autosomal dominant manner - no ataxia, spasticity, or extrapyramidal involvement (AFG3L2 contribution to phenotype?).
Functional study: Yeast cells lacking the endogenous m-AAA protease exhibit a respiratory defect (OXPHOS phenotype), which is complemented by wild-type AFG3L2 (AFG3L2-WT) but not by mutant AFG3L2-R468C.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

Functional evidence: SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes (PMID: 24767997 Almontashiri et al., 2014). In 6-month-old mice, EM analysis showed the presence of swollen mitochondria in Spg7−/− spinal cord axons; Spg7−/− mice display motor impairment at 6 and 10 months of age; Spg7+/- mice were used as controls (PMID: 33045469 Sambri et al., 2020).

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Likely inborn error of metabolism v8.86 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24466038; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Intellectual disability v9.227 GLUL Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are >10 unrelated individuals reported with developmental and epileptic encephalopathy, including global developmental delay and monoallelic GLUL variants. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Intellectual disability v9.227 GLUL Achchuthan Shanmugasundram Mode of inheritance for gene: GLUL was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.226 GLUL Achchuthan Shanmugasundram Phenotypes for gene: GLUL were changed from CONGENITAL SYSTEMIC GLUTAMINE DEFICIENCY (CSGD) to Glutamine deficiency, congenital, OMIM:610015; Developmental and epileptic encephalopathy 116, OMIM:620806; congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393; developmental and epileptic encephalopathy 116, MONDO:0970945
Intellectual disability v9.225 GLUL Achchuthan Shanmugasundram Publications for gene: GLUL were set to 21353613; 16267323
Intellectual disability v9.224 GLUL Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: GLUL.
Intellectual disability v9.224 GLUL Achchuthan Shanmugasundram reviewed gene: GLUL: Rating: GREEN; Mode of pathogenicity: None; Publications: 38579670, 39985170, 41083803; Phenotypes: Glutamine deficiency, congenital, OMIM:610015, Developmental and epileptic encephalopathy 116, OMIM:620806, congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393, developmental and epileptic encephalopathy 116, MONDO:0970945; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.88 GLUL Achchuthan Shanmugasundram changed review comment from: PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).; to: PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).
Early onset or syndromic epilepsy v8.88 GLUL Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are >10 unrelated individuals reported with developmental and epileptic encephalopathy and monoallelic GLUL variants. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Early onset or syndromic epilepsy v8.88 GLUL Achchuthan Shanmugasundram Mode of inheritance for gene: GLUL was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.87 GLUL Achchuthan Shanmugasundram Phenotypes for gene: GLUL were changed from Glutamine deficiency, congenital, 610015; seizures to Glutamine deficiency, congenital, OMIM:610015; Developmental and epileptic encephalopathy 116, OMIM:620806; congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393; developmental and epileptic encephalopathy 116, MONDO:0970945
Early onset or syndromic epilepsy v8.86 GLUL Achchuthan Shanmugasundram Publications for gene: GLUL were set to 21353613; 16267323; 30158707
Early onset or syndromic epilepsy v8.85 GLUL Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: GLUL.
Early onset or syndromic epilepsy v8.85 GLUL Achchuthan Shanmugasundram commented on gene: GLUL: PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).
Early onset or syndromic epilepsy v8.85 GLUL Achchuthan Shanmugasundram reviewed gene: GLUL: Rating: GREEN; Mode of pathogenicity: None; Publications: 38579670, 39985170, 41083803; Phenotypes: Glutamine deficiency, congenital, OMIM:610015, Developmental and epileptic encephalopathy 116, OMIM:620806, congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393, developmental and epileptic encephalopathy 116, MONDO:0970945; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.28 EIF3B Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are 14 unrelated individuals reported with monoallelic EIF3B variants and with a complex phenotype involving cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioral abnormalities. The phenotypes displayed do not fit into the scope of intellectual disability panel, but fits into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.; to: Comment on list classification: There are 14 unrelated individuals reported with monoallelic EIF3B variants and with a complex phenotype involving cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioural abnormalities. The phenotypes displayed do not fit into the scope of intellectual disability panel, but fit into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
Paediatric disorders - additional genes v7.28 EIF3A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are four unrelated individuals reported with monoallelic EIF3A variants and with a complex phenotype involving mild developmental/ speech delays, cardiac anomalies and craniofacial dysmorphism. The phenotypes displayed does not fit into the scope of intellectual disability panel, but fits into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.; to: Comment on list classification: There are four unrelated individuals reported with monoallelic EIF3A variants and with a complex phenotype involving mild developmental/ speech delays, cardiac anomalies and craniofacial dysmorphism. The phenotypes displayed do not fit into the scope of intellectual disability panel, but fit into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
Paediatric disorders - additional genes v7.28 EIF3A Achchuthan Shanmugasundram changed review comment from: PMID:41033306 (2025) reported four unrelated individuals identified with heterozygous loss-of-function variants in EIF3A gene (2.58 kpb intragenic deletion, p.Glu99Lysfs*3, p.Cys404Ter & p.Arg1030Ter). The phenotypes were varied, but included cardiac defects, craniofacial dysmorphisms and mild developmental delays.

Cardiac features: Two individuals presented with tetralogy of Fallot, a third individual had a perimembranous VSD, ASD, and patent foramen ovale and the fourth individual presented with VSD, right-sided aortic arch, and a vascular ring.

Neurodevelopmental features: One individual had a history of speech and language delays but is currently within normal limits. Another was suspected of having a learning difficulty, although all developmental milestones were met. Third exhibited mild articulation issues, and fourth was reported to have a developmental delay. Seizures were reported in one of these individuals.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 06 January 2026).
Sources: Literature; to: PMID:41033306 (2025) reported four unrelated individuals identified with heterozygous loss-of-function variants in EIF3A gene (2.58 kpb intragenic deletion, p.Glu99Lysfs*3, p.Cys404Ter & p.Arg1030Ter). The phenotypes were varied, but included cardiac defects, craniofacial dysmorphisms and mild developmental delays.

Cardiac features: Two individuals presented with tetralogy of Fallot, a third individual had a perimembranous VSD, ASD, and patent foramen ovale and the fourth individual presented with VSD, right-sided aortic arch, and a vascular ring.

Neurodevelopmental features: One individual had a history of speech and language delays but is currently within normal limits. Another was suspected of having a learning difficulty, although all developmental milestones were met. Third exhibited mild articulation issues, and fourth was reported to have a developmental delay. Seizures were reported in one of these individuals.

Functional evidence was available from zebrafish model with mutations in the orthologous eif3s10 gene, which resulted in developmental abnormalities, including thin heart tubes, lack of craniofacial cartilage, and embryonic lethality.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 06 January 2026).
Sources: Literature
Paediatric disorders - additional genes v7.28 EIF3B Achchuthan Shanmugasundram Classified gene: EIF3B as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.28 EIF3B Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 14 unrelated individuals reported with monoallelic EIF3B variants and with a complex phenotype involving cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioral abnormalities. The phenotypes displayed do not fit into the scope of intellectual disability panel, but fits into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
Paediatric disorders - additional genes v7.28 EIF3B Achchuthan Shanmugasundram Gene: eif3b has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.27 EIF3B Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: EIF3B.
Severe microcephaly v8.27 EIPR1 Achchuthan Shanmugasundram changed review comment from: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Microcephaly was present in five patients from three unrelated families, of which three patients from two families had Severe microcephaly (OFC beyond -3SD).

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Microcephaly was present in five patients from three unrelated families, of which three patients from two families had Severe microcephaly (OFC beyond -3SD).

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.224 EIPR1 Achchuthan Shanmugasundram changed review comment from: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. All had global developmental delay, with significant motor delay (5/8 never attained walking). Severe or profound intellectual disability was present in 3 individuals from two unrelated families.

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. All had global developmental delay, with significant motor delay (5/8 never attained walking). Severe or profound intellectual disability was present in 3 individuals from two unrelated families.

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.224 GTF2I Achchuthan Shanmugasundram changed review comment from: PMID:40962490 (2025) reported the identification of heterozygous de novo variants in GTF2I gene (two non-sense, two splice-site, one missense, one indel and one intragenic deletion) via whole genome/ exome sequencing in seven unrelated individuals with a neurodevelopmental disorder. They all presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in six of them. GDD was severe and moderate in one each, and was mild in the rest. The effect of the two splice-site variants was confirmed by RNA sequencing.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:40962490 (2025) reported the identification of heterozygous de novo variants in GTF2I gene (two non-sense, two splice-site, one missense, one indel and one intragenic deletion) via whole genome/ exome sequencing in seven unrelated individuals with a neurodevelopmental disorder. They all presented with global developmental delay/ intellectual disability and facial dysmorphic features, with speech delay and/or autistic features in six of them. GDD was severe and moderate in one each, and was mild in the rest. The effect of the two splice-site variants was confirmed by RNA sequencing.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Hereditary ataxia with onset in adulthood v8.16 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Hereditary ataxia with onset in adulthood v8.16 SPG7 Ida Ertmanska Publications for gene: SPG7 were set to 25681447; 9635427; 16534102; 17646629; 18200586; 20186691; 22571692
Hereditary ataxia with onset in adulthood v8.15 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v8.9 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Adult onset neurodegenerative disorder v8.9 SPG7 Ida Ertmanska edited their review of gene: SPG7: Added comment: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.; Changed rating: GREEN; Changed publications to: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Changed phenotypes to: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v8.9 SPG7 Ida Ertmanska commented on gene: SPG7
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21). Method: SPG7 sequencing only / NGS targeted panel.

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Adult onset hereditary spastic paraplegia v6.3 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.27 EIF3B Achchuthan Shanmugasundram gene: EIF3B was added
gene: EIF3B was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: EIF3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF3B were set to 41033306
Phenotypes for gene: EIF3B were set to syndromic disease, MONDO:0002254
Review for gene: EIF3B was set to GREEN
Added comment: PMID:41033306 (2025) reported 14 unrelated individuals with heterozygous de novo or loss-of-function variants in EIF3B gene. The clinical phenotype varied but predominantly included cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioral abnormalities.

11 of 14 individuals had congenital heart defect including four with tetralogy of Fallot, neurodevelopmental phenotype including developmental delay, speech and language delay, and mild or specific learning disabilities were reported in eight individuals. Behavioral abnormalities, including attention-deficit hyperactivity disorder and autism spectrum disorder, were also noted.

Facial differences were observed in eleven individuals. While features varied, several individuals exhibited differences in the eye region that overlapped with those previously reported in individuals with 7q22.3 micro-deletions, including ptosis, arched eyebrows, downslanting palpebral fissures, hypertelorism, and epicanthal folds. Cleft lip and palate and hearing loss and/or inner and middle ear malformations were reported in four individuals each.

Functional evidence was available from zebrafish model with mutations in the orthologous eif3ba gene, which resulted in developmental abnormalities, including thin heart tubes, lack of craniofacial cartilage, and embryonic lethality.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 06 January 2026).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21). Method: SPG7 sequencing only / NGS targeted panel.

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Ataxia and cerebellar anomalies - narrow panel v8.46 SPG7 Ida Ertmanska Publications for gene: SPG7 were set to 25681447; 32893728; 33774748; 32161564; 31068484; 23065789; 9635427; 16534102; 17646629; 18200586; 20186691; 22571692
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska Tag digenic tag was added to gene: SPG7.
Tag Q1_26_MOI tag was added to gene: SPG7.
Tag Q1_26_NHS_review tag was added to gene: SPG7.
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detected only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.

PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detected only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748).; to: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detected only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detected only by WGS - PMID: 31854126) and possible digenic inheritance with variants in SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748).
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska edited their review of gene: SPG7: Changed publications to: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Changed phenotypes to: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
PMID: 34405107 Campins-Romeu et al., 2021
Report of a 28‐year‐old Caucasian male with gait and speech problems, neurological problems started at age 17 years. Brain MRI demonstrated mild cerebellar atrophy and T2‐weighted hyperintensities of the cerebral peduncles. Carried compound heterozygous variants in SPG7: c.1529C > T (p.Ala510Val) and c.1715C > T (p.Ala572Val).

PMID: 26506339 Thal et al., 2015
Caucasian man with a homozygous Ala510Val SPG7 case with spastic ataxia. Developed a slowly-progressive spastic-ataxic gait disorder starting at age 59 years accompanied by mild dysdiadochokinesis, mild dysmetria in finger-nose test as well as mild dysmetria in the heel-shin slide, corresponding to a mild cerebellar atrophy, followed by chronic progressive external ophthalmoplegia (cPEO) in later years.
SPG7 variant c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported.

PMID: 22964162 van Gassen et al., 2012
Large Dutch cohort - identified 60 patients with mutations in the SPG7 gene, with clinical details provided for 49 patients from 37 families - all with confirmed homozygous or compound heterozygous variants in SPG7.

MONOALLELIC CASES:
PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. p.Ala510Val was the most commonly detected SPG7 mutation (65%).
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs:
In Family 13, the mother had a heterozygous Arg485_Glu487del mutation: at age 72 years, she had a very slight cerebellar phenotype without spasticity or pyramidal signs.
The mother of Patient 5, who also had a heterozygous Arg485_Glu487del mutation, had a cerebellar gait and cerebellar atrophy on MRI.
The brother of the index case in Family 3 with a heterozygous Ala510Val mutation developed a late-onset peripheral neuropathy. The patient had abolished reflexes at the age of 59 years, with pyramidal signs.

Patient 24 - from PMID: 16534102 Elleuch et al., 2006 - heterozygous for SPG7: c.246_248del, p.Gln82del - transmitted from an asymptomatic mother (?)
Patient 25 - isolated index case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

CONTRADICTORY EVIDENCE:
PMID: 31854126 Verdura et al., 2019
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts. 'This case challenges the notion of an autosomal dominant inheritance for SPG7'; to: BIALLELIC CASES:
Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).
Paediatric disorders - additional genes v7.26 EIF3A Achchuthan Shanmugasundram Classified gene: EIF3A as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.26 EIF3A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated individuals reported with monoallelic EIF3A variants and with a complex phenotype involving mild developmental/ speech delays, cardiac anomalies and craniofacial dysmorphism. The phenotypes displayed does not fit into the scope of intellectual disability panel, but fits into the scope of R27 Paediatric disorders super panel. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
Paediatric disorders - additional genes v7.26 EIF3A Achchuthan Shanmugasundram Gene: eif3a has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.25 EIF3A Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: EIF3A.
Paediatric disorders - additional genes v7.25 EIF3A Achchuthan Shanmugasundram gene: EIF3A was added
gene: EIF3A was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: EIF3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF3A were set to 41033306
Phenotypes for gene: EIF3A were set to syndromic disease, MONDO:0002254
Review for gene: EIF3A was set to GREEN
Added comment: PMID:41033306 (2025) reported four unrelated individuals identified with heterozygous loss-of-function variants in EIF3A gene (2.58 kpb intragenic deletion, p.Glu99Lysfs*3, p.Cys404Ter & p.Arg1030Ter). The phenotypes were varied, but included cardiac defects, craniofacial dysmorphisms and mild developmental delays.

Cardiac features: Two individuals presented with tetralogy of Fallot, a third individual had a perimembranous VSD, ASD, and patent foramen ovale and the fourth individual presented with VSD, right-sided aortic arch, and a vascular ring.

Neurodevelopmental features: One individual had a history of speech and language delays but is currently within normal limits. Another was suspected of having a learning difficulty, although all developmental milestones were met. Third exhibited mild articulation issues, and fourth was reported to have a developmental delay. Seizures were reported in one of these individuals.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 06 January 2026).
Sources: Literature
Intellectual disability v9.224 LSM1 Achchuthan Shanmugasundram Classified gene: LSM1 as Amber List (moderate evidence)
Intellectual disability v9.224 LSM1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families reported with biallelic LSM 1 variants (c.231+4A>C in five families and p.Asn40Tyr in one family) and with FICUS syndrome (which includes global developmental delay/ intellectual disability). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.224 LSM1 Achchuthan Shanmugasundram Gene: lsm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.223 LSM1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: LSM1.
Intellectual disability v9.223 LSM1 Achchuthan Shanmugasundram gene: LSM1 was added
gene: LSM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LSM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM1 were set to 31010896; 36100156; 40204357
Phenotypes for gene: LSM1 were set to FICUS syndrome, OMIM:621193; FICUS syndrome, MONDO:0978296
Review for gene: LSM1 was set to GREEN
Added comment: PMID:31010896 (2019) reported two siblings with global developmental delay, and multiple congenital anomalies affecting the cardiac, genitourinary, and skeletal systems, and abnormal eye movements. They were identified with a homozygous non-canonical splice variant in LSM1 gene (c.231+4A>C) through whole-genome sequencing. There is also functional evidence available from expression studies and mouse model. Lsm1 knockout mice had a partially overlapping phenotype that affected the brain, heart, and eye.

PMID:36100156 (2022) reported the identification of a homozygous missense variant (p.Asn40Tyr) in LSM1 gene via whole-exome in two similarly affected siblings with global neurodevelopmental delay and intellectual disability.

PMID:40204357 (2025) reported six paediatric patients from four unrelated families with homozygous c.231+4A>C variant. They presented with dysmorphic facial features, global developmental delay/ intellectual disability and multisystemic involvement, including urological, cardiac and skeletal manifestations. This variant was identified in Muslim Arab and Ashkenazi Jewish populations and determined as representing a hotspot variant through haplotype analysis. RT-qPCR functional validation demonstrated exon 3 skipping and elevated mutant isoform. The variant was classified as 'Pathogenic' according to the ACMG classification.

This gene has been associated with relevant phenotypes in OMIM (MIM #621193, OMIM record last accessed 06 January 2026), but not yet in Gene2Phenotype.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.92 ATAD3A Matthew Edwards reviewed gene: ATAD3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33575671, 39472908; Phenotypes: perinatal mitochondrial cardiac failure; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v8.45 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Epidermolysis bullosa and congenital skin fragility v2.12 ATP2A2 Ida Ertmanska edited their review of gene: ATP2A2: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Epidermolysis bullosa and congenital skin fragility v2.12 ATP2A2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: ATP2A2.
Tag Q1_26_NHS_review tag was added to gene: ATP2A2.
Epidermolysis bullosa and congenital skin fragility v2.12 ATP2A2 Ida Ertmanska Mode of inheritance for gene: ATP2A2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Epidermolysis bullosa and congenital skin fragility v2.11 ATP2A2 Ida Ertmanska Classified gene: ATP2A2 as Amber List (moderate evidence)
Epidermolysis bullosa and congenital skin fragility v2.11 ATP2A2 Ida Ertmanska Gene: atp2a2 has been classified as Amber List (Moderate Evidence).
Epidermolysis bullosa and congenital skin fragility v2.10 ATP2A2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in childhood/adolescence. Due to the age of onset, this gene does not fit into the scope of this panel and should be rated Red.; to: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in adolescence. Based on the available evidence, this gene should be updated to Green on Epidermolysis bullosa and congenital skin fragility. As per internal communication with Veronica Kinsler, this is the closest Dermatology panel fit at this time.
Epidermolysis bullosa and congenital skin fragility v2.10 ATP2A2 Ida Ertmanska edited their review of gene: ATP2A2: Changed rating: GREEN
Intellectual disability v9.222 GTF2I Achchuthan Shanmugasundram Mode of inheritance for gene: GTF2I was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram edited their review of gene: GTF2I: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram Classified gene: GTF2I as Amber List (moderate evidence)
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram Added comment: Comment on list classification: Although five of seven patients presented with mild global developmental delay/ intellectual disability (moderate and severe in one each), they all displayed syndromic phenotype including dysmorphic features. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.221 GTF2I Achchuthan Shanmugasundram Gene: gtf2i has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.220 GTF2I Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: GTF2I.
Intellectual disability v9.220 GTF2I Achchuthan Shanmugasundram gene: GTF2I was added
gene: GTF2I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GTF2I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GTF2I were set to 40962490
Phenotypes for gene: GTF2I were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: GTF2I was set to GREEN
Added comment: PMID:40962490 (2025) reported the identification of heterozygous de novo variants in GTF2I gene (two non-sense, two splice-site, one missense, one indel and one intragenic deletion) via whole genome/ exome sequencing in seven unrelated individuals with a neurodevelopmental disorder. They all presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in six of them. GDD was severe and moderate in one each, and was mild in the rest. The effect of the two splice-site variants was confirmed by RNA sequencing.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Severe microcephaly v8.27 EIPR1 Achchuthan Shanmugasundram Classified gene: EIPR1 as Amber List (moderate evidence)
Severe microcephaly v8.27 EIPR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Severe microcephaly v8.27 EIPR1 Achchuthan Shanmugasundram Gene: eipr1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.26 EIPR1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: EIPR1.
Severe microcephaly v8.26 EIPR1 Achchuthan Shanmugasundram gene: EIPR1 was added
gene: EIPR1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: EIPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIPR1 were set to 41058046
Phenotypes for gene: EIPR1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: EIPR1 was set to GREEN
Added comment: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Microcephaly was present in five patients from three unrelated families, of which three patients from two families had Severe microcephaly (OFC beyond -3SD).

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.219 EIPR1 Achchuthan Shanmugasundram Classified gene: EIPR1 as Amber List (moderate evidence)
Intellectual disability v9.219 EIPR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (six unrelated families) for the association of this gene with global developmental delay/ intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.219 EIPR1 Achchuthan Shanmugasundram Gene: eipr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.218 EIPR1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: EIPR1.
Intellectual disability v9.218 EIPR1 Achchuthan Shanmugasundram gene: EIPR1 was added
gene: EIPR1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIPR1 were set to 41058046
Phenotypes for gene: EIPR1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: EIPR1 was set to GREEN
Added comment: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. All had global developmental delay, with significant motor delay (5/8 never attained walking). Severe or profound intellectual disability was present in 3 individuals from two unrelated families.

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families. The age of onset of the syndrome was in infancy/ early childhood.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families. The age of onset of the syndrome was in infancy/ early childhood.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families. The age of onset of the syndrome was in infancy/ early childhood.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram Classified gene: RPS6KC1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram Gene: rps6kc1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.23 RPS6KC1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: RPS6KC1.
Childhood onset hereditary spastic paraplegia v8.23 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram Classified gene: RPS6KC1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram Gene: rps6kc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.84 RPS6KC1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: RPS6KC1.
Early onset or syndromic epilepsy v8.84 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram Classified gene: RPS6KC1 as Amber List (moderate evidence)
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.217 RPS6KC1 Achchuthan Shanmugasundram Gene: rps6kc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.216 RPS6KC1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: RPS6KC1.
Intellectual disability v9.216 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.83 UNC13A Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of both monoallelic and biallelic UNC13A variants with seizures, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Early onset or syndromic epilepsy v8.83 UNC13A Achchuthan Shanmugasundram Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.82 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.82 UNC13A Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369; 39634123
Early onset or syndromic epilepsy v8.81 UNC13A Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: UNC13A.
Early onset or syndromic epilepsy v8.81 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Added comment: PMID:41125872 (2025) identified a neurodevelopmental syndrome caused by variants in the UNC13A gene. Systematic patient and variant characterisation enabled classification of three disease subtypes.

A first group of six patients (18 months to ~15 years old) presented with severe-to-profound global developmental delay (GDD) or intellectual disability (ID), hypotonia and seizures of different types (largely controllable with medication) or death in early childhood caused by respiratory failure after pneumonia in one case. UNC13A variants in these patients were homozygous or compound heterozygous missense, insertion–deletion or splice-site variants with gene-disrupting splicing effects proven by minigene assays.

A second group of 13 patients (21 months to 32 years old) harboured pathogenic, heterozygous de novo missense variants with multiple substitutions at amino acids 808, 811 and 814. They presented with variable degrees of GDD, hypotonia, seizures of different types (mainly refractory to treatment) and typically exhibited ataxia, tremor or dyskinetic movements rarely observed in other patients.

The third group of patients consisted of a family with at least four affected members across two generations (4 years to 35 years old) harbouring a pathogenic heterozygous missense variant (p.Cys587Phe) that caused learning difficulties to mild–moderate intellectual disability as well as controlled seizures.

Both monoallelic and biallelic UNC13A variants have been associated with relevant phenotypes in Gene2Phenotype (both with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 02 January 2026).; Changed publications to: 28192369, 39634123, 41125872; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.215 UNC13A Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of both monoallelic and biallelic UNC13A variants with GDD/ ID, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Intellectual disability v9.215 UNC13A Achchuthan Shanmugasundram Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.214 UNC13A Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369; 39634123
Intellectual disability v9.213 UNC13A Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: UNC13A.
Intellectual disability v9.213 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Added comment: PMID:41125872 (2025) identified a neurodevelopmental syndrome caused by variants in the UNC13A gene. Systematic patient and variant characterisation enabled classification of three disease subtypes.

A first group of six patients (18 months to ~15 years old) presented with severe-to-profound global developmental delay (GDD) or intellectual disability (ID), hypotonia and seizures of different types (largely controllable with medication) or death in early childhood caused by respiratory failure after pneumonia in one case. UNC13A variants in these patients were homozygous or compound heterozygous missense, insertion–deletion or splice-site variants with gene-disrupting splicing effects proven by minigene assays.

A second group of 13 patients (21 months to 32 years old) harboured pathogenic, heterozygous de novo missense variants with multiple substitutions at amino acids 808, 811 and 814. They presented with variable degrees of GDD, hypotonia, seizures of different types (mainly refractory to treatment) and typically exhibited ataxia, tremor or dyskinetic movements rarely observed in other patients.

The third group of patients consisted of a family with at least four affected members across two generations (4 years to 35 years old) harbouring a pathogenic heterozygous missense variant (p.Cys587Phe) that caused learning difficulties to mild–moderate intellectual disability as well as controlled seizures.

Both monoallelic and biallelic UNC13A variants have been associated with relevant phenotypes in Gene2Phenotype (both with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 02 January 2026).; Changed publications to: 28192369, 39634123, 41125872; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v8.25 TM2D3 Achchuthan Shanmugasundram changed review comment from: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Microcephaly was severe in three of four patients (beyond -3 SD), while it is -2.5 SD in the fourth patient. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature; to: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Microcephaly was severe in three of four patients (OFC beyond -3 SD), while OFC is -2.5 SD in the fourth patient. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Severe microcephaly v8.25 TM2D3 Achchuthan Shanmugasundram Classified gene: TM2D3 as Amber List (moderate evidence)
Severe microcephaly v8.25 TM2D3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with severe microcephaly (OFC beyond -3 SD). Hence, this gene can be promoted to green rating in the next GMS update.
Severe microcephaly v8.25 TM2D3 Achchuthan Shanmugasundram Gene: tm2d3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.24 TM2D3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: TM2D3.
Severe microcephaly v8.24 TM2D3 Achchuthan Shanmugasundram gene: TM2D3 was added
gene: TM2D3 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TM2D3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TM2D3 were set to 40449487
Phenotypes for gene: TM2D3 were set to Neurocardiorenal malformation syndrome, OMIM:621379
Review for gene: TM2D3 was set to GREEN
Added comment: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Microcephaly was severe in three of four patients (beyond -3 SD), while it is -2.5 SD in the fourth patient. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Intellectual disability v9.213 TM2D3 Achchuthan Shanmugasundram Classified gene: TM2D3 as Amber List (moderate evidence)
Intellectual disability v9.213 TM2D3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients reported with severe global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.213 TM2D3 Achchuthan Shanmugasundram Gene: tm2d3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.212 TM2D3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: TM2D3.
Intellectual disability v9.212 TM2D3 Achchuthan Shanmugasundram changed review comment from: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Severe GDD was reported in all four patients. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature; to: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Severe GDD was reported in all four patients. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harbouring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Intellectual disability v9.212 TM2D3 Achchuthan Shanmugasundram gene: TM2D3 was added
gene: TM2D3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TM2D3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TM2D3 were set to 40449487
Phenotypes for gene: TM2D3 were set to Neurocardiorenal malformation syndrome, OMIM:621379
Review for gene: TM2D3 was set to GREEN
Added comment: PMID:40449487 (2025) reported four unrelated individuals with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. Severe GDD was reported in all four patients. They were all identified with homozygous or compound heterozygous variants in TM2D3 gene via exome sequencing.

There is also functional evidence available from SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele.

This gene has been associated with relevant phenotype in OMIM (MIM #621379, last accessed 02 January 2026) and Gene2Phenotype (with 'moderate' rating on DD panel), but not yet in ClinGen.
Sources: Literature
Severe microcephaly v8.23 SNAPIN Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although there are three patients reported with microcephaly (excluding foetuses), only one had information on severity of microcephaly (severe - -8SD). Hence, this gene can only be rated amber with current evidence.; to: Comment on list classification: Although there are three unrelated patients reported with microcephaly (excluding foetuses), only one had information on severity of microcephaly (being severe - -8SD). Hence, this gene can only be rated amber with current evidence.
Severe microcephaly v8.23 SNAPIN Achchuthan Shanmugasundram Classified gene: SNAPIN as Amber List (moderate evidence)
Severe microcephaly v8.23 SNAPIN Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are three patients reported with microcephaly (excluding foetuses), only one had information on severity of microcephaly (severe - -8SD). Hence, this gene can only be rated amber with current evidence.
Severe microcephaly v8.23 SNAPIN Achchuthan Shanmugasundram Gene: snapin has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.22 SNAPIN Achchuthan Shanmugasundram gene: SNAPIN was added
gene: SNAPIN was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 26539891; 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393
Review for gene: SNAPIN was set to AMBER
Added comment: PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia. The severity of microcephaly is not available in the publication.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). The eight-year-old patient had severe microcephaly (−8 SD), while severity of microcephaly was not recorded for one-year-old patient.

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.45 SNAPIN Achchuthan Shanmugasundram changed review comment from: PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.45 SNAPIN Achchuthan Shanmugasundram Classified gene: SNAPIN as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.45 SNAPIN Achchuthan Shanmugasundram Added comment: Comment on list classification: Cerebellar hypoplasia/atrophy was reported in three unrelated foetuses and three other unrelated patients. Hence, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.45 SNAPIN Achchuthan Shanmugasundram Gene: snapin has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.44 SNAPIN Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: SNAPIN.
Ataxia and cerebellar anomalies - narrow panel v8.44 SNAPIN Achchuthan Shanmugasundram gene: SNAPIN was added
gene: SNAPIN was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 26539891; 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393
Review for gene: SNAPIN was set to GREEN
Added comment: PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Fetal anomalies v6.135 SNAPIN Achchuthan Shanmugasundram Classified gene: SNAPIN as Amber List (moderate evidence)
Fetal anomalies v6.135 SNAPIN Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four foetuses from three unrelated families reported with biallelic SNAPIN variants and with neuroanatomical, craniofacial, and skeletal anomalies on prenatal ultrasound/MRI. Hence, this gene can be promoted to green rating in the next GMS update.
Fetal anomalies v6.135 SNAPIN Achchuthan Shanmugasundram Gene: snapin has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.134 SNAPIN Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: SNAPIN.
Fetal anomalies v6.134 BHLHE22 Arina Puzriakova Classified gene: BHLHE22 as Amber List (moderate evidence)
Fetal anomalies v6.134 BHLHE22 Arina Puzriakova Gene: bhlhe22 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.133 BHLHE22 Arina Puzriakova Tag watchlist tag was added to gene: BHLHE22.
Fetal anomalies v6.133 BHLHE22 Arina Puzriakova changed review comment from: PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.; to: PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication. Discussed with R21 expert group and agreed to demote to Amber awaiting publication.
Fetal anomalies v6.133 SNAPIN Achchuthan Shanmugasundram gene: SNAPIN was added
gene: SNAPIN was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393
Review for gene: SNAPIN was set to GREEN
Added comment: PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination.

Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Iron metabolism disorders - NOT common HFE mutations v3.3 FECH Ida Ertmanska commented on gene: FECH: Comment on list classification: As the iron deficiency resulting from FECH mutations is mild (low to low-normal serum iron), this gene does not fit into the scope of this panel, and it should remain Amber.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: MNS1.
Amelogenesis imperfecta v4.25 SMARCD2 Ida Ertmanska commented on gene: SMARCD2: Comment on list classification: While there are several cases reported with biallelic SMARCD2 variants and a 'dental' phenotype, the symptoms are very mild and they do not fit into the scope of this panel. Hence, this gene should remain Amber for Amelogenesis imperfecta until more evidence emerges.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene is recommended for promotion to Green if agreed under additional Expert Review.; to: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene will be recommended for promotion to Green if agreed under additional Expert Review.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene is recommended for promotion to Green with additional Expert Review.; to: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene is recommended for promotion to Green if agreed under additional Expert Review.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska Tag watchlist was removed from gene: MNS1.
Tag Q1_26_promote_green tag was added to gene: MNS1.
Tag Q1_26_NHS_review tag was added to gene: MNS1.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska edited their review of gene: MNS1: Changed rating: GREEN
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects would mean laterality of organs is determined at random (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance, this gene is recommended for promotion to Green with Expert Review. ; to: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects result in randomization of left-right asymmetry (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance and Disputed classification in ClinGen, this gene is recommended for promotion to Green with additional Expert Review.
Laterality disorders and isomerism v4.9 MNS1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. However, there is a number of confounding factors to highlight here. 7/9 families were reported to be consanguineous. 3 families were genotyped using a PCD gene panel only. The most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. The laterality defect presented with incomplete penetrance, although a mouse model supports this finding. Additionally, association of this gene with primary ciliary dyskinesia (PCD) - a primary finding for most cases described here - is Disputed in ClinGen.
Due to some conflicting evidence present in literature, this gene can only be rated Amber for Laterality disorders and isomerism.; to: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. The laterality defect presented with incomplete penetrance, and the most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. However, incomplete penetrance is somewhat expected, as motile cilia defects would mean laterality of organs is determined at random (also possible to result in WT). A mouse model supports this hypothesis, as only 14/36 (39%) of Mns1 deficient mice presented with organ laterality defects. Of note, the association of this gene with primary ciliary dyskinesia (PCD) is Disputed in ClinGen.
Due to incomplete penetrance, this gene is recommended for promotion to Green with Expert Review.
Ehlers Danlos syndrome with a likely monogenic cause v4.5 FLNA Ida Ertmanska Mode of inheritance for gene: FLNA was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Ehlers Danlos syndrome with a likely monogenic cause v4.4 FLNA Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: FLNA.
Tag Q1_26_NHS_review tag was added to gene: FLNA.
Ataxia and cerebellar anomalies - narrow panel v8.43 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.43 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two unrelated patients reported with cerebellar hypoplasia. There is also functional evidence available from mouse model, which does not provide any details on cerebellar abnormalities. Hence, this gene should be rated amber with current evidence. The 'watchlist' tag is added.
Ataxia and cerebellar anomalies - narrow panel v8.43 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.42 WSB2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: WSB2.
Ataxia and cerebellar anomalies - narrow panel v8.42 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to AMBER
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Although brain abnormalities were reported in four of five patients, cerebellar hypoplasia and/ or atrophy was only reported in two patients.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Fetal anomalies v6.132 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Fetal anomalies v6.132 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with either IUGR or Oligohydramnios. Hence, this gene can be promoted to green rating in the next GMS update.
Fetal anomalies v6.132 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.131 WSB2 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: WSB2.
Fetal anomalies v6.131 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to GREEN
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Intrauterine growth restriction (IUGR) was reported in two unrelated patients and Oligohydramnios was reported in a different unrelated patient.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: WSB2.
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.80 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to AMBER
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Seizures were reported in three of five patients including one of two patients from the Ashkenazi Jew family. One of the patients is now free of seizures and not on medication, while the other two patients responded to treatments.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram changed review comment from: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. All five patients had global developmental delay. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen
Sources: Literature; to: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. All five patients had global developmental delay. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although intellectual disability has only been noted in one of four families (family with two patients where ID is moderate in one and severity not given in other), the phenotype is syndromic and GDD is present in all four families. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.211 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.210 WSB2 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: WSB2.
Intellectual disability v9.210 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to GREEN
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. All five patients had global developmental delay. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.2 GNAS Ida Ertmanska reviewed gene: GNAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 41307550; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v8.30 MIA3 Arina Puzriakova changed review comment from: Comment on phenotypes: OMIM phenotype (Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025; to: Comment on phenotypes: OMIM phenotype (?Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025
Fetal anomalies v6.130 MIA3 Arina Puzriakova changed review comment from: Comment on phenotypes: OMIM phenotype (Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025; to: Comment on phenotypes: OMIM phenotype (?Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025
Skeletal dysplasia v8.30 MIA3 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype (Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025
Skeletal dysplasia v8.30 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269 to ?Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.130 MIA3 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype (Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025
Fetal anomalies v6.130 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269 to ?Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Severe insulin resistance and lipodystrophy syndromes v4.66 WRN Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: WRN.
Severe insulin resistance and lipodystrophy syndromes v4.66 PSMB8 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PSMB8.
Severe insulin resistance and lipodystrophy syndromes v4.66 PSMB4 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PSMB4.
Severe insulin resistance and lipodystrophy syndromes v4.66 POC1A Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: POC1A.
Severe insulin resistance and lipodystrophy syndromes v4.66 PIK3R1 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PIK3R1.
Severe insulin resistance and lipodystrophy syndromes v4.66 PCYT1A Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PCYT1A.
Severe insulin resistance and lipodystrophy syndromes v4.66 PCNT Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: PCNT.
Severe insulin resistance and lipodystrophy syndromes v4.66 MFN2 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: MFN2.
Severe insulin resistance and lipodystrophy syndromes v4.66 EPHX1 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: EPHX1.
Severe insulin resistance and lipodystrophy syndromes v4.66 BLM Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: BLM.
Severe insulin resistance and lipodystrophy syndromes v4.66 ALMS1 Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: ALMS1.
Severe insulin resistance and lipodystrophy syndromes v4.66 WRN Achchuthan Shanmugasundram commented on gene: WRN: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PSMB8 Achchuthan Shanmugasundram commented on gene: PSMB8: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PSMB4 Achchuthan Shanmugasundram commented on gene: PSMB4: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 POC1A Achchuthan Shanmugasundram commented on gene: POC1A: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PIK3R1 Achchuthan Shanmugasundram commented on gene: PIK3R1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PCYT1A Achchuthan Shanmugasundram commented on gene: PCYT1A: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 PCNT Achchuthan Shanmugasundram commented on gene: PCNT: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 MFN2 Achchuthan Shanmugasundram commented on gene: MFN2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 EPHX1 Achchuthan Shanmugasundram commented on gene: EPHX1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 BLM Achchuthan Shanmugasundram commented on gene: BLM: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.66 ALMS1 Achchuthan Shanmugasundram commented on gene: ALMS1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Severe insulin resistance and lipodystrophy syndromes v4.65 WRN Achchuthan Shanmugasundram Source Expert Review Green was added to WRN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PSMB8 Achchuthan Shanmugasundram Source Expert Review Green was added to PSMB8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PSMB4 Achchuthan Shanmugasundram Source Expert Review Green was added to PSMB4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 POC1A Achchuthan Shanmugasundram Source Expert Review Green was added to POC1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PIK3R1 Achchuthan Shanmugasundram Source Expert Review Green was added to PIK3R1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PCYT1A Achchuthan Shanmugasundram Source Expert Review Green was added to PCYT1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 PCNT Achchuthan Shanmugasundram Source Expert Review Green was added to PCNT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 MFN2 Achchuthan Shanmugasundram Source Expert Review Green was added to MFN2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 EPHX1 Achchuthan Shanmugasundram Source Expert Review Green was added to EPHX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 BLM Achchuthan Shanmugasundram Source Expert Review Green was added to BLM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.65 ALMS1 Achchuthan Shanmugasundram Source Expert Review Green was added to ALMS1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Childhood interstitial lung disease v0.4 RAB5B Achchuthan Shanmugasundram Classified gene: RAB5B as Amber List (moderate evidence)
Childhood interstitial lung disease v0.4 RAB5B Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is only one human case and functional evidence from C. elegans and proband's lung biopsy reported so far, this gene should be rated amber with current evidence.
Childhood interstitial lung disease v0.4 RAB5B Achchuthan Shanmugasundram Gene: rab5b has been classified as Amber List (Moderate Evidence).
Childhood interstitial lung disease v0.3 RAB5B Achchuthan Shanmugasundram changed review comment from: PMID:35121658 reported a female child of Pakistani descent presenting with interstitial lung disease (ILD) suggestive of a surfactant dysfunction disorder, dysmorphic features, and global developmental delay. A de novo heterozygous variant in RAB5B gene (c.406G>C/ p.Asp136His) was identified via trio exome sequencing and confirmed by Sanger sequencing.

There is functional evidence available from Caenorhabditis elegans, where knocking the proband variant into the conserved position (Asp135) of the ortholog showed that the variant is damaging, producing a strong dominant negative gene product. Evidence is also available from immunostaining studies of the proband's lung biopsy, indicating dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease.

This gene has not yet been associated with any phenotypes either in ClinGen, Gene2Phenotype or PanelApp Australia; to: PMID:35121658 reported a female child of Pakistani descent presenting with interstitial lung disease (ILD) suggestive of a surfactant dysfunction disorder, dysmorphic features, and global developmental delay. A de novo heterozygous variant in RAB5B gene (c.406G>C/ p.Asp136His) was identified via trio exome sequencing and confirmed by Sanger sequencing.

There is functional evidence available from Caenorhabditis elegans, where knocking the proband variant into the conserved position (Asp135) of the ortholog showed that the variant is damaging, producing a strong dominant negative gene product. Evidence is also available from immunostaining studies of the proband's lung biopsy, indicating dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease.

This gene has not yet been associated with any phenotypes either in ClinGen, Gene2Phenotype or PanelApp Australia.
Childhood interstitial lung disease v0.3 RAB5B Achchuthan Shanmugasundram edited their review of gene: RAB5B: Added comment: PMID:35121658 reported a female child of Pakistani descent presenting with interstitial lung disease (ILD) suggestive of a surfactant dysfunction disorder, dysmorphic features, and global developmental delay. A de novo heterozygous variant in RAB5B gene (c.406G>C/ p.Asp136His) was identified via trio exome sequencing and confirmed by Sanger sequencing.

There is functional evidence available from Caenorhabditis elegans, where knocking the proband variant into the conserved position (Asp135) of the ortholog showed that the variant is damaging, producing a strong dominant negative gene product. Evidence is also available from immunostaining studies of the proband's lung biopsy, indicating dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease.

This gene has not yet been associated with any phenotypes either in ClinGen, Gene2Phenotype or PanelApp Australia; Changed rating: AMBER
Mosaic skin disorders - deep sequencing v3.25 MVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: MVK.
Mosaic skin disorders - deep sequencing v3.25 MVK Ida Ertmanska edited their review of gene: MVK: Added comment: Comment on list classification: There are at least 9 unrelated families reported in literature with porokeratosis / disseminated superficial actinic porokeratosis (DSAP), with heterozygous germline mutations in MVK, with confirmed postnatal second-hit mosaic MVK mutation in 2 cases. Other genes in the pathway have been implicated in porokeratosis. Based on available evidence, this gene should be promoted to Green for Mosaic skin disorders - deep sequencing.; Changed rating: GREEN
Mosaic skin disorders - deep sequencing v3.25 MVK Ida Ertmanska Phenotypes for gene: MVK were changed from Porokeratosis 3, multiple types, OMIM:175900 to Porokeratosis 3, multiple types, OMIM:175900; porokeratosis 3, disseminated superficial actinic type, MONDO:0008293
Mosaic skin disorders - deep sequencing v3.24 MVK Ida Ertmanska Publications for gene: MVK were set to 24781643
Mosaic skin disorders - deep sequencing v3.23 MVK Ida Ertmanska Classified gene: MVK as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v3.23 MVK Ida Ertmanska Gene: mvk has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v3.22 MVK Ida Ertmanska Tag curated_removed was removed from gene: MVK.
Mosaic skin disorders - deep sequencing v3.22 MVK Ida Ertmanska reviewed gene: MVK: Rating: AMBER; Mode of pathogenicity: None; Publications: 22983302, 26794421, 31207227, 31753123, 39386107; Phenotypes: Porokeratosis 3, multiple types, OMIM:175900, porokeratosis 3, disseminated superficial actinic type, MONDO:0008293; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare genetic inflammatory skin disorders v4.13 MVK Ida Ertmanska Phenotypes for gene: MVK were changed from Porokeratosis 3, multiple types, OMIM:175900 to Porokeratosis 3, multiple types, OMIM:175900; porokeratosis 3, disseminated superficial actinic type, MONDO:0008293
Rare genetic inflammatory skin disorders v4.12 MVK Ida Ertmanska Publications for gene: MVK were set to 26794421; 39386107
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska changed review comment from: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 31753123 Atzmony et al., 2019
Authors pose that biallelic mutations are needed to cause mevalonate kinase deficiency (MKD), with mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) being on the MKD spectrum (HIDS being the milder presentation, and mevalonic aciduria on the severe end). Other genes in the pathway have been implicated in porokeratosis: MVD, PMVK and FDPS.

PMID: 31207227 Kubo et al., 2019
DSAP7 - Japanese patient with disseminated superficial actinic porokeratosis - Heterozygote of MVK c.1073A>C (p.Q358P) mutation with two postnatal second-hit epidermis specific mutations in MVK: c.575G>A and c.602C>T.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic DSAP cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature; to: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 31753123 Atzmony et al., 2019
Authors pose that biallelic mutations are needed to cause mevalonate kinase deficiency (MKD), with mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) being on the MKD spectrum (HIDS being the milder presentation, and mevalonic aciduria on the severe end). Other genes in the pathway have been implicated in porokeratosis: MVD, PMVK and FDPS.

PMID: 31207227 Kubo et al., 2019
DSAP7 - Japanese patient with disseminated superficial actinic porokeratosis - Heterozygote of MVK c.1073A>C (p.Q358P) mutation with two postnatal second-hit epidermis specific mutations in MVK: c.575G>A and c.602C>T.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska edited their review of gene: MVK: Added comment: Comment on list classification: There are at least 9 unrelated families reported in literature with porokeratosis / disseminated superficial actinic porokeratosis (DSAP), with heterozygous germline mutations in MVK, with confirmed postnatal second-hit mosaic MVK mutation in 2 cases. Other genes in the pathway have been implicated in porokeratosis. Based on available evidence, this gene should be promoted to Green for Rare genetic inflammatory skin disorders.; Changed phenotypes to: Porokeratosis 3, multiple types, OMIM:175900, porokeratosis 3, disseminated superficial actinic type, MONDO:0008293
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska edited their review of gene: MVK: Changed publications to: 22983302, 26794421, 31207227, 31753123, 39386107
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska Classified gene: MVK as Amber List (moderate evidence)
Rare genetic inflammatory skin disorders v4.11 MVK Ida Ertmanska Gene: mvk has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v4.10 MVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: MVK.
Rare genetic inflammatory skin disorders v4.10 MVK Ida Ertmanska changed review comment from: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic DSAP cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature; to: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 31753123 Atzmony et al., 2019
Authors pose that biallelic mutations are needed to cause mevalonate kinase deficiency (MKD), with mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) being on the MKD spectrum (HIDS being the milder presentation, and mevalonic aciduria on the severe end). Other genes in the pathway have been implicated in porokeratosis: MVD, PMVK and FDPS.

PMID: 31207227 Kubo et al., 2019
DSAP7 - Japanese patient with disseminated superficial actinic porokeratosis - Heterozygote of MVK c.1073A>C (p.Q358P) mutation with two postnatal second-hit epidermis specific mutations in MVK: c.575G>A and c.602C>T.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic DSAP cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature
Rare genetic inflammatory skin disorders v4.10 MVK Ida Ertmanska gene: MVK was added
gene: MVK was added to Rare genetic inflammatory skin disorders. Sources: Literature
Mode of inheritance for gene: MVK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MVK were set to 26794421; 39386107
Phenotypes for gene: MVK were set to Porokeratosis 3, multiple types, OMIM:175900
Review for gene: MVK was set to GREEN
Added comment: PMID: 39386107 Zhao et al., 2024
Epidermal second-hit mutation in MVK gene associated with linear porokeratosis. Reported a case of 6-year-old boy diagnosed with linear porokeratosis and a germline heterozygous MVK c.389_394del: p.D130_I131del mutation, along with somatic LOH confined to the lesional epidermis. Father, heterozygous for the germline MVK mutation, was unaffected. The MVK c.389_394del mutation was shown to be mosaic in affected skin lesions (59% mutant vs 41% WT).
Method: panel sequencing targeting ∼500 causative genes of genodermatoses on DNA.

PMID: 26794421 Liu et al., 2016
Report of three mutations in the MVK gene in six sporadic DSAP cases with disseminated superficial actinic porokeratosis (DSAP). Method: direct sequencing of MVK. Variants detected: p.Gly335Asp, p.Pro11Ser, p.Gly376Ser. All three mutations were shown to reduce protein stability compared to WT.

PMID: 22983302 Zhang et al., 2012
Family with 3 affected individuals with DSAP, heterozygous for MVK c.764T>C, p.Leu255Pro. Unaffected family members did not carry the mutation. Method: exome seq + linkage analysis.

MVK is associated with AD Porokeratosis 3, multiple types, OMIM:175900 (OMIM accessed 31st Dec 2025).
Sources: Literature
Rare genetic inflammatory skin disorders v4.9 PMVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: PMVK.
Pigmentary skin disorders v4.12 PMVK Ida Ertmanska Tag Q4_25_promote_green was removed from gene: PMVK.
Tag curated_removed tag was added to gene: PMVK.
Pigmentary skin disorders v4.12 PMVK Ida Ertmanska Classified gene: PMVK as No list
Pigmentary skin disorders v4.12 PMVK Ida Ertmanska Added comment: Comment on list classification: Gene added to Rare genetic inflammatory skin disorders instead.
Pigmentary skin disorders v4.12 PMVK Ida Ertmanska Gene: pmvk has been removed from the panel.
Pigmentary skin disorders v4.11 PMVK Ida Ertmanska Classified gene: PMVK as No list
Pigmentary skin disorders v4.11 PMVK Ida Ertmanska Gene: pmvk has been removed from the panel.
Pigmentary skin disorders v4.10 PMVK Ida Ertmanska Deleted their review
Rare genetic inflammatory skin disorders v4.9 PMVK Ida Ertmanska Classified gene: PMVK as Amber List (moderate evidence)
Rare genetic inflammatory skin disorders v4.9 PMVK Ida Ertmanska Added comment: Comment on list classification: There are at least 13 unrelated individuals reported in literature with germline heterozygous variants in PMVK, diagnosed with a type of porokeratosis. Based on the available evidence, PMVK should be promoted to Green for Rare genetic inflammatory skin disorders.
Rare genetic inflammatory skin disorders v4.9 PMVK Ida Ertmanska Gene: pmvk has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v4.8 PMVK Ida Ertmanska gene: PMVK was added
gene: PMVK was added to Rare genetic inflammatory skin disorders. Sources: Literature
Mode of inheritance for gene: PMVK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMVK were set to 26202976; 27052676; 37315547; 41296516
Phenotypes for gene: PMVK were set to Porokeratosis 1, multiple types, OMIM:175800; porokeratosis, MONDO:0006602
Review for gene: PMVK was set to GREEN
Added comment: Porokeratosis is characterised by keratotic lesions with an atrophic center rimmed by an elevated border. Disease onset is mostly in childhood or adolescence.

PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated cases (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES. Age of onset: mostly between 5-10 yo.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man, presented with persistent non-pruritic skin lesions since childhood: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Sources: Literature
Cerebellar hypoplasia v1.86 TSEN34 Ida Ertmanska Phenotypes for gene: TSEN34 were changed from Pontocerebellar Hypoplasia type 2C; Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia type 2C,612390 to Pontocerebellar hypoplasia type 2C, OMIM:612390; pontocerebellar hypoplasia type 2C, MONDO:0012891
Cerebellar hypoplasia v1.85 TSEN34 Ida Ertmanska Publications for gene: TSEN34 were set to PMID: 18711368
Cerebellar hypoplasia v1.84 TSEN34 Ida Ertmanska Classified gene: TSEN34 as Amber List (moderate evidence)
Cerebellar hypoplasia v1.84 TSEN34 Ida Ertmanska Added comment: Comment on list classification: There is only one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2 (PMID: 20952379 Namavar et al., 2011). While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature (see literature review on Intellectual disability panel). Hence, TSEN34 should be demoted from Green, until more evidence emerges.
Cerebellar hypoplasia v1.84 TSEN34 Ida Ertmanska Gene: tsen34 has been classified as Amber List (Moderate Evidence).
DDG2P v6.14 TSEN34 Ida Ertmanska commented on gene: TSEN34
Fetal anomalies v6.129 TSEN34 Ida Ertmanska Tag Q4_25_demote_amber tag was added to gene: TSEN34.
Fetal anomalies v6.129 TSEN34 Ida Ertmanska commented on gene: TSEN34: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges.
Fetal anomalies v6.129 TSEN34 Ida Ertmanska reviewed gene: TSEN34: Rating: AMBER; Mode of pathogenicity: None; Publications: 20952379, 27370523, 32476018, 37544645; Phenotypes: Pontocerebellar hypoplasia type 2C, OMIM:612390, pontocerebellar hypoplasia type 2C, MONDO:0012891; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.129 BHLHE22 Arina Puzriakova commented on gene: BHLHE22: PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.
Childhood onset hereditary spastic paraplegia v8.22 BHLHE22 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: BHLHE22.
Tag watchlist tag was added to gene: BHLHE22.
Childhood onset hereditary spastic paraplegia v8.22 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.; to: Comment on list classification: There is sufficient evidence to support classification of this gene as Green (tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients). However, PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.
Intellectual disability v9.209 BHLHE22 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: BHLHE22.
Tag watchlist tag was added to gene: BHLHE22.
Intellectual disability v9.209 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.; to: Comment on list classification: There is sufficient evidence to support classification of this gene as Green (6/7 individuals available for examination exhibited significant GDD and ID). However, PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.
Childhood interstitial lung disease v0.2 TMEM173 Achchuthan Shanmugasundram commented on gene: TMEM173: The 'new-gene-name' tag has been added as the official HGNC gene symbol for TMEM173 is STING1.
Childhood interstitial lung disease v0.2 TMEM173 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: TMEM173.
Childhood interstitial lung disease v0.2 TERC Achchuthan Shanmugasundram Tag locus-type-rna-long-non-coding tag was added to gene: TERC.
Childhood interstitial lung disease v0.2 NAF1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: NAF1.
Childhood interstitial lung disease v0.2 MARS Achchuthan Shanmugasundram commented on gene: MARS: Added new-gene-name tag, new approved HGNC gene symbol for MARS is MARS1
Childhood interstitial lung disease v0.2 MARS Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: MARS.
Childhood interstitial lung disease v0.2 CSF2RA Achchuthan Shanmugasundram Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Childhood interstitial lung disease v0.2 FARSB Achchuthan Shanmugasundram reviewed gene: FARSB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Rajab interstitial lung disease with brain calcifications 1, OMIM:613658, Rajab interstitial lung disease with brain calcifications 1, MONDO:0100215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 FARSA Achchuthan Shanmugasundram reviewed gene: FARSA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013, Rajab interstitial lung disease with brain calcifications 2, MONDO:0100220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 LRBA Achchuthan Shanmugasundram reviewed gene: LRBA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: combined immunodeficiency due to LRBA deficiency, MONDO:0013863, Immunodeficiency, common variable, 8, with autoimmunity, OMIM:614700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 SLC7A7 Achchuthan Shanmugasundram reviewed gene: SLC7A7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: lysinuric protein intolerance, MONDO:0009109, Lysinuric protein intolerance, OMIM:222700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 GATA2 Achchuthan Shanmugasundram reviewed gene: GATA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Immunodeficiency 21, OMIM:614172, monocytopenia with susceptibility to infections, MONDO:0013607; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 RAB5B Achchuthan Shanmugasundram reviewed gene: RAB5B: Rating: GREEN; Mode of pathogenicity: ; Publications: 35121658; Phenotypes: interstitial lung disease, MONDO:0015925; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 TBX4 Achchuthan Shanmugasundram reviewed gene: TBX4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, OMIM:147891, Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, OMIM:601360, congenital alveolar dysplasia due to TBX4, MONDO:0100097, autosomal recessive amelia, MONDO:0011054; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 PSMB9 Achchuthan Shanmugasundram reviewed gene: PSMB9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: proteasome-associated autoinflammatory syndrome 6, MONDO:0968983, Proteasome-associated autoinflammatory syndrome 6, OMIM:620796; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 OAS1 Achchuthan Shanmugasundram reviewed gene: OAS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary alveolar proteinosis with hypogammaglobulinemia, MONDO:0020840, Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia, OMIM:618042; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 NKX2-1 Achchuthan Shanmugasundram reviewed gene: NKX2-1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Choreoathetosis, hypothyroidism, and neonatal respiratory distress, OMIM:610978, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, MONDO:0100520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 CSF2RB Achchuthan Shanmugasundram reviewed gene: CSF2RB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: surfactant metabolism dysfunction, pulmonary, 5, MONDO:0013712, Surfactant metabolism dysfunction, pulmonary, 5, OMIM:614370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 BMPR2 Achchuthan Shanmugasundram reviewed gene: BMPR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated, OMIM:178600, Pulmonary venoocclusive disease 1, OMIM:265450, pulmonary hypertension, primary, 1, MONDO:0024533, pulmonary venoocclusive disease 1, MONDO:0020713, Pulmonary hypertension, familial primary, 1, with or without HHT, OMIM:178600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 PSMB8 Achchuthan Shanmugasundram reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: proteasome-associated autoinflammatory syndrome 1, MONDO:0054698, Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 RTEL1 Achchuthan Shanmugasundram reviewed gene: RTEL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, MONDO:0014613, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 3, OMIM:616373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 ABCA3 Achchuthan Shanmugasundram reviewed gene: ABCA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921, interstitial lung disease due to ABCA3 deficiency, MONDO:0012582; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 CSF2RA Achchuthan Shanmugasundram reviewed gene: CSF2RA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 4, OMIM:300770, surfactant metabolism dysfunction, pulmonary, 4, MONDO:0010424; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 SLC34A2 Achchuthan Shanmugasundram reviewed gene: SLC34A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary alveolar microlithiasis, MONDO:0009928, Pulmonary alveolar microlithiasis, OMIM:265100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 PSMB4 Achchuthan Shanmugasundram reviewed gene: PSMB4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: proteasome-associated autoinflammatory syndrome 3, MONDO:0054699, ?Proteasome-associated autoinflammatory syndrome 3 and digenic forms, OMIM:617591; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 MARS Achchuthan Shanmugasundram reviewed gene: MARS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Interstitial lung and liver disease, OMIM:615486, severe early-onset pulmonary alveolar proteinosis due to MARS deficiency, MONDO:0014206; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 SFTPC Achchuthan Shanmugasundram reviewed gene: SFTPC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: surfactant metabolism dysfunction, pulmonary, 2, MONDO:0024465, SFTPC-related interstitial lung disease, MONDO:0018603, Surfactant metabolism dysfunction, pulmonary, 2, OMIM:610913; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 ITGA3 Achchuthan Shanmugasundram reviewed gene: ITGA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, OMIM:614748, epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, MONDO:0013881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 TMEM173 Achchuthan Shanmugasundram reviewed gene: TMEM173: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: STING-associated vasculopathy, infantile-onset, OMIM:615934, STING-associated vasculopathy with onset in infancy, MONDO:0014405; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 COPA Achchuthan Shanmugasundram reviewed gene: COPA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Autoinflammation and autoimmunity, systemic, with immune dysregulation 1}, OMIM:616414, autoimmune interstitial lung disease-arthritis syndrome, MONDO:0014629; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 NAF1 Achchuthan Shanmugasundram reviewed gene: NAF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MONDO:0957261, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, OMIM:620365; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 SFTPB Achchuthan Shanmugasundram reviewed gene: SFTPB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: surfactant metabolism dysfunction, pulmonary, 1, MONDO:0009929, Surfactant metabolism dysfunction, pulmonary, 1, OMIM:265120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 FOXF1 Achchuthan Shanmugasundram reviewed gene: FOXF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380, alveolar capillary dysplasia with misalignment of pulmonary veins, MONDO:0009934; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 STAT5B Achchuthan Shanmugasundram reviewed gene: STAT5B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: growth hormone insensitivity with immune dysregulation 1, autosomal recessive, MONDO:0100211, Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, OMIM:245590; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 TINF2 Achchuthan Shanmugasundram reviewed gene: TINF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Dyskeratosis congenita, autosomal dominant 3, OMIM:613990; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 TERC Achchuthan Shanmugasundram reviewed gene: TERC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2, MONDO:0013879, Dyskeratosis congenita, autosomal dominant 1, OMIM:127550, dyskeratosis congenita, autosomal dominant 1, MONDO:0007485, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 2, OMIM:614743; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 SFTPA2 Achchuthan Shanmugasundram reviewed gene: SFTPA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Interstitial lung disease 2, OMIM:178500, interstitial lung disease 2, MONDO:0800497; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 FLNA Achchuthan Shanmugasundram reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: heterotopia, periventricular, X-linked dominant, MONDO:0010233, Heterotopia, periventricular, 1, OMIM:300049; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Childhood interstitial lung disease v0.2 STAT1 Achchuthan Shanmugasundram reviewed gene: STAT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Immunodeficiency 31C, chronic mucocutaneous candidiasis, autosomal dominant, OMIM:614162, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, MONDO:0013599; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 PARN Achchuthan Shanmugasundram reviewed gene: PARN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4, OMIM:616371, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, MONDO:0014612; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood interstitial lung disease v0.2 TERT Achchuthan Shanmugasundram reviewed gene: TERT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Dyskeratosis congenita, autosomal recessive 4, OMIM:613989, dyskeratosis congenita, autosomal dominant 2, MONDO:0013521, Dyskeratosis congenita, autosomal dominant 2, OMIM:613989, Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 1, OMIM:614742, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, MONDO:0013878; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood interstitial lung disease v0.2 SFTPA1 Achchuthan Shanmugasundram reviewed gene: SFTPA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Interstitial lung disease 1, OMIM:619611, interstitial lung disease 1, MONDO:0030608; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Childhood interstitial lung disease v0.1 FARSB Achchuthan Shanmugasundram gene: FARSB was added
gene: FARSB was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FARSB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FARSB were set to Rajab interstitial lung disease with brain calcifications 1, OMIM:613658; Rajab interstitial lung disease with brain calcifications 1, MONDO:0100215
Childhood interstitial lung disease v0.1 FARSA Achchuthan Shanmugasundram gene: FARSA was added
gene: FARSA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013; Rajab interstitial lung disease with brain calcifications 2, MONDO:0100220
Childhood interstitial lung disease v0.1 LRBA Achchuthan Shanmugasundram gene: LRBA was added
gene: LRBA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: LRBA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LRBA were set to Immunodeficiency, common variable, 8, with autoimmunity, OMIM:614700; combined immunodeficiency due to LRBA deficiency, MONDO:0013863
Childhood interstitial lung disease v0.1 SLC7A7 Achchuthan Shanmugasundram gene: SLC7A7 was added
gene: SLC7A7 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SLC7A7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC7A7 were set to Lysinuric protein intolerance, OMIM:222700; lysinuric protein intolerance, MONDO:0009109
Childhood interstitial lung disease v0.1 GATA2 Achchuthan Shanmugasundram gene: GATA2 was added
gene: GATA2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GATA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GATA2 were set to Immunodeficiency 21, OMIM:614172; monocytopenia with susceptibility to infections, MONDO:0013607
Childhood interstitial lung disease v0.1 RAB5B Achchuthan Shanmugasundram gene: RAB5B was added
gene: RAB5B was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: RAB5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB5B were set to 35121658
Phenotypes for gene: RAB5B were set to interstitial lung disease, MONDO:0015925
Childhood interstitial lung disease v0.1 TBX4 Achchuthan Shanmugasundram gene: TBX4 was added
gene: TBX4 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TBX4 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: TBX4 were set to autosomal recessive amelia, MONDO:0011054; Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, OMIM:147891; Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, OMIM:601360; congenital alveolar dysplasia due to TBX4, MONDO:0100097
Childhood interstitial lung disease v0.1 PSMB9 Achchuthan Shanmugasundram gene: PSMB9 was added
gene: PSMB9 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PSMB9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PSMB9 were set to proteasome-associated autoinflammatory syndrome 6, MONDO:0968983; Proteasome-associated autoinflammatory syndrome 6, OMIM:620796
Childhood interstitial lung disease v0.1 OAS1 Achchuthan Shanmugasundram gene: OAS1 was added
gene: OAS1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: OAS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: OAS1 were set to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia, OMIM:618042; pulmonary alveolar proteinosis with hypogammaglobulinemia, MONDO:0020840
Childhood interstitial lung disease v0.1 NKX2-1 Achchuthan Shanmugasundram gene: NKX2-1 was added
gene: NKX2-1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NKX2-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NKX2-1 were set to Choreoathetosis, hypothyroidism, and neonatal respiratory distress, OMIM:610978; NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, MONDO:0100520
Childhood interstitial lung disease v0.1 CSF2RB Achchuthan Shanmugasundram gene: CSF2RB was added
gene: CSF2RB was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CSF2RB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CSF2RB were set to Surfactant metabolism dysfunction, pulmonary, 5, OMIM:614370; surfactant metabolism dysfunction, pulmonary, 5, MONDO:0013712
Childhood interstitial lung disease v0.1 BMPR2 Achchuthan Shanmugasundram gene: BMPR2 was added
gene: BMPR2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: BMPR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BMPR2 were set to Pulmonary hypertension, familial primary, 1, with or without HHT, OMIM:178600; pulmonary hypertension, primary, 1, MONDO:0024533; Pulmonary venoocclusive disease 1, OMIM:265450; Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated, OMIM:178600; pulmonary venoocclusive disease 1, MONDO:0020713
Childhood interstitial lung disease v0.1 PSMB8 Achchuthan Shanmugasundram gene: PSMB8 was added
gene: PSMB8 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PSMB8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PSMB8 were set to proteasome-associated autoinflammatory syndrome 1, MONDO:0054698; Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040
Childhood interstitial lung disease v0.1 RTEL1 Achchuthan Shanmugasundram gene: RTEL1 was added
gene: RTEL1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: RTEL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RTEL1 were set to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 3, OMIM:616373; pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, MONDO:0014613
Childhood interstitial lung disease v0.1 ABCA3 Achchuthan Shanmugasundram gene: ABCA3 was added
gene: ABCA3 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ABCA3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ABCA3 were set to interstitial lung disease due to ABCA3 deficiency, MONDO:0012582; Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921
Childhood interstitial lung disease v0.1 CSF2RA Achchuthan Shanmugasundram gene: CSF2RA was added
gene: CSF2RA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CSF2RA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CSF2RA were set to Surfactant metabolism dysfunction, pulmonary, 4, OMIM:300770; surfactant metabolism dysfunction, pulmonary, 4, MONDO:0010424
Childhood interstitial lung disease v0.1 SLC34A2 Achchuthan Shanmugasundram gene: SLC34A2 was added
gene: SLC34A2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SLC34A2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC34A2 were set to Pulmonary alveolar microlithiasis, OMIM:265100; pulmonary alveolar microlithiasis, MONDO:0009928
Childhood interstitial lung disease v0.1 PSMB4 Achchuthan Shanmugasundram gene: PSMB4 was added
gene: PSMB4 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PSMB4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PSMB4 were set to proteasome-associated autoinflammatory syndrome 3, MONDO:0054699; ?Proteasome-associated autoinflammatory syndrome 3 and digenic forms, OMIM:617591
Childhood interstitial lung disease v0.1 MARS Achchuthan Shanmugasundram gene: MARS was added
gene: MARS was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: MARS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MARS were set to severe early-onset pulmonary alveolar proteinosis due to MARS deficiency, MONDO:0014206; Interstitial lung and liver disease, OMIM:615486
Childhood interstitial lung disease v0.1 SFTPC Achchuthan Shanmugasundram gene: SFTPC was added
gene: SFTPC was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SFTPC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SFTPC were set to Surfactant metabolism dysfunction, pulmonary, 2, OMIM:610913; SFTPC-related interstitial lung disease, MONDO:0018603; surfactant metabolism dysfunction, pulmonary, 2, MONDO:0024465
Childhood interstitial lung disease v0.1 ITGA3 Achchuthan Shanmugasundram gene: ITGA3 was added
gene: ITGA3 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ITGA3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ITGA3 were set to epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, MONDO:0013881; Epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome, OMIM:614748
Childhood interstitial lung disease v0.1 TMEM173 Achchuthan Shanmugasundram gene: TMEM173 was added
gene: TMEM173 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TMEM173 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TMEM173 were set to STING-associated vasculopathy with onset in infancy, MONDO:0014405; STING-associated vasculopathy, infantile-onset, OMIM:615934
Childhood interstitial lung disease v0.1 COPA Achchuthan Shanmugasundram gene: COPA was added
gene: COPA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: COPA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: COPA were set to autoimmune interstitial lung disease-arthritis syndrome, MONDO:0014629; {Autoinflammation and autoimmunity, systemic, with immune dysregulation 1}, OMIM:616414
Childhood interstitial lung disease v0.1 NAF1 Achchuthan Shanmugasundram gene: NAF1 was added
gene: NAF1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NAF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NAF1 were set to pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MONDO:0957261; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, OMIM:620365
Childhood interstitial lung disease v0.1 SFTPB Achchuthan Shanmugasundram gene: SFTPB was added
gene: SFTPB was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SFTPB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SFTPB were set to Surfactant metabolism dysfunction, pulmonary, 1, OMIM:265120; surfactant metabolism dysfunction, pulmonary, 1, MONDO:0009929
Childhood interstitial lung disease v0.1 FOXF1 Achchuthan Shanmugasundram gene: FOXF1 was added
gene: FOXF1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FOXF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FOXF1 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380; alveolar capillary dysplasia with misalignment of pulmonary veins, MONDO:0009934
Childhood interstitial lung disease v0.1 STAT5B Achchuthan Shanmugasundram gene: STAT5B was added
gene: STAT5B was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: STAT5B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STAT5B were set to Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, OMIM:245590; growth hormone insensitivity with immune dysregulation 1, autosomal recessive, MONDO:0100211
Childhood interstitial lung disease v0.1 TINF2 Achchuthan Shanmugasundram gene: TINF2 was added
gene: TINF2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TINF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TINF2 were set to Dyskeratosis congenita, autosomal dominant 3, OMIM:613990
Childhood interstitial lung disease v0.1 TERC Achchuthan Shanmugasundram gene: TERC was added
gene: TERC was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TERC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TERC were set to dyskeratosis congenita, autosomal dominant 1, MONDO:0007485; Dyskeratosis congenita, autosomal dominant 1, OMIM:127550; pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2, MONDO:0013879; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 2, OMIM:614743
Childhood interstitial lung disease v0.1 SFTPA2 Achchuthan Shanmugasundram gene: SFTPA2 was added
gene: SFTPA2 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SFTPA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SFTPA2 were set to interstitial lung disease 2, MONDO:0800497; Interstitial lung disease 2, OMIM:178500
Childhood interstitial lung disease v0.1 FLNA Achchuthan Shanmugasundram gene: FLNA was added
gene: FLNA was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FLNA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: FLNA were set to heterotopia, periventricular, X-linked dominant, MONDO:0010233; Heterotopia, periventricular, 1, OMIM:300049
Childhood interstitial lung disease v0.1 STAT1 Achchuthan Shanmugasundram gene: STAT1 was added
gene: STAT1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: STAT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: STAT1 were set to Immunodeficiency 31C, chronic mucocutaneous candidiasis, autosomal dominant, OMIM:614162; autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, MONDO:0013599
Childhood interstitial lung disease v0.1 PARN Achchuthan Shanmugasundram gene: PARN was added
gene: PARN was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PARN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PARN were set to pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, MONDO:0014612; Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4, OMIM:616371
Childhood interstitial lung disease v0.1 TERT Achchuthan Shanmugasundram gene: TERT was added
gene: TERT was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TERT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: TERT were set to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 1, OMIM:614742; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; dyskeratosis congenita, autosomal dominant 2, MONDO:0013521; pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, MONDO:0013878
Childhood interstitial lung disease v0.1 SFTPA1 Achchuthan Shanmugasundram gene: SFTPA1 was added
gene: SFTPA1 was added to Childhood interstitial lung disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SFTPA1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: SFTPA1 were set to Interstitial lung disease 1, OMIM:619611; interstitial lung disease 1, MONDO:0030608
Childhood interstitial lung disease v0.0 Achchuthan Shanmugasundram Added Panel Childhood interstitial lung disease
Set list of related panels to R462
Set panel types to: GMS Rare Disease Virtual; GMS Rare Disease
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram changed review comment from: It is only duplications in this gene are relevant for this panel.; to: Duplications in this gene are only relevant for this panel. Hence, 'gene-duplication' tag has been added.
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram Tag gene-duplication tag was added to gene: T.
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram commented on gene: T: It is only duplications in this gene are relevant for this panel.
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram commented on gene: T: Added new-gene-name tag, new approved HGNC gene symbol is TBXT.
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram reviewed gene: T: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 T Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: T.
Sarcoma of possible germline origin v0.2 TP53 Achchuthan Shanmugasundram reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Colorectal cancer}, OMIM:114500, basal cell carcinoma, susceptibility to, 7, MONDO:0013876, adrenocortical carcinoma, hereditary, MONDO:0008734, {Glioma susceptibility 1}, OMIM:137800, nasopharyngeal carcinoma, susceptibility to, 1, MONDO:0011775, Li-Fraumeni syndrome, OMIM:151623, Li-Fraumeni syndrome, MONDO:0018875, {Basal cell carcinoma 7}, OMIM:614740, choroid plexus papilloma, MONDO:0009837, {Adrenocortical carcinoma, pediatric}, OMIM:202300, {Choroid plexus papilloma}, OMIM:260500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 RECQL4 Achchuthan Shanmugasundram reviewed gene: RECQL4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Rothmund-Thomson syndrome, type 2, OMIM:268400, Rothmund-Thomson syndrome type 2, MONDO:0016369; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sarcoma of possible germline origin v0.2 WRN Achchuthan Shanmugasundram reviewed gene: WRN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Werner syndrome, MONDO:0010196, Werner syndrome, OMIM:277700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sarcoma of possible germline origin v0.2 RB1 Achchuthan Shanmugasundram reviewed gene: RB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Retinoblastoma, OMIM:180200, Retinoblastoma, trilateral, OMIM:180200, hereditary retinoblastoma, MONDO:0018160; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 PTPN11 Achchuthan Shanmugasundram reviewed gene: PTPN11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome 1, OMIM:163950, Noonan syndrome 1, MONDO:0008104; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: neurofibromatosis type 1, MONDO:0018975, Neurofibromatosis, type 1, OMIM:162200, neurofibromatosis-Noonan syndrome, MONDO:0011035, Neurofibromatosis, familial spinal, OMIM:162210, Leukemia, juvenile myelomonocytic, OMIM:607785, Neurofibromatosis-Noonan syndrome, OMIM:601321; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 NBN Achchuthan Shanmugasundram reviewed gene: NBN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Nijmegen breakage syndrome, OMIM:251260, Nijmegen breakage syndrome, MONDO:0009623; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sarcoma of possible germline origin v0.2 KRAS Achchuthan Shanmugasundram reviewed gene: KRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome 3, OMIM:609942, cardiofaciocutaneous syndrome 2, MONDO:0014112, Noonan syndrome 3, MONDO:0012371, Cardiofaciocutaneous syndrome 2, OMIM:615278, RAS-associated autoimmune leukoproliferative disorder, OMIM:614470; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 HRAS Achchuthan Shanmugasundram reviewed gene: HRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Costello syndrome, MONDO:0009026, Costello syndrome, OMIM:218040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 DICER1 Achchuthan Shanmugasundram reviewed gene: DICER1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pleuropulmonary blastoma, OMIM:601200, Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800, Rhabdomyosarcoma, embryonal, 2, OMIM:180295, rhabdomyosarcoma, embryonal, 2, MONDO:0859046, DICER1-related tumor predisposition, MONDO:0100216; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sarcoma of possible germline origin v0.2 CBL Achchuthan Shanmugasundram reviewed gene: CBL: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563, CBL-related disorder, MONDO:0013308, ?Juvenile myelomonocytic leukemia, OMIM:607785; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.2 BUB1B Achchuthan Shanmugasundram reviewed gene: BUB1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: mosaic variegated aneuploidy syndrome 1, MONDO:0009759, Mosaic variegated aneuploidy syndrome 1, OMIM:257300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sarcoma of possible germline origin v0.1 TP53 Achchuthan Shanmugasundram gene: TP53 was added
gene: TP53 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TP53 were set to {Colorectal cancer}, OMIM:114500; basal cell carcinoma, susceptibility to, 7, MONDO:0013876; adrenocortical carcinoma, hereditary, MONDO:0008734; {Glioma susceptibility 1}, OMIM:137800; nasopharyngeal carcinoma, susceptibility to, 1, MONDO:0011775; Li-Fraumeni syndrome, OMIM:151623; Li-Fraumeni syndrome, MONDO:0018875; {Basal cell carcinoma 7}, OMIM:614740; choroid plexus papilloma, MONDO:0009837; {Adrenocortical carcinoma, pediatric}, OMIM:202300; {Choroid plexus papilloma}, OMIM:260500
Sarcoma of possible germline origin v0.1 T Achchuthan Shanmugasundram gene: T was added
gene: T was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: T was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sarcoma of possible germline origin v0.1 RECQL4 Achchuthan Shanmugasundram gene: RECQL4 was added
gene: RECQL4 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: RECQL4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RECQL4 were set to Rothmund-Thomson syndrome, type 2, OMIM:268400; Rothmund-Thomson syndrome type 2, MONDO:0016369
Sarcoma of possible germline origin v0.1 WRN Achchuthan Shanmugasundram gene: WRN was added
gene: WRN was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: WRN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WRN were set to Werner syndrome, MONDO:0010196; Werner syndrome, OMIM:277700
Sarcoma of possible germline origin v0.1 RB1 Achchuthan Shanmugasundram gene: RB1 was added
gene: RB1 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: RB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RB1 were set to Retinoblastoma, OMIM:180200; Retinoblastoma, trilateral, OMIM:180200; hereditary retinoblastoma, MONDO:0018160
Sarcoma of possible germline origin v0.1 PTPN11 Achchuthan Shanmugasundram gene: PTPN11 was added
gene: PTPN11 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PTPN11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PTPN11 were set to Noonan syndrome 1, OMIM:163950; Noonan syndrome 1, MONDO:0008104
Sarcoma of possible germline origin v0.1 NF1 Achchuthan Shanmugasundram gene: NF1 was added
gene: NF1 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: NF1 were set to neurofibromatosis type 1, MONDO:0018975; Neurofibromatosis, type 1, OMIM:162200; neurofibromatosis-Noonan syndrome, MONDO:0011035; Neurofibromatosis, familial spinal, OMIM:162210; Leukemia, juvenile myelomonocytic, OMIM:607785; Neurofibromatosis-Noonan syndrome, OMIM:601321
Sarcoma of possible germline origin v0.1 NBN Achchuthan Shanmugasundram gene: NBN was added
gene: NBN was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NBN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NBN were set to Nijmegen breakage syndrome, OMIM:251260; Nijmegen breakage syndrome, MONDO:0009623
Sarcoma of possible germline origin v0.1 KRAS Achchuthan Shanmugasundram gene: KRAS was added
gene: KRAS was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: KRAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: KRAS were set to Noonan syndrome 3, OMIM:609942; cardiofaciocutaneous syndrome 2, MONDO:0014112; Noonan syndrome 3, MONDO:0012371; Cardiofaciocutaneous syndrome 2, OMIM:615278; RAS-associated autoimmune leukoproliferative disorder, OMIM:614470
Sarcoma of possible germline origin v0.1 HRAS Achchuthan Shanmugasundram gene: HRAS was added
gene: HRAS was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: HRAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: HRAS were set to Costello syndrome, MONDO:0009026; Costello syndrome, OMIM:218040
Sarcoma of possible germline origin v0.1 DICER1 Achchuthan Shanmugasundram gene: DICER1 was added
gene: DICER1 was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DICER1 were set to Pleuropulmonary blastoma, OMIM:601200; Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800; Rhabdomyosarcoma, embryonal, 2, OMIM:180295; rhabdomyosarcoma, embryonal, 2, MONDO:0859046; DICER1-related tumor predisposition, MONDO:0100216
Sarcoma of possible germline origin v0.1 CBL Achchuthan Shanmugasundram gene: CBL was added
gene: CBL was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CBL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: CBL were set to Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563; CBL-related disorder, MONDO:0013308; ?Juvenile myelomonocytic leukemia, OMIM:607785
Sarcoma of possible germline origin v0.1 BUB1B Achchuthan Shanmugasundram gene: BUB1B was added
gene: BUB1B was added to Sarcoma of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: BUB1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BUB1B were set to mosaic variegated aneuploidy syndrome 1, MONDO:0009759; Mosaic variegated aneuploidy syndrome 1, OMIM:257300
Sarcoma of possible germline origin v0.0 Achchuthan Shanmugasundram Added Panel Sarcoma of possible germline origin
Set list of related panels to R457
Set panel types to: GMS Rare Disease Virtual; GMS Rare Disease
Embryonal tumour of possible germline origin v0.5 ISCA-37401-Loss Achchuthan Shanmugasundram Phenotypes for Region: ISCA-37401-Loss were changed from Wilms tumor, aniridia, genitourinary anomalies and impaired intellectual development syndrome, OMIM:194072 to Wilms tumor, aniridia, genitourinary anomalies and impaired intellectual development syndrome, OMIM:194072; WAGR syndrome, MONDO:0008681
Embryonal tumour of possible germline origin v0.4 ISCA-37401-Loss Achchuthan Shanmugasundram edited their review of Region: ISCA-37401-Loss: Changed rating: GREEN; Changed phenotypes to: Wilms tumor, aniridia, genitourinary anomalies and impaired intellectual development syndrome, OMIM:194072, WAGR syndrome, MONDO:0008681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.4 ISCA-37401-Loss Achchuthan Shanmugasundram Added comment: Comment on phenotypes: The OMIM record (MIM #194072) was last accessed on 30 December 2025.
Embryonal tumour of possible germline origin v0.4 ISCA-37401-Loss Achchuthan Shanmugasundram Phenotypes for Region: ISCA-37401-Loss were changed from Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome; 194072 to Wilms tumor, aniridia, genitourinary anomalies and impaired intellectual development syndrome, OMIM:194072
Ataxia and cerebellar anomalies - narrow panel v8.41 ZNF865 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: ZNF865.
Ataxia and cerebellar anomalies - narrow panel v8.41 ZNF865 Ida Ertmanska Classified gene: ZNF865 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.41 ZNF865 Ida Ertmanska Gene: znf865 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.209 ZNF865 Ida Ertmanska Classified gene: ZNF865 as Amber List (moderate evidence)
Intellectual disability v9.209 ZNF865 Ida Ertmanska Gene: znf865 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.208 ZNF865 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: ZNF865.
Ataxia and cerebellar anomalies - narrow panel v8.40 ZNF865 Ida Ertmanska gene: ZNF865 was added
gene: ZNF865 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: ZNF865 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF865 were set to 40936200
Phenotypes for gene: ZNF865 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: ZNF865 was set to GREEN
Added comment: PMID: 40936200 Bradbrook et al., 2025
Report of 18 unrelated individuals (Caucasian / Latino ethnicity) with developmental delay and shared dysmorphic features, harbouring heterozygous variants in ZNF865. Method: WGS / WES. Majority described as severely delayed, with speech delay and moderate to severe learning difficulties; avg age of walking = 24 months, 9/18 patients presented with hypotonia, 1 patient diagnosed with epilepsy, 9/15 had digit anomalies.
On MRI, 8/14 patients had brain abnormalities, including hypoplasia of corpus callosum and ventriculomegaly. Shared dysmorphic features: broad nasal bridge, hypertelorism, low-set ears.
14 unique variants (nonsense of frameshift) were detected, mostly towards the C-terminus. Variants were confirmed as de novo in 15 individuals.

This gene is not yet linked to any phenotype in OMIM (accessed 30th Dec 2025).
Sources: Literature
Intellectual disability v9.208 ZNF865 Ida Ertmanska gene: ZNF865 was added
gene: ZNF865 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF865 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF865 were set to 40936200
Phenotypes for gene: ZNF865 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: ZNF865 was set to GREEN
Added comment: PMID: 40936200 Bradbrook et al., 2025
Report of 18 unrelated individuals (Caucasian / Latino ethnicity) with developmental delay and shared dysmorphic features, harbouring heterozygous variants in ZNF865. Method: WGS / WES. Majority described as severely delayed, with speech delay and moderate to severe learning difficulties; avg age of walking = 24 months, 9/18 patients presented with hypotonia, 1 patient diagnosed with epilepsy, 9/15 had digit anomalies.
On MRI, 8/14 patients had brain abnormalities, including hypoplasia of corpus callosum and ventriculomegaly. Shared dysmorphic features: broad nasal bridge, hypertelorism, low-set ears.
14 unique variants (nonsense of frameshift) were detected, mostly towards the C-terminus. Variants were confirmed as de novo in 15 individuals.

This gene is not yet linked to any phenotype in OMIM (accessed 30th Dec 2025).
Sources: Literature
Embryonal tumour of possible germline origin v0.3 ISCA-37401-Loss Achchuthan Shanmugasundram Entity copied from Childhood solid tumours v5.8
Embryonal tumour of possible germline origin v0.3 ISCA-37401-Loss Achchuthan Shanmugasundram Region: ISCA-37401-Loss was added
Region: ISCA-37401-Loss was added to Embryonal tumour of possible germline origin. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-37401-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37401-Loss were set to Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome; 194072
Embryonal tumour of possible germline origin v0.2 WT1 Achchuthan Shanmugasundram reviewed gene: WT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Frasier syndrome, OMIM:136680, Denys-Drash syndrome, OMIM:194080, Wilms tumor 1, MONDO:0008679, Frasier syndrome, MONDO:0007635, Denys-Drash syndrome, MONDO:0008682, Wilms tumor, type 1, OMIM:194070; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 TRIP13 Achchuthan Shanmugasundram reviewed gene: TRIP13: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: mosaic variegated aneuploidy syndrome 3, MONDO:0054736, Mosaic variegated aneuploidy syndrome 3, OMIM:617598; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Embryonal tumour of possible germline origin v0.2 TRIM37 Achchuthan Shanmugasundram reviewed gene: TRIM37: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: mulibrey nanism, MONDO:0009664, Mulibrey nanism, OMIM:253250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Embryonal tumour of possible germline origin v0.2 TRIM28 Achchuthan Shanmugasundram reviewed gene: TRIM28: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Wilms tumor 7, MONDO:0979876, Wilms tumor 7, OMIM:621332; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin v0.2 TP53 Achchuthan Shanmugasundram reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Basal cell carcinoma 7}, OMIM:614740, Li-Fraumeni syndrome, MONDO:0018875, adrenocortical carcinoma, hereditary, MONDO:0008734, nasopharyngeal carcinoma, susceptibility to, 1, MONDO:0011775, {Glioma susceptibility 1}, OMIM:137800, {Colorectal cancer}, OMIM:114500, {Adrenocortical carcinoma, pediatric}, OMIM:202300, choroid plexus papilloma, MONDO:0009837, Li-Fraumeni syndrome, OMIM:151623, {Choroid plexus papilloma}, OMIM:260500, basal cell carcinoma, susceptibility to, 7, MONDO:0013876; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 SUFU Achchuthan Shanmugasundram reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: basal cell nevus syndrome 2, MONDO:0958189, {Medulloblastoma}, OMIM:155255, {Meningioma, familial, susceptibility to}, OMIM:607174, Basal cell nevus syndrome 2, OMIM:620343; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 SOS1 Achchuthan Shanmugasundram reviewed gene: SOS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome 4, MONDO:0012547, Noonan syndrome 4, OMIM:610733; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 SMARCB1 Achchuthan Shanmugasundram reviewed gene: SMARCB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: SMARCB1-related schwannomatosis, MONDO:0024517, {Schwannomatosis-1, susceptibility to}, OMIM:162091, rhabdoid tumor predisposition syndrome 1, MONDO:0012252, {Rhabdoid tumor predisposition syndrome 1}, OMIM:609322; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 SMARCA4 Achchuthan Shanmugasundram reviewed gene: SMARCA4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Rhabdoid tumor predisposition syndrome 2}, OMIM:613325, Rhabdoid tumor predisposition syndrome 2, MONDO:0013224; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 REST Achchuthan Shanmugasundram reviewed gene: REST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Wilms tumor 6, MONDO:0014779, {Wilms tumor 6, susceptibility to}, OMIM:616806; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin v0.2 PTPN11 Achchuthan Shanmugasundram reviewed gene: PTPN11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome 1, MONDO:0008104, Noonan syndrome 1, OMIM:163950; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 PTCH1 Achchuthan Shanmugasundram reviewed gene: PTCH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Basal cell nevus syndrome 1, OMIM:109400, basal cell nevus syndrome 1, MONDO:0958174; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 PHOX2B Achchuthan Shanmugasundram reviewed gene: PHOX2B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: neuroblastoma, susceptibility to, 2, MONDO:0700041, Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, OMIM:209880, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, MONDO:0800026, {Neuroblastoma, susceptibility to, 2}, OMIM:613013; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 KRAS Achchuthan Shanmugasundram reviewed gene: KRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: RAS-associated autoimmune leukoproliferative disorder, OMIM:614470, cardiofaciocutaneous syndrome 2, MONDO:0014112, Cardiofaciocutaneous syndrome 2, OMIM:615278, Noonan syndrome 3, OMIM:609942, Noonan syndrome 3, MONDO:0012371; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 HRAS Achchuthan Shanmugasundram reviewed gene: HRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Costello syndrome, MONDO:0009026, Costello syndrome, OMIM:218040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 GPR161 Achchuthan Shanmugasundram reviewed gene: GPR161: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Medulloblastoma predisposition syndrome}, OMIM:155255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 GPC3 Achchuthan Shanmugasundram reviewed gene: GPC3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Simpson-Golabi-Behmel syndrome type 1, MONDO:0020602, Simpson-Golabi-Behmel syndrome, type 1, OMIM:312870; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Embryonal tumour of possible germline origin v0.2 EZH2 Achchuthan Shanmugasundram reviewed gene: EZH2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Weaver syndrome, OMIM:277590, Weaver syndrome, MONDO:0010193; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 ELP1 Achchuthan Shanmugasundram reviewed gene: ELP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: {Medulloblastoma}, OMIM:155255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 DIS3L2 Achchuthan Shanmugasundram reviewed gene: DIS3L2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Perlman syndrome, MONDO:0009965, Perlman syndrome, OMIM:267000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Embryonal tumour of possible germline origin v0.2 DICER1 Achchuthan Shanmugasundram reviewed gene: DICER1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800, rhabdomyosarcoma, embryonal, 2, MONDO:0859046, DICER1-related tumor predisposition, MONDO:0100216, Rhabdomyosarcoma, embryonal, 2, OMIM:180295, Pleuropulmonary blastoma, OMIM:601200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin v0.2 CTR9 Achchuthan Shanmugasundram reviewed gene: CTR9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Wilms tumor, MONDO:0006058; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Embryonal tumour of possible germline origin v0.2 CDKN1C Achchuthan Shanmugasundram reviewed gene: CDKN1C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Beckwith-Wiedemann syndrome, MONDO:0007534, Beckwith-Wiedemann syndrome, OMIM:130650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Embryonal tumour of possible germline origin v0.2 CBL Achchuthan Shanmugasundram reviewed gene: CBL: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563, ?Juvenile myelomonocytic leukemia, OMIM:607785, CBL-related disorder, MONDO:0013308; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.2 BUB1B Achchuthan Shanmugasundram reviewed gene: BUB1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: mosaic variegated aneuploidy syndrome 1, MONDO:0009759, Mosaic variegated aneuploidy syndrome 1, OMIM:257300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Embryonal tumour of possible germline origin v0.2 ALK Achchuthan Shanmugasundram reviewed gene: ALK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: neuroblastoma, susceptibility to, 3, MONDO:0013083, {Neuroblastoma, susceptibility to, 3}, OMIM:613014; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin v0.1 WT1 Achchuthan Shanmugasundram gene: WT1 was added
gene: WT1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: WT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: WT1 were set to Frasier syndrome, OMIM:136680; Wilms tumor, type 1, OMIM:194070; Wilms tumor 1, MONDO:0008679; Frasier syndrome, MONDO:0007635; Denys-Drash syndrome, OMIM:194080; Denys-Drash syndrome, MONDO:0008682
Embryonal tumour of possible germline origin v0.1 TRIP13 Achchuthan Shanmugasundram gene: TRIP13 was added
gene: TRIP13 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TRIP13 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRIP13 were set to Mosaic variegated aneuploidy syndrome 3, OMIM:617598; mosaic variegated aneuploidy syndrome 3, MONDO:0054736
Embryonal tumour of possible germline origin v0.1 TRIM37 Achchuthan Shanmugasundram gene: TRIM37 was added
gene: TRIM37 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TRIM37 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRIM37 were set to mulibrey nanism, MONDO:0009664; Mulibrey nanism, OMIM:253250
Embryonal tumour of possible germline origin v0.1 TRIM28 Achchuthan Shanmugasundram gene: TRIM28 was added
gene: TRIM28 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TRIM28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TRIM28 were set to Wilms tumor 7, MONDO:0979876; Wilms tumor 7, OMIM:621332
Embryonal tumour of possible germline origin v0.1 TP53 Achchuthan Shanmugasundram gene: TP53 was added
gene: TP53 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TP53 were set to {Colorectal cancer}, OMIM:114500; {Adrenocortical carcinoma, pediatric}, OMIM:202300; choroid plexus papilloma, MONDO:0009837; {Choroid plexus papilloma}, OMIM:260500; Li-Fraumeni syndrome, MONDO:0018875; nasopharyngeal carcinoma, susceptibility to, 1, MONDO:0011775; {Basal cell carcinoma 7}, OMIM:614740; Li-Fraumeni syndrome, OMIM:151623; basal cell carcinoma, susceptibility to, 7, MONDO:0013876; {Glioma susceptibility 1}, OMIM:137800; adrenocortical carcinoma, hereditary, MONDO:0008734
Embryonal tumour of possible germline origin v0.1 SUFU Achchuthan Shanmugasundram gene: SUFU was added
gene: SUFU was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SUFU were set to {Medulloblastoma}, OMIM:155255; Basal cell nevus syndrome 2, OMIM:620343; {Meningioma, familial, susceptibility to}, OMIM:607174; basal cell nevus syndrome 2, MONDO:0958189
Embryonal tumour of possible germline origin v0.1 SOS1 Achchuthan Shanmugasundram gene: SOS1 was added
gene: SOS1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SOS1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SOS1 were set to Noonan syndrome 4, OMIM:610733; Noonan syndrome 4, MONDO:0012547
Embryonal tumour of possible germline origin v0.1 SMARCB1 Achchuthan Shanmugasundram gene: SMARCB1 was added
gene: SMARCB1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SMARCB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SMARCB1 were set to SMARCB1-related schwannomatosis, MONDO:0024517; rhabdoid tumor predisposition syndrome 1, MONDO:0012252; {Schwannomatosis-1, susceptibility to}, OMIM:162091; {Rhabdoid tumor predisposition syndrome 1}, OMIM:609322
Embryonal tumour of possible germline origin v0.1 SMARCA4 Achchuthan Shanmugasundram gene: SMARCA4 was added
gene: SMARCA4 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SMARCA4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SMARCA4 were set to Rhabdoid tumor predisposition syndrome 2, MONDO:0013224; {Rhabdoid tumor predisposition syndrome 2}, OMIM:613325
Embryonal tumour of possible germline origin v0.1 REST Achchuthan Shanmugasundram gene: REST was added
gene: REST was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: REST was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: REST were set to Wilms tumor 6, MONDO:0014779; {Wilms tumor 6, susceptibility to}, OMIM:616806
Embryonal tumour of possible germline origin v0.1 PTPN11 Achchuthan Shanmugasundram gene: PTPN11 was added
gene: PTPN11 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PTPN11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PTPN11 were set to Noonan syndrome 1, MONDO:0008104; Noonan syndrome 1, OMIM:163950
Embryonal tumour of possible germline origin v0.1 PTCH1 Achchuthan Shanmugasundram gene: PTCH1 was added
gene: PTCH1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PTCH1 were set to Basal cell nevus syndrome 1, OMIM:109400; basal cell nevus syndrome 1, MONDO:0958174
Embryonal tumour of possible germline origin v0.1 PHOX2B Achchuthan Shanmugasundram gene: PHOX2B was added
gene: PHOX2B was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PHOX2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PHOX2B were set to central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, MONDO:0800026; neuroblastoma, susceptibility to, 2, MONDO:0700041; {Neuroblastoma, susceptibility to, 2}, OMIM:613013; Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, OMIM:209880
Embryonal tumour of possible germline origin v0.1 KRAS Achchuthan Shanmugasundram gene: KRAS was added
gene: KRAS was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: KRAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: KRAS were set to Noonan syndrome 3, MONDO:0012371; cardiofaciocutaneous syndrome 2, MONDO:0014112; Cardiofaciocutaneous syndrome 2, OMIM:615278; RAS-associated autoimmune leukoproliferative disorder, OMIM:614470; Noonan syndrome 3, OMIM:609942
Embryonal tumour of possible germline origin v0.1 HRAS Achchuthan Shanmugasundram gene: HRAS was added
gene: HRAS was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: HRAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: HRAS were set to Costello syndrome, MONDO:0009026; Costello syndrome, OMIM:218040
Embryonal tumour of possible germline origin v0.1 GPR161 Achchuthan Shanmugasundram gene: GPR161 was added
gene: GPR161 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: GPR161 were set to {Medulloblastoma predisposition syndrome}, OMIM:155255
Embryonal tumour of possible germline origin v0.1 GPC3 Achchuthan Shanmugasundram gene: GPC3 was added
gene: GPC3 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GPC3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: GPC3 were set to Simpson-Golabi-Behmel syndrome type 1, MONDO:0020602; Simpson-Golabi-Behmel syndrome, type 1, OMIM:312870
Embryonal tumour of possible germline origin v0.1 EZH2 Achchuthan Shanmugasundram gene: EZH2 was added
gene: EZH2 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: EZH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: EZH2 were set to Weaver syndrome, OMIM:277590; Weaver syndrome, MONDO:0010193
Embryonal tumour of possible germline origin v0.1 ELP1 Achchuthan Shanmugasundram gene: ELP1 was added
gene: ELP1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ELP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ELP1 were set to {Medulloblastoma}, OMIM:155255
Embryonal tumour of possible germline origin v0.1 DIS3L2 Achchuthan Shanmugasundram gene: DIS3L2 was added
gene: DIS3L2 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: DIS3L2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DIS3L2 were set to Perlman syndrome, MONDO:0009965; Perlman syndrome, OMIM:267000
Embryonal tumour of possible germline origin v0.1 DICER1 Achchuthan Shanmugasundram gene: DICER1 was added
gene: DICER1 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DICER1 were set to Rhabdomyosarcoma, embryonal, 2, OMIM:180295; DICER1-related tumor predisposition, MONDO:0100216; rhabdomyosarcoma, embryonal, 2, MONDO:0859046; Pleuropulmonary blastoma, OMIM:601200; Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800
Embryonal tumour of possible germline origin v0.1 CTR9 Achchuthan Shanmugasundram gene: CTR9 was added
gene: CTR9 was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CTR9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CTR9 were set to Wilms tumor, MONDO:0006058
Embryonal tumour of possible germline origin v0.1 CDKN1C Achchuthan Shanmugasundram gene: CDKN1C was added
gene: CDKN1C was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CDKN1C was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Phenotypes for gene: CDKN1C were set to Beckwith-Wiedemann syndrome, MONDO:0007534; Beckwith-Wiedemann syndrome, OMIM:130650
Embryonal tumour of possible germline origin v0.1 CBL Achchuthan Shanmugasundram gene: CBL was added
gene: CBL was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CBL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: CBL were set to CBL-related disorder, MONDO:0013308; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563; ?Juvenile myelomonocytic leukemia, OMIM:607785
Embryonal tumour of possible germline origin v0.1 BUB1B Achchuthan Shanmugasundram gene: BUB1B was added
gene: BUB1B was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: BUB1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BUB1B were set to Mosaic variegated aneuploidy syndrome 1, OMIM:257300; mosaic variegated aneuploidy syndrome 1, MONDO:0009759
Embryonal tumour of possible germline origin v0.1 ALK Achchuthan Shanmugasundram gene: ALK was added
gene: ALK was added to Embryonal tumour of possible germline origin. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ALK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ALK were set to {Neuroblastoma, susceptibility to, 3}, OMIM:613014; neuroblastoma, susceptibility to, 3, MONDO:0013083
Mitochondrial disorders v9.40 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Mitochondrial DNA Depletion Syndrome to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Likely inborn error of metabolism v8.86 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Mitochondrial DNA Depletion Syndrome; Disorders of mitochondrial DNA maintenance and integrity; Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Thymidine kinase 2 deficiency (Disorders of pyrimidine metabolism) to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Possible mitochondrial disorder - nuclear genes v4.19 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, 617069 to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Undiagnosed metabolic disorders v1.642 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Thymidine kinase 2 deficiency (Disorders of pyrimidine metabolism); Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Mitochondrial DNA Depletion Syndrome to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Mitochondrial DNA maintenance disorder v3.7 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, 617069 to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, OMIM:617069
Intellectual disability v9.207 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560 to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560
Rhabdomyolysis and metabolic muscle disorders v5.13 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from Mitochondrial DNA depletion syndrome 2 (myopathic type), 609560 to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560
Neonatal diabetes v5.13 RNU6ATAC Ida Ertmanska Phenotypes for gene: RNU6ATAC were changed from neonatal diabetes; hypothyroidism; humoral immunue defect; hepatic disorder; growth failure; failure to thrive; skeletal abnormalities; atopic dermatitis; vitiligo; alopecia to neonatal diabetes mellitus, MONDO:0016391; hypothyroidism; humoral immunue defect; hepatic disorder; growth failure; failure to thrive; skeletal abnormalities; atopic dermatitis; vitiligo; alopecia
Neonatal diabetes v5.12 RNU6ATAC Ida Ertmanska Classified gene: RNU6ATAC as Amber List (moderate evidence)
Neonatal diabetes v5.12 RNU6ATAC Ida Ertmanska Gene: rnu6atac has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6ATAC.
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska changed review comment from: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.
Around 60% of patients also had microcephaly and developmental delay.

Among the 4 families with biallelic RNU4ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).; to: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.
Around 60% of patients also had microcephaly and developmental delay.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska commented on gene: RNU6ATAC: Comment on list classification: There are 7 individuals from 4 unrelated families with biallelic RNU6ATAC variants and early-onset diabetes (article not yet peer-reviewed). Hence, this gene will be recommended for promotion to Green on Neonatal diabetes panel once the article is published.
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska edited their review of gene: RNU6ATAC: Changed rating: GREEN
Neonatal diabetes v5.11 RNU6ATAC Ida Ertmanska reviewed gene: RNU6ATAC: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: neonatal diabetes mellitus, MONDO:0016391; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.85 MT-ATP8 Arina Puzriakova Phenotypes for gene: MT-ATP8 were changed from CARDIOMYOPATHY, APICAL HYPERTROPHIC, AND NEUROPATHY; CARDIOMYOPATHY, INFANTILE HYPERTROPHIC; BRAIN PSEUDOATROPHY, REVERSIBLE, VALPROATE-INDUCED, SUSCEPTIBILITY TO to Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency
Undiagnosed metabolic disorders v1.641 MT-ATP8 Arina Puzriakova Phenotypes for gene: MT-ATP8 were changed from CARDIOMYOPATHY, INFANTILE HYPERTROPHIC; CARDIOMYOPATHY, APICAL HYPERTROPHIC, AND NEUROPATHY; BRAIN PSEUDOATROPHY, REVERSIBLE, VALPROATE-INDUCED, SUSCEPTIBILITY TO to Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency
Skeletal muscle channelopathy v3.7 MT-ATP8 Arina Puzriakova Phenotypes for gene: MT-ATP8 were changed from Can resemble skeletal muscle channelopathy to Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency
Neonatal diabetes v5.11 RNU4ATAC Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU4ATAC.
Neonatal diabetes v5.11 RNU4ATAC Ida Ertmanska Phenotypes for gene: RNU4ATAC were changed from neonatal diabetes; developmental delay; microcephaly; skeletal abnormalities; hypothyroidism; humoral immune defect; hepatic disorder; growth failure; failure to thrive; atopic dermatitis to RNU4ATAC spectrum disorder, MONDO:0100558; neonatal diabetes; developmental delay; microcephaly; skeletal abnormalities; hypothyroidism; humoral immune defect; hepatic disorder; growth failure; failure to thrive; atopic dermatitis
Neonatal diabetes v5.10 RNU4ATAC Ida Ertmanska Classified gene: RNU4ATAC as Amber List (moderate evidence)
Neonatal diabetes v5.10 RNU4ATAC Ida Ertmanska Gene: rnu4atac has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.9 RNU4ATAC Ida Ertmanska commented on gene: RNU4ATAC: Comment on list classification: There are 12 unrelated individuals with biallelic RNU4ATAC variants and early-onset diabetes (article not yet peer-reviewed). Hence, this gene will be recommended for promotion to Green on Neonatal diabetes panel once the article is published.
Neonatal diabetes v5.9 RNU4ATAC Ida Ertmanska reviewed gene: RNU4ATAC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: RNU4ATAC spectrum disorder, MONDO:0100558; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v4.5 RAP1B Ida Ertmanska Phenotypes for gene: RAP1B were changed from Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies (OMIM #620654) to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, MONDO:0958000
Bleeding and platelet disorders v4.4 RAP1B Ida Ertmanska Publications for gene: RAP1B were set to PMID: 32627184; 35451551; 37850357
Bleeding and platelet disorders v4.3 RAP1B Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: RAP1B.
Tag Q4_25_NHS_review tag was added to gene: RAP1B.
Bleeding and platelet disorders v4.3 RAP1B Ida Ertmanska Classified gene: RAP1B as Amber List (moderate evidence)
Bleeding and platelet disorders v4.3 RAP1B Ida Ertmanska Gene: rap1b has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v4.2 RAP1B Ida Ertmanska reviewed gene: RAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32627184, 35451551; Phenotypes: Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v7.92 BRAF Matthew Edwards reviewed gene: BRAF: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Skeletal dysplasia v8.29 H2AFY Ida Ertmanska Tag currently-ngs-unreportable tag was added to gene: H2AFY.
Tag cnv tag was added to gene: H2AFY.
Skeletal dysplasia v8.29 H2AFY Ida Ertmanska Phenotypes for gene: H2AFY were changed from Liebenberg syndrome to Liebenberg syndrome; brachydactyly-elbow wrist dysplasia syndrome, MONDO:0008520
Skeletal dysplasia v8.28 H2AFY Ida Ertmanska Publications for gene: H2AFY were set to PMID: 30711920, PMID: 23587911
Skeletal dysplasia v8.27 H2AFY Ida Ertmanska Classified gene: H2AFY as Amber List (moderate evidence)
Skeletal dysplasia v8.27 H2AFY Ida Ertmanska Gene: h2afy has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v8.26 H2AFY Ida Ertmanska changed review comment from: Comment on list classification: There are at least 5 unrelated families reported in literature with individuals affected by Liebenberg syndrome (brachydactyly-elbow wrist dysplasia syndrome), harbouring heterozygous CNVs which affect the H2AFY promoter region. Both deletions and translocations have been reported. In addition, PMID: 30711920 Kragesteen et al., 2021 describe a mouse model supporting Pitx1 upregulation through H2afy promoter loss as the likely mechanism of disease. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber for Skeletal dysplasia.; to: Comment on list classification: There are at least 5 unrelated families reported in literature with individuals affected by Liebenberg syndrome (brachydactyly-elbow wrist dysplasia syndrome), harbouring heterozygous CNVs which affect the H2AFY promoter region. Both deletions and translocations have been reported. In addition, PMID: 30711920 Kragesteen et al., 2021 describe a mouse model supporting Pitx1 upregulation through H2afy promoter loss as the likely mechanism of disease. However, these structural variants would not be detected in the current NGS analysis pipeline and H2AFY should remain Amber for Skeletal dysplasia.
Ataxia and cerebellar anomalies - narrow panel v8.39 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 analysis pipeline and the the 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.
Skeletal dysplasia v8.26 H2AFY Ida Ertmanska commented on gene: H2AFY: Comment on list classification: There are at least 5 unrelated families reported in literature with individuals affected by Liebenberg syndrome (brachydactyly-elbow wrist dysplasia syndrome), harbouring heterozygous CNVs which affect the H2AFY promoter region. Both deletions and translocations have been reported. In addition, PMID: 30711920 Kragesteen et al., 2021 describe a mouse model supporting Pitx1 upregulation through H2afy promoter loss as the likely mechanism of disease. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber for Skeletal dysplasia.
Ataxia and cerebellar anomalies - narrow panel v8.39 ATP6V0C Ida Ertmanska commented on gene: ATP6V0C: 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 analysis pipeline and the the gene should remain Amber.
Ataxia and cerebellar anomalies - narrow panel v8.39 ATP6V0C Ida Ertmanska Phenotypes for gene: ATP6V0C were changed from to progressive ataxia and cognitive decline
Ataxia and cerebellar anomalies - narrow panel v8.38 ATP6V0C Ida Ertmanska edited their review of gene: ATP6V0C: Changed phenotypes to: progressive ataxia and cognitive decline
Embryonal tumour of possible germline origin v0.0 Achchuthan Shanmugasundram Added Panel Embryonal tumour of possible germline origin
Set list of related panels to R456
Set panel types to: GMS Rare Disease Virtual; GMS Rare Disease
Skeletal dysplasia v8.26 H2AFY Ida Ertmanska reviewed gene: H2AFY: Rating: AMBER; Mode of pathogenicity: None; Publications: 23022097, 23587911, 30711920; Phenotypes: brachydactyly-elbow wrist dysplasia syndrome, MONDO:0008520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ataxia and cerebellar anomalies - narrow panel v8.38 ATP6V0C Ida Ertmanska Classified gene: ATP6V0C as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.38 ATP6V0C Ida Ertmanska Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.37 ATP6V0C Ida Ertmanska Tag currently-ngs-unreportable tag was added to gene: ATP6V0C.
Pulmonary alveolar microlithiasis v1.2 SLC34A2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #265100) and the OMIM record was last accessed on 29 December 2025.
Pulmonary alveolar microlithiasis v1.2 SLC34A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC34A2 were changed from to Pulmonary alveolar microlithiasis, OMIM:265100; pulmonary alveolar microlithiasis, MONDO:0009928
Familial tumours of the nervous system v2.13 SUFU Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #155255 & #607174) and the OMIM records were last accessed on 29 December 2025.
Familial tumours of the nervous system v2.13 SUFU Achchuthan Shanmugasundram Phenotypes for gene: SUFU were changed from to {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Familial tumours of the nervous system v2.12 SMARCE1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #607174) and the OMIM record was last accessed on 29 December 2025.
Familial tumours of the nervous system v2.12 SMARCE1 Achchuthan Shanmugasundram Phenotypes for gene: SMARCE1 were changed from to {Meningioma, familial, susceptibility to}, OMIM:607174
Familial tumours of the nervous system v2.11 SMARCB1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162091 & #609322) and the OMIM records were last accessed on 29 December 2025.
Familial tumours of the nervous system v2.11 SMARCB1 Achchuthan Shanmugasundram Phenotypes for gene: SMARCB1 were changed from to {Schwannomatosis-1, susceptibility to}, OMIM:162091; {Rhabdoid tumor predisposition syndrome 1}, OMIM:609322; rhabdoid tumor predisposition syndrome 1, MONDO:0012252; SMARCB1-related schwannomatosis, MONDO:0024517
Familial tumours of the nervous system v2.10 NF2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #101000 in OMIM and the OMIM record was last accessed on 29 December 2025.
Familial tumours of the nervous system v2.10 NF2 Achchuthan Shanmugasundram Phenotypes for gene: NF2 were changed from to Schwannomatosis, vestibular, OMIM:101000; NF2-related schwannomatosis, MONDO:0007039
Familial tumours of the nervous system v2.9 LZTR1 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #615670) and the OMIM record was last accessed on 29 December 2025.; to: Comment on phenotypes: This gene has been associated with MIM #615670 in OMIM and the OMIM record was last accessed on 29 December 2025.
Familial tumours of the nervous system v2.9 LZTR1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #615670) and the OMIM record was last accessed on 29 December 2025.
Familial tumours of the nervous system v2.9 LZTR1 Achchuthan Shanmugasundram Phenotypes for gene: LZTR1 were changed from to {Schwannomatosis-2, susceptibility to}, OMIM:615670; LZTR1-related schwannomatosis, MONDO:0014299
Familial tumours of the nervous system v2.8 CDKN2A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #155601, #155755 & #606719) and the OMIM records were last accessed on 29 December 2025.
Familial tumours of the nervous system v2.8 CDKN2A Achchuthan Shanmugasundram Phenotypes for gene: CDKN2A were changed from {Melanoma and neural system tumor syndrome}, OMIM:155755; Astrocytoma; Glioblastoma; Schwannoma; Neurofibroma; Meningioma; Malignant peripheral nerve sheath tumours to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719; melanoma, cutaneous malignant, susceptibility to, 2, MONDO:0007964; melanoma and neural system tumor syndrome, MONDO:0007967; melanoma-pancreatic cancer syndrome, MONDO:0011713
Wiskott-Aldrich syndrome v1.3 WAS Achchuthan Shanmugasundram Phenotypes for gene: WAS were changed from Wiskott-Aldrich syndrome, OMIM:301000; Wilson disease, MONDO:0010200 to Wiskott-Aldrich syndrome, OMIM:301000; Wiskott-Aldrich syndrome, MONDO:0010518
Wiskott-Aldrich syndrome v1.2 WAS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #301000) and the OMIM record was last accessed on 29 December 2025.
Wiskott-Aldrich syndrome v1.2 WAS Achchuthan Shanmugasundram Phenotypes for gene: WAS were changed from to Wiskott-Aldrich syndrome, OMIM:301000; Wilson disease, MONDO:0010200
Wilson disease v1.2 ATP7B Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #277900) and the OMIM record was last accessed on 29 December 2025.
Wilson disease v1.2 ATP7B Achchuthan Shanmugasundram Phenotypes for gene: ATP7B were changed from to Wilson disease, OMIM:277900; Wilson disease, MONDO:0010200
von Willebrand disease v1.3 VWF Achchuthan Shanmugasundram Phenotypes for gene: VWF were changed from von Willebrand disease, type 1, OMIM:193400; von Willebrand disease, type 3, OMIM:277480; von Willebrand disease, types 2A, 2B, 2M, and 2N, OMIM:613554; von Willebrand disease 1, MONDO:0008668; von Willebrand disease 2, MONDO:001330; von Willebrand disease 3, MONDO:0010191 to von Willebrand disease, type 1, OMIM:193400; von Willebrand disease, type 3, OMIM:277480; von Willebrand disease, types 2A, 2B, 2M, and 2N, OMIM:613554; von Willebrand disease 1, MONDO:0008668; von Willebrand disease 2, MONDO:0013304; von Willebrand disease 3, MONDO:0010191
von Willebrand disease v1.2 VWF Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #193400, #277480 & #613554) and the OMIM records were last accessed on 29 December 2025.
von Willebrand disease v1.2 VWF Achchuthan Shanmugasundram Phenotypes for gene: VWF were changed from to von Willebrand disease, type 1, OMIM:193400; von Willebrand disease, type 3, OMIM:277480; von Willebrand disease, types 2A, 2B, 2M, and 2N, OMIM:613554; von Willebrand disease 1, MONDO:0008668; von Willebrand disease 2, MONDO:001330; von Willebrand disease 3, MONDO:0010191
Ataxia and cerebellar anomalies - narrow panel v8.37 ATP6V0C Ida Ertmanska changed review comment from: PMID: 41349538 Fasham et al., 2025
Report of 11 individuals from 9 unrelated families with copy-number gains at 16p13.3, with early-onset progressive ataxia and cognitive decline (9-32 years). Method: mostly microarray + WGS. The structural variants arose de novo in 5 patients, one was inherited from an unaffected mosaic father, and 2 inherited from an affected mother; 3 cases with unknown inheritance. In addition to cognitive impairment and progressive ataxia, individuals presented with: regression 8/10, dysarthria 10/11, axonal neuropathy 9/11, nystagmus 4/11, pes cavus 5/6, scoliosis/kyphosis 7/10, optic atrophy 2/10.
Cerebellar and caudate atrophy was seen in 11/11 individuals.

ATP6V0C is linked to Epilepsy, early-onset, 3, with or without developmental delay, MIM:620465 in OMIM (accessed 29th Dec 2025).
Sources: Literature; to: PMID: 41349538 Fasham et al., 2025
Report of 11 individuals from 9 unrelated families with copy-number gains at 16p13.3, with early-onset progressive ataxia and cognitive decline (9-32 years). Method: mostly microarray + WGS. The structural variants arose de novo in 5 patients, one was inherited from an unaffected mosaic father, and 2 inherited from an affected mother; 3 cases with unknown inheritance. In addition to cognitive impairment and progressive ataxia, individuals presented with: regression 8/10, dysarthria 10/11, axonal neuropathy 9/11, nystagmus 4/11, pes cavus 5/6, scoliosis/kyphosis 7/10, optic atrophy 2/10.
Cerebellar and caudate atrophy was seen in 11/11 individuals.

The minimal region of overlap for all patients included a single gene (ATP6V0C); RNA-seq using whole-blood and fibroblast/lymphoblast cultures indicated increased expression of several genes within the SV, with ATP6V0C showing the most significant increase. Hence, ATP6V0C is the mostly likely candidate gene.

ATP6V0C is linked to Epilepsy, early-onset, 3, with or without developmental delay, MIM:620465 in OMIM (accessed 29th Dec 2025).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.37 ATP6V0C Ida Ertmanska gene: ATP6V0C was added
gene: ATP6V0C was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
cnv tags were added to gene: ATP6V0C.
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP6V0C were set to 41349538
Review for gene: ATP6V0C was set to AMBER
Added comment: PMID: 41349538 Fasham et al., 2025
Report of 11 individuals from 9 unrelated families with copy-number gains at 16p13.3, with early-onset progressive ataxia and cognitive decline (9-32 years). Method: mostly microarray + WGS. The structural variants arose de novo in 5 patients, one was inherited from an unaffected mosaic father, and 2 inherited from an affected mother; 3 cases with unknown inheritance. In addition to cognitive impairment and progressive ataxia, individuals presented with: regression 8/10, dysarthria 10/11, axonal neuropathy 9/11, nystagmus 4/11, pes cavus 5/6, scoliosis/kyphosis 7/10, optic atrophy 2/10.
Cerebellar and caudate atrophy was seen in 11/11 individuals.

ATP6V0C is linked to Epilepsy, early-onset, 3, with or without developmental delay, MIM:620465 in OMIM (accessed 29th Dec 2025).
Sources: Literature
Von Hippel Lindau syndrome v1.2 VHL Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #193300 in OMIM and the OMIM record was last accessed on 29 December 2025.
Von Hippel Lindau syndrome v1.2 VHL Achchuthan Shanmugasundram Phenotypes for gene: VHL were changed from to von Hippel-Lindau syndrome, OMIM:193300; von Hippel-Lindau disease, MONDO:0008667
Tuberous sclerosis v1.3 TSC2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613254) and the OMIM record was last accessed on 29 December 2025.
Tuberous sclerosis v1.3 TSC2 Achchuthan Shanmugasundram Phenotypes for gene: TSC2 were changed from to Tuberous sclerosis-2, OMIM:613254; tuberous sclerosis 2, MONDO:0013199
Tuberous sclerosis v1.2 TSC1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #191100) and the OMIM record was last accessed on 29 December 2025.
Tuberous sclerosis v1.2 TSC1 Achchuthan Shanmugasundram Phenotypes for gene: TSC1 were changed from to Tuberous sclerosis-1, OMIM:191100; tuberous sclerosis 1, MONDO:0008612
Thiamine metabolism dysfunction syndrome 2 v1.2 SLC19A3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #607483) and the OMIM record was last accessed on 29 December 2025.
Thiamine metabolism dysfunction syndrome 2 v1.2 SLC19A3 Achchuthan Shanmugasundram Phenotypes for gene: SLC19A3 were changed from to Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type), OMIM:607483; biotin-responsive basal ganglia disease, MONDO:0011841
Thanatophoric dysplasia v1.2 FGFR3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #187600 & #187601) and the OMIM records were last accessed on 29 December 2025.
Thanatophoric dysplasia v1.2 FGFR3 Achchuthan Shanmugasundram Phenotypes for gene: FGFR3 were changed from to Thanatophoric dysplasia, type I, OMIM:187600; Thanatophoric dysplasia, type II, OMIM:187601; thanatophoric dysplasia, MONDO:0017042
Tay-Sachs disease v1.2 HEXA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #272800) and the OMIM record was last accessed on 29 December 2025.
Tay-Sachs disease v1.2 HEXA Achchuthan Shanmugasundram Phenotypes for gene: HEXA were changed from to Tay-Sachs disease, OMIM:272800; Tay-Sachs disease, MONDO:0010100
Syndromic and non syndromic craniosynostosis involving midline sutures v1.2 SMAD6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #617439) and the OMIM record was last accessed on 29 December 2025.
Syndromic and non syndromic craniosynostosis involving midline sutures v1.2 SMAD6 Achchuthan Shanmugasundram Phenotypes for gene: SMAD6 were changed from to {Craniosynostosis 7, susceptibility to}, OMIM:617439; craniosynostosis 7, MONDO:0044315
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v1.2 HAVCR2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #618398) and the OMIM record was last accessed on 29 December 2025.
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v1.2 HAVCR2 Achchuthan Shanmugasundram Phenotypes for gene: HAVCR2 were changed from to T-cell lymphoma, subcutaneous panniculitis-like, OMIM:618398; subcutaneous panniculitis-like T-cell lymphoma, MONDO:0019475
Spinal muscular atrophy type 1 rare mutation testing v1.2 SMN1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #253300 in OMIM and the OMIM record was last accessed on 29 December 2025.
Spinal muscular atrophy type 1 rare mutation testing v1.2 SMN1 Achchuthan Shanmugasundram Phenotypes for gene: SMN1 were changed from to Spinal muscular atrophy-1, OMIM:253300; spinal muscular atrophy, type 1, MONDO:0009669
Smith-Lemli-Opitz syndrome v1.2 DHCR7 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #270400) and the OMIM record was last accessed on 29 December 2025.
Smith-Lemli-Opitz syndrome v1.2 DHCR7 Achchuthan Shanmugasundram Phenotypes for gene: DHCR7 were changed from to Smith-Lemli-Opitz syndrome, OMIM:270400; Smith-Lemli-Opitz syndrome, MONDO:0010035
Sitosterolaemia v1.3 ABCG8 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #210250) and the OMIM record was last accessed on 29 December 2025.
Sitosterolaemia v1.3 ABCG8 Achchuthan Shanmugasundram Phenotypes for gene: ABCG8 were changed from to Sitosterolemia 1, OMIM:210250; sitosterolemia 1, MONDO:0020747
Sitosterolaemia v1.2 ABCG5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #618666) and the OMIM record was last accessed on 29 December 2025.
Sitosterolaemia v1.2 ABCG5 Achchuthan Shanmugasundram Phenotypes for gene: ABCG5 were changed from to Sitosterolemia 2, OMIM:618666; sitosterolemia 2, MONDO:0020748
Short stature - SHOX deficiency v1.2 SHOX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #12730, #249700 & #300582) and the OMIM records were last accessed on 29 December 2025.
Short stature - SHOX deficiency v1.2 SHOX Achchuthan Shanmugasundram Phenotypes for gene: SHOX were changed from to Leri-Weill dyschondrosteosis, OMIM:127300; Langer mesomelic dysplasia, OMIM:249700; Short stature, idiopathic familial, OMIM:300582; SHOX-related short stature, MONDO:0010367
Severe combined immunodeficiency with PNP deficiency v1.2 PNP Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613179) and the OMIM record was last accessed on 29 December 2025.
Severe combined immunodeficiency with PNP deficiency v1.2 PNP Achchuthan Shanmugasundram Phenotypes for gene: PNP were changed from to Immunodeficiency due to purine nucleoside phosphorylase deficiency, OMIM:613179; purine nucleoside phosphorylase deficiency, MONDO:0013171
Severe combined immunodeficiency with adenosine deaminase deficiency v1.4 ADA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #102700) and the OMIM record was last accessed on 29 December 2025.
Severe combined immunodeficiency with adenosine deaminase deficiency v1.4 ADA Achchuthan Shanmugasundram Phenotypes for gene: ADA were changed from Severe combined immunodeficiency due to ADA deficiency, OMIM:102700 to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, MONDO:0007064
Segmental or atypical neurofibromatosis type 1 testing v1.2 NF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162200, #162210 & #60132) and the OMIM records were last accessed on 29 December 2025.
Segmental or atypical neurofibromatosis type 1 testing v1.2 NF1 Achchuthan Shanmugasundram Phenotypes for gene: NF1 were changed from to Neurofibromatosis, type 1, OMIM:162200; Neurofibromatosis, familial spinal, OMIM:162210; Neurofibromatosis-Noonan syndrome, OMIM:601321; neurofibromatosis type 1, MONDO:0018975; neurofibromatosis-Noonan syndrome, MONDO:0011035
SCID with features of gamma chain deficiency v1.2 IL2RG Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #300400 & #312863) and the OMIM records were last accessed on 29 December 2025.
SCID with features of gamma chain deficiency v1.2 IL2RG Achchuthan Shanmugasundram Phenotypes for gene: IL2RG were changed from to Severe combined immunodeficiency, X-linked, OMIM:300400; Combined immunodeficiency, X-linked, moderate, OMIM:312863; T-B+ severe combined immunodeficiency due to gamma chain deficiency, MONDO:0010315; combined immunodeficiency, X-linked, MONDO:0010730
Sandhoff disease v1.2 HEXB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #268800) and the OMIM record was last accessed on 29 December 2025.
Sandhoff disease v1.2 HEXB Achchuthan Shanmugasundram Phenotypes for gene: HEXB were changed from to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800; Sandhoff disease, MONDO:0010006
Retinoblastoma v1.2 RB1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #180200) and the OMIM record was last accessed on 29 December 2025.
Retinoblastoma v1.2 RB1 Achchuthan Shanmugasundram Phenotypes for gene: RB1 were changed from to Retinoblastoma, OMIM:180200; Retinoblastoma, trilateral, OMIM:180200; hereditary retinoblastoma, MONDO:0018160
PTEN Hamartoma Tumour Syndrome v1.4 PTEN Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #158350) and the OMIM record was last accessed on 29 December 2025.
PTEN Hamartoma Tumour Syndrome v1.4 PTEN Achchuthan Shanmugasundram Phenotypes for gene: PTEN were changed from to Cowden syndrome 1, OMIM:158350; Lhermitte-Duclos disease, OMIM:158350; PTEN harmartoma tumor syndrome with immune disorder, MONDO:0700330
Pseudoxanthoma elasticum v1.3 ENPP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #208000) and the OMIM record was last accessed on 29 December 2025.
Pseudoxanthoma elasticum v1.3 ENPP1 Achchuthan Shanmugasundram Phenotypes for gene: ENPP1 were changed from to Arterial calcification, generalized, of infancy, 1, OMIM:208000; arterial calcification, generalized, of infancy, 1, MONDO:0008817
Intellectual disability v9.206 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.206 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska Tag Q4_25_MOI tag was added to gene: MUC5B.
Pseudoxanthoma elasticum v1.2 ABCC6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #264800) and the OMIM record was last accessed on 29 December 2025.
Pseudoxanthoma elasticum v1.2 ABCC6 Achchuthan Shanmugasundram Phenotypes for gene: ABCC6 were changed from to Pseudoxanthoma elasticum, OMIM:264800; autosomal recessive inherited pseudoxanthoma elasticum, MONDO:0009925
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at least 3 unrelated families where individuals with bronchiectasis and recurrent pulmonary infections carried homozygous or compound heterozygous variants in MUCB5. In addition, a supportive mouse model showed that muc5b knockout leads to airway obstruction and spontaneous pulmonary infections. Based on available evidence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Pulmonary fibrosis familial.; to: Comment on mode of inheritance: There are at least 3 unrelated families where individuals with bronchiectasis and recurrent pulmonary infections carried homozygous or compound heterozygous variants in MUCB5. In addition, a supportive mouse model showed that muc5b -/- knockout leads to airway obstruction and spontaneous pulmonary infections. Based on available evidence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Pulmonary fibrosis familial.
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska commented on gene: MUC5B: Comment on mode of inheritance: There are at least 3 unrelated families where individuals with bronchiectasis and recurrent pulmonary infections carried homozygous or compound heterozygous variants in MUCB5. In addition, a supportive mouse model showed that muc5b knockout leads to airway obstruction and spontaneous pulmonary infections. Based on available evidence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Pulmonary fibrosis familial.
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska edited their review of gene: MUC5B: Changed rating: GREEN; Changed publications to: 24317696, 33526882, 35023825; Changed phenotypes to: {Pulmonary fibrosis, idiopathic, susceptibility to}, OMIM:178500, Pulmonary fibrosis, HP:0002206; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary hyperaldosteronism - KCNJ5 v1.2 KCNJ5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613677) and the OMIM record was last accessed on 29 December 2025.
Primary hyperaldosteronism - KCNJ5 v1.2 KCNJ5 Achchuthan Shanmugasundram Phenotypes for gene: KCNJ5 were changed from to Hyperaldosteronism, familial, type III, OMIM:613677; familial hyperaldosteronism type III, MONDO:0013359
POLG-related disorder v1.2 POLG Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #157640, #203700, #258450, #607459 & #613662) and the OMIM records were last accessed on 29 December 2025.
POLG-related disorder v1.2 POLG Achchuthan Shanmugasundram Phenotypes for gene: POLG were changed from to Progressive external ophthalmoplegia, autosomal dominant 1, OMIM:157640; Progressive external ophthalmoplegia, autosomal recessive 1, OMIM:258450; Mitochondrial DNA depletion syndrome 4A (Alpers type), OMIM:203700; Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459; Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662; progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1, MONDO:0024528; progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, MONDO:0009783; sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, MONDO:0011835; mitochondrial DNA depletion syndrome 4a, MONDO:0008758; mitochondrial DNA depletion syndrome 4b, MONDO:0013350
Pulmonary fibrosis familial v1.7 MUC5B Ida Ertmanska commented on gene: MUC5B
Phenylketonuria v1.2 PAH Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #261600) and the OMIM record was last accessed on 29 December 2025.
Phenylketonuria v1.2 PAH Achchuthan Shanmugasundram Phenotypes for gene: PAH were changed from to Phenylketonuria, OMIM:261600; phenylketonuria, MONDO:0009861
Peutz Jeghers Syndrome v1.2 STK11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #175200) and the OMIM record was last accessed on 29 December 2025.
Peutz Jeghers Syndrome v1.2 STK11 Achchuthan Shanmugasundram Phenotypes for gene: STK11 were changed from to Peutz-Jeghers syndrome, OMIM:175200; Peutz-Jeghers syndrome, MONDO:0008280
Nijmegen breakage syndrome v1.2 NBN Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #251260) and the OMIM record was last accessed on 29 December 2025.
Nijmegen breakage syndrome v1.2 NBN Achchuthan Shanmugasundram Phenotypes for gene: NBN were changed from to Nijmegen breakage syndrome, OMIM:251260; Nijmegen breakage syndrome, MONDO:0009623
Niemann-Pick disease type A or B v1.2 SMPD1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #257200 & #607616) and the OMIM records were last accessed on 29 December 2025.
Niemann-Pick disease type A or B v1.2 SMPD1 Achchuthan Shanmugasundram Phenotypes for gene: SMPD1 were changed from to Niemann-Pick disease, type A, OMIM:257200; Niemann-Pick disease, type B, OMIM:607616; Niemann-Pick disease type A, MONDO:0009756; Niemann-Pick disease type B, MONDO:0011871
Niemann Pick disease type C v1.3 NPC2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #607625) and the OMIM record was last accessed on 29 December 2025.
Niemann Pick disease type C v1.3 NPC2 Achchuthan Shanmugasundram Phenotypes for gene: NPC2 were changed from to Niemann-pick disease, type C2, OMIM:607625; Niemann-Pick disease, type C2, MONDO:0011873
Niemann Pick disease type C v1.2 NPC1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #257220) and the OMIM record was last accessed on 29 December 2025.
Niemann Pick disease type C v1.2 NPC1 Achchuthan Shanmugasundram Phenotypes for gene: NPC1 were changed from to Niemann-Pick disease, type C1, OMIM:257220; Niemann-Pick disease, type D, OMIM:257220; Niemann-Pick disease, type C1, MONDO:0009757
Neurofibromatosis type 1 (GMS) v1.3 SPRED1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #611431) and the OMIM record was last accessed on 29 December 2025.
Neurofibromatosis type 1 (GMS) v1.3 SPRED1 Achchuthan Shanmugasundram Phenotypes for gene: SPRED1 were changed from to Legius syndrome, OMIM:611431; Legius syndrome, MONDO:0012669
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.3 SUFU Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620343) and the OMIM record was last accessed on 29 December 2025.
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.3 SUFU Achchuthan Shanmugasundram Phenotypes for gene: SUFU were changed from to Basal cell nevus syndrome 2, OMIM:620343; basal cell nevus syndrome 2, MONDO:0958189
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.2 PTCH1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #109400) and the OMIM record was last accessed on 29 December 2025.
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.2 PTCH1 Achchuthan Shanmugasundram Phenotypes for gene: PTCH1 were changed from to Basal cell nevus syndrome 1, OMIM:109400; basal cell nevus syndrome 1, MONDO:0958174
Neutropaenia consistent with ELANE mutations v1.2 ELANE Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162800 & #202700) and the OMIM records were last accessed on 29 December 2025.
Neutropaenia consistent with ELANE mutations v1.2 ELANE Achchuthan Shanmugasundram Phenotypes for gene: ELANE were changed from to Neutropenia, cyclic, OMIM:162800; Neutropenia, severe congenital 1, autosomal dominant, OMIM:202700; ELANE-related neutropenia, MONDO:1060165
Neuronal ceroid lipofuscinosis type 2 v1.2 TPP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #204500) and the OMIM record was last accessed on 29 December 2025.
Neuronal ceroid lipofuscinosis type 2 v1.2 TPP1 Achchuthan Shanmugasundram Phenotypes for gene: TPP1 were changed from to Ceroid lipofuscinosis, neuronal, 2, OMIM:204500; neuronal ceroid lipofuscinosis 2, MONDO:0008769
Neurofibromatosis type 1 (GMS) v1.2 NF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162200, #162210 & #60132) and the OMIM records were last accessed on 29 December 2025.
Neurofibromatosis type 1 (GMS) v1.2 NF1 Achchuthan Shanmugasundram Phenotypes for gene: NF1 were changed from to Neurofibromatosis, type 1, OMIM:162200; Neurofibromatosis, familial spinal, OMIM:162210; Neurofibromatosis-Noonan syndrome, OMIM:601321; neurofibromatosis type 1, MONDO:0018975; neurofibromatosis-Noonan syndrome, MONDO:0011035
Neonatal diabetes - small panel v1.5 KCNJ11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #610582 & #618856) and the OMIM records were last accessed on 29 December 2025.
Neonatal diabetes - small panel v1.5 KCNJ11 Achchuthan Shanmugasundram Phenotypes for gene: KCNJ11 were changed from to Diabetes mellitus, transient neonatal 3, OMIM:610582; Diabetes, permanent neonatal 2, with or without neurologic features, OMIM:618856; diabetes mellitus, transient neonatal, 3, MONDO:0012522; diabetes mellitus, permanent neonatal 2, MONDO:0030087
Neonatal diabetes - small panel v1.4 ABCC8 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #618857 & #610374) and the OMIM records were last accessed on 29 December 2025.
Neonatal diabetes - small panel v1.4 ABCC8 Achchuthan Shanmugasundram Phenotypes for gene: ABCC8 were changed from to Diabetes mellitus, permanent neonatal 3, OMIM:618857; Diabetes mellitus, transient neonatal 2, OMIM:610374; diabetes mellitus, permanent neonatal 3, MONDO:0030088; diabetes mellitus, transient neonatal, 2, MONDO:0012480
Multiple exostoses v1.3 EXT2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #133701) and the OMIM record was last accessed on 29 December 2025.
Multiple exostoses v1.3 EXT2 Achchuthan Shanmugasundram Phenotypes for gene: EXT2 were changed from to Exostoses, multiple, type 2, OMIM:133701; exostoses, multiple, type 2, MONDO:0007586
Multiple exostoses v1.2 EXT1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #133700) and the OMIM record was last accessed on 29 December 2025.
Multiple exostoses v1.2 EXT1 Achchuthan Shanmugasundram Phenotypes for gene: EXT1 were changed from to Exostoses, multiple, type 1, OMIM:133700; exostoses, multiple, type 1, MONDO:0007585
Multiple endocrine neoplasia type 2 v1.2 RET Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #162300 & #171400) and the OMIM records were last accessed on 29 December 2025.
Multiple endocrine neoplasia type 2 v1.2 RET Achchuthan Shanmugasundram Phenotypes for gene: RET were changed from to Multiple endocrine neoplasia IIA, OMIM:171400; Multiple endocrine neoplasia IIB, OMIM:162300; multiple endocrine neoplasia type 2A, MONDO:0008234; multiple endocrine neoplasia type 2B, MONDO:0008082
Hereditary neuropathy or pain disorder v7.32 KIF21A Eleanor Williams Phenotypes for gene: KIF21A were changed from CFEOM; agenesis of the corpus callosum; peripheral neuropathy to CFEOM; agenesis of the corpus callosum; peripheral neuropathy, MONDO:0005244
Amelogenesis imperfecta v4.25 LTBP3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype correct as of 22nd Dec 2025
Amelogenesis imperfecta v4.25 LTBP3 Eleanor Williams Phenotypes for gene: LTBP3 were changed from Dental anomalies and short stature, OMIM:601216; Amelogenesis Imperfecta; syndromic AI with brachyolmia to Dental anomalies and short stature, OMIM:601216
Mucopolysaccharidosis type VI v1.2 ARSB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #253200) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type VI v1.2 ARSB Achchuthan Shanmugasundram Phenotypes for gene: ARSB were changed from to Mucopolysaccharidosis type VI (Maroteaux-Lamy), OMIM:253200; mucopolysaccharidosis type 6, MONDO:0009661
Mucopolysaccharidosis type IVA v1.2 GALNS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #253000) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type IVA v1.2 GALNS Achchuthan Shanmugasundram Phenotypes for gene: GALNS were changed from to Mucopolysaccharidosis IVA, OMIM:253000; mucopolysaccharidosis type 4A, MONDO:0009659
Mucopolysaccharidosis type IIIB v1.2 NAGLU Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #252920) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type IIIB v1.2 NAGLU Achchuthan Shanmugasundram Phenotypes for gene: NAGLU were changed from to Mucopolysaccharidosis type IIIB (Sanfilippo B), OMIM:252920; mucopolysaccharidosis type 3B, MONDO:0009656
Mucopolysaccharidosis type IIIA v1.2 SGSH Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #252900) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type IIIA v1.2 SGSH Achchuthan Shanmugasundram Phenotypes for gene: SGSH were changed from to Mucopolysaccharidosis type IIIA (Sanfilippo A), OMIM:252900; mucopolysaccharidosis type 3A, MONDO:0009655
Mucopolysaccharidosis type II v1.2 IDS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #309900) and the OMIM record was last accessed on 20 December 2025.
Mucopolysaccharidosis type II v1.2 IDS Achchuthan Shanmugasundram Phenotypes for gene: IDS were changed from to Mucopolysaccharidosis II, OMIM:309900; mucopolysaccharidosis type 2, MONDO:0010674
Mucopolysaccharidosis type IH or S v1.2 IDUA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #607014, #607015 & #607016) and the OMIM records were last accessed on 20 December 2025.
Mucopolysaccharidosis type IH or S v1.2 IDUA Achchuthan Shanmugasundram Phenotypes for gene: IDUA were changed from to Mucopolysaccharidosis Ih, OMIM:607014; Mucopolysaccharidosis Ih/s, OMIM:607015; Mucopolysaccharidosis Is, OMIM:607016; Hurler syndrome, MONDO:0011758; Hurler-Scheie syndrome, MONDO:0011759; Scheie syndrome, MONDO:0011760
Mucolipidosis II and III Alpha or Beta v1.2 GNPTAB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #252500 & #252600) and the OMIM records were last accessed on 20 December 2025.
Mucolipidosis II and III Alpha or Beta v1.2 GNPTAB Achchuthan Shanmugasundram Phenotypes for gene: GNPTAB were changed from to Mucolipidosis II alpha/beta, OMIM:252500; Mucolipidosis III alpha/beta, OMIM:252600; GNPTAB-mucolipidosis, MONDO:0100122
Monitoring for G(M)CSF escape mutations v1.2 CSF3R Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #617014) and the OMIM record was last accessed on 20 December 2025.
Monitoring for G(M)CSF escape mutations v1.2 CSF3R Achchuthan Shanmugasundram Phenotypes for gene: CSF3R were changed from to Neutropenia, severe congenital, 7, autosomal recessive, OMIM:617014; autosomal recessive severe congenital neutropenia due to CSF3R deficiency, MONDO:0014865
Mitochondrial neurogastrointestinal encephalopathy v1.2 TYMP Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #603041) and the OMIM record was last accessed on 20 December 2025.
Mitochondrial neurogastrointestinal encephalopathy v1.2 TYMP Achchuthan Shanmugasundram Phenotypes for gene: TYMP were changed from to Mitochondrial DNA depletion syndrome 1 (MNGIE type), OMIM:603041; mitochondrial DNA depletion syndrome 1, MONDO:0011283
Mitochondrial Complex V deficiency, TMEM70 type v1.2 TMEM70 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #614052) and the OMIM record was last accessed on 20 December 2025.
Mitochondrial Complex V deficiency, TMEM70 type v1.2 TMEM70 Achchuthan Shanmugasundram Phenotypes for gene: TMEM70 were changed from to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, OMIM:614052; mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, MONDO:0013546
Lysosomal acid lipase deficiency v1.2 LIPA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #278000 & #620151) and the OMIM records were last accessed on 20 December 2025.
Lysosomal acid lipase deficiency v1.2 LIPA Achchuthan Shanmugasundram Phenotypes for gene: LIPA were changed from to Cholesteryl ester storage disease, OMIM:278000; Wolman disease, OMIM:620151; Wolman disease, MONDO:0019148; cholesteryl ester storage disease, MONDO:0019149
Lymphoproliferative syndrome with absent SAP expression v1.2 SH2D1A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #308240) and the OMIM record was last accessed on 20 December 2025.
Lymphoproliferative syndrome with absent SAP expression v1.2 SH2D1A Achchuthan Shanmugasundram Phenotypes for gene: SH2D1A were changed from to Lymphoproliferative syndrome, X-linked, 1, OMIM:308240; X-linked lymphoproliferative disease due to SH2D1A deficiency, MONDO:0024551
Li Fraumeni Syndrome v1.5 TP53 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #151623) and the OMIM record was last accessed on 20 December 2025.
Li Fraumeni Syndrome v1.5 TP53 Achchuthan Shanmugasundram Phenotypes for gene: TP53 were changed from to Li-Fraumeni syndrome, OMIM:151623; Li-Fraumeni syndrome, MONDO:0018875
Li Fraumeni Syndrome v1.4 POT1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #61584 & #620367) and the OMIM records were last accessed on 20 December 2025.
Li Fraumeni Syndrome v1.4 POT1 Achchuthan Shanmugasundram Phenotypes for gene: POT1 were changed from to Tumor predisposition syndrome 3, OMIM:615848; ?Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8, OMIM:620367; tumor predisposition syndrome 3, MONDO:0014368
Krabbe disease - Saposin A deficiency v1.2 PSAP Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #611721 & #611722) and the OMIM records were last accessed on 20 December 2025.
Krabbe disease - Saposin A deficiency v1.2 PSAP Achchuthan Shanmugasundram Phenotypes for gene: PSAP were changed from to Combined SAP deficiency, OMIM:611721; Krabbe disease, atypical, OMIM:611722; PSAP-related sphingolipidosis, MONDO:0100517
Krabbe disease - GALC deficiency v1.2 GALC Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #245200) and the OMIM record was last accessed on 20 December 2025.
Krabbe disease - GALC deficiency v1.2 GALC Achchuthan Shanmugasundram Phenotypes for gene: GALC were changed from to Krabbe disease, OMIM:245200; Krabbe disease, MONDO:0009499
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v1.2 FOXP3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #304790) and the OMIM record was last accessed on 20 December 2025.
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v1.2 FOXP3 Achchuthan Shanmugasundram Phenotypes for gene: FOXP3 were changed from to Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked, OMIM:304790; immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, MONDO:0010580
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.3 PAX5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #615545) and the OMIM record was last accessed on 20 December 2025.
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.3 PAX5 Achchuthan Shanmugasundram Phenotypes for gene: PAX5 were changed from to {Leukemia, acute lymphoblastic, susceptibility to, 3}, OMIM:615545; leukemia, acute lymphoblastic, susceptibility to, 3, MONDO:0014241
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.2 ETV6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #616216) and the OMIM record was last accessed on 20 December 2025.
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.2 ETV6 Achchuthan Shanmugasundram Phenotypes for gene: ETV6 were changed from to Thrombocytopenia 5, OMIM:616216; thrombocytopenia 5, MONDO:0014536
Inherited parathyroid cancer v1.2 CDC73 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #145001 & #608266) and the OMIM records were last accessed on 20 December 2025.
Inherited parathyroid cancer v1.2 CDC73 Achchuthan Shanmugasundram Phenotypes for gene: CDC73 were changed from to Hyperparathyroidism-jaw tumor syndrome, OMIM:145001; Parathyroid adenoma with cystic changes, OMIM:145001; Parathyroid carcinoma, OMIM:608266; parathyroid gland carcinoma, MONDO:0012004
Incontinentia pigmenti v1.3 IKBKG Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #308300) and the OMIM record was last accessed on 20 December 2025.
Incontinentia pigmenti v1.3 IKBKG Achchuthan Shanmugasundram Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, OMIM:308300 to Incontinentia pigmenti, OMIM:308300; incontinentia pigmenti, MONDO:0010631
Hereditary angioedema types I and II v1.2 SERPING1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #106100) and the OMIM record was last accessed on 20 December 2025.
Hereditary angioedema types I and II v1.2 SERPING1 Achchuthan Shanmugasundram Phenotypes for gene: SERPING1 were changed from to Angioedema, hereditary, 1 and 2, OMIM:106100; hereditary angioedema with C1Inh deficiency, MONDO:0033946
Haemophagocytic syndrome with absent XIAP expression v1.3 XIAP Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #300635 in OMIM and the OMIM record was last accessed on 20 December 2025.
Haemophagocytic syndrome with absent XIAP expression v1.3 XIAP Achchuthan Shanmugasundram Phenotypes for gene: XIAP were changed from Lymphoproliferative syndrome, X-linked, 2, OMIM:300635; X-linked lymphoproliferative disease due to XIAP deficiency, MONDO:0010385 to Lymphoproliferative syndrome, X-linked, 2, OMIM:300635; X-linked lymphoproliferative disease due to XIAP deficiency, MONDO:0010385
Haemophagocytic syndrome with absent XIAP expression v1.2 XIAP Achchuthan Shanmugasundram Phenotypes for gene: XIAP were changed from to Lymphoproliferative syndrome, X-linked, 2, OMIM:300635; X-linked lymphoproliferative disease due to XIAP deficiency, MONDO:0010385
Haemophagocytic syndrome with absent perforin expression v1.3 PRF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #603553 in OMIM and the OMIM record was last accessed on 20 December 2025.
Haemophagocytic syndrome with absent perforin expression v1.3 PRF1 Achchuthan Shanmugasundram Phenotypes for gene: PRF1 were changed from Hemophagocytic lymphohistiocytosis, familial, 2, OMIM:603553 to Hemophagocytic lymphohistiocytosis, familial, 2, OMIM:603553; familial hemophagocytic lymphohistiocytosis 2, MONDO:0011337
Sickle cell, thalassaemia and other haemoglobinopathies v2.8 HBG2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #141749 & #613977), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.8 HBG2 Achchuthan Shanmugasundram Phenotypes for gene: HBG2 were changed from to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Cyanosis, transient neonatal, OMIM:613977; cyanosis, transient neonatal, MONDO:0013511
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.8 HBG2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #141749 & #613977), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.8 HBG2 Achchuthan Shanmugasundram Phenotypes for gene: HBG2 were changed from to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Cyanosis, transient neonatal, OMIM:613977; cyanosis, transient neonatal, MONDO:0013511
Sickle cell, thalassaemia and other haemoglobinopathies v2.7 HBG1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #141749 in OMIM and the OMIM record was last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.7 HBG1 Achchuthan Shanmugasundram Phenotypes for gene: HBG1 were changed from to Fetal hemoglobin quantitative trait locus 1, OMIM:141749
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.7 HBG1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #141749 in OMIM and the OMIM record was last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.7 HBG1 Achchuthan Shanmugasundram Phenotypes for gene: HBG1 were changed from to Fetal hemoglobin quantitative trait locus 1, OMIM:141749
Sickle cell, thalassaemia and other haemoglobinopathies v2.6 HBB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #141749, #603902, #603903, #613985, #617971 & #617980), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.6 HBB Achchuthan Shanmugasundram Phenotypes for gene: HBB were changed from to Heinz body anemia, OMIM:140700; Delta-beta thalassemia, OMIM:141749; Hereditary persistence of fetal hemoglobin, OMIM:141749; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell disease, OMIM:603903; Thalassemia, beta, OMIM:613985; Methemoglobinemia, beta type, OMIM:617971; Erythrocytosis, familial, 6, OMIM:617980; dominant beta-thalassemia, MONDO:0011381; sickle cell disease, MONDO:0011382; beta-thalassemia HBB/LCRB, MONDO:0013517; hemoglobin M disease, MONDO:0018023; erythrocytosis, familial, 6, MONDO:0054801
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.6 HBB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #141749, #603902, #603903, #613985, #617971 & #617980), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.6 HBB Achchuthan Shanmugasundram Phenotypes for gene: HBB were changed from to Heinz body anemia, OMIM:140700; Delta-beta thalassemia, OMIM:141749; Hereditary persistence of fetal hemoglobin, OMIM:141749; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell disease, OMIM:603903; Thalassemia, beta, OMIM:613985; Methemoglobinemia, beta type, OMIM:617971; Erythrocytosis, familial, 6, OMIM:617980; dominant beta-thalassemia, MONDO:0011381; sickle cell disease, MONDO:0011382; beta-thalassemia HBB/LCRB, MONDO:0013517; hemoglobin M disease, MONDO:0018023; erythrocytosis, familial, 6, MONDO:0054801
Sickle cell, thalassaemia and other haemoglobinopathies v2.5 HBA2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #604131, #613978 & #617981), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.5 HBA2 Achchuthan Shanmugasundram Phenotypes for gene: HBA2 were changed from to Heinz body anemias, alpha-, OMIM:140700; Thalassemias, alpha-, OMIM:604131; Hemoglobin H disease, deletional and nondeletional, OMIM:613978; Erythrocytosis, familial, 7, OMIM:617981; HBA2-related alpha thalassemia spectrum, MONDO:0100562
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.5 HBA2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #604131, #613978 & #617981), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.5 HBA2 Achchuthan Shanmugasundram Phenotypes for gene: HBA2 were changed from to Heinz body anemias, alpha-, OMIM:140700; Thalassemias, alpha-, OMIM:604131; Hemoglobin H disease, deletional and nondeletional, OMIM:613978; Erythrocytosis, familial, 7, OMIM:617981; HBA2-related alpha thalassemia spectrum, MONDO:0100562
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.4 HBA1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #604131, #613978, #617973 & #617981), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.4 HBA1 Achchuthan Shanmugasundram Phenotypes for gene: HBA1 were changed from to Heinz body anemias, alpha-, OMIM:140700; Thalassemias, alpha-, OMIM:604131; Hemoglobin H disease, nondeletional, OMIM:613978; Methemoglobinemia, alpha type, OMIM:617973; Erythrocytosis, familial, 7, OMIM:617981; HBA1-related alpha thalassemia spectrum, MONDO:0100561; methemoglobinemia, alpha type, MONDO:0020835
Sickle cell, thalassaemia and other haemoglobinopathies v2.4 HBA1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #140700, #604131, #613978, #617973 & #617981), and the OMIM records were last accessed on 20 December 2025.
Sickle cell, thalassaemia and other haemoglobinopathies v2.4 HBA1 Achchuthan Shanmugasundram Phenotypes for gene: HBA1 were changed from to Heinz body anemias, alpha-, OMIM:140700; Thalassemias, alpha-, OMIM:604131; Hemoglobin H disease, nondeletional, OMIM:613978; Methemoglobinemia, alpha type, OMIM:617973; Erythrocytosis, familial, 7, OMIM:617981; HBA1-related alpha thalassemia spectrum, MONDO:0100561; methemoglobinemia, alpha type, MONDO:0020835
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v1.2 GLB1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #230500, #230600, #230650 & #253010), and these OMIM records were last accessed on 19 December 2025.
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v1.2 GLB1 Achchuthan Shanmugasundram Phenotypes for gene: GLB1 were changed from to GM1-gangliosidosis, type I, OMIM:230500; GM1-gangliosidosis, type II, OMIM:230600; GM1-gangliosidosis, type III, OMIM:230650; Mucopolysaccharidosis type IVB (Morquio), OMIM:253010; GM1 gangliosidosis, MONDO:0018149; mucopolysaccharidosis type 4B, MONDO:0009660
Glycogen storage disease V v1.3 PYGM Achchuthan Shanmugasundram Phenotypes for gene: PYGM were changed from Glycogen storage disease V, OMIM:232600; glycogen storage disease V, MONDO:0009293 to McArdle disease, OMIM:232600; glycogen storage disease V, MONDO:0009293
Glycogen storage disease V v1.2 PYGM Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #232600) and the OMIM record was last accessed on 18 December 2025.
Glycogen storage disease V v1.2 PYGM Achchuthan Shanmugasundram Phenotypes for gene: PYGM were changed from to Glycogen storage disease V, OMIM:232600; glycogen storage disease V, MONDO:0009293
Glucokinase-related fasting hyperglycaemia v1.2 GCK Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #125851, #125853, #602485 & #606176) and these OMIM records were last accessed on 19 December 2025.
Glucokinase-related fasting hyperglycaemia v1.2 GCK Achchuthan Shanmugasundram Phenotypes for gene: GCK were changed from to MODY, type II, OMIM:125851; Diabetes mellitus, noninsulin-dependent, late onset, OMIM:125853; Hyperinsulinemic hypoglycemia, familial, 3, OMIM:602485; Diabetes mellitus, permanent neonatal 1, OMIM:606176; maturity-onset diabetes of the young type 2, MONDO:0007453; permanent neonatal diabetes mellitus 1, MONDO:0100165; hyperinsulinism due to glucokinase deficiency, MONDO:0011236
Fetal anomalies v6.129 DHRSX Achchuthan Shanmugasundram Tag Pseudoautosomal region 1 tag was added to gene: DHRSX.
Mitochondrial disorders v9.39 NDUFA4 Achchuthan Shanmugasundram commented on gene: NDUFA4: The 'new-gene-name' tag has been added as the official HGNC gene symbol of NDUFA4 is COXFA4.
Mitochondrial disorders v9.39 NDUFA4 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: NDUFA4.
Mitochondrial disorders v9.39 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619065) and the OMIM record was last accessed on 19 December 2025.
Mitochondrial disorders v9.39 NDUFA4 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from Isolated complex IV deficiency; No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
Possible mitochondrial disorder - nuclear genes v4.18 NDUFA4 Achchuthan Shanmugasundram commented on gene: NDUFA4: The 'new-gene-name' tag has been added as the official HGNC gene symbol of NDUFA4 is COXFA4.
Possible mitochondrial disorder - nuclear genes v4.18 NDUFA4 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: NDUFA4.
Likely inborn error of metabolism v8.84 NDUFA4 Achchuthan Shanmugasundram commented on gene: NDUFA4: The 'new-gene-name' tag has been added as the official HGNC gene symbol of NDUFA4 is COXFA4.
Likely inborn error of metabolism v8.84 NDUFA4 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: NDUFA4.
Possible mitochondrial disorder - nuclear genes v4.18 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619065) and the OMIM record was last accessed on 19 December 2025.
Possible mitochondrial disorder - nuclear genes v4.18 NDUFA4 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from No OMIM phenotype; Mitochondrial complex IV deficiency to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
Likely inborn error of metabolism v8.84 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619065) and the OMIM record was last accessed on 19 December 2025.
Likely inborn error of metabolism v8.84 NDUFA4 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from Isolated complex IV deficiency; No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
Mitochondrial disorder with complex IV deficiency v4.12 NDUFA4 Achchuthan Shanmugasundram commented on gene: NDUFA4: The 'new-gene-name' tag has been added as the official HGNC gene symbol of NDUFA4 is COXFA4.
Mitochondrial disorder with complex IV deficiency v4.12 NDUFA4 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: NDUFA4.
Mitochondrial disorder with complex IV deficiency v4.12 NDUFA4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619065) and the OMIM record was last accessed on 19 December 2025.
Mitochondrial disorder with complex IV deficiency v4.12 NDUFA4 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA4 were changed from No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656
Monogenic short stature v1.29 SLC13A1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SLC13A1.
Skeletal dysplasia v8.26 SLC13A1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SLC13A1.
Intellectual disability v9.206 BHLHE22 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BHLHE22.
Fetal anomalies v6.129 BHLHE22 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BHLHE22.
Childhood onset hereditary spastic paraplegia v8.22 BHLHE22 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BHLHE22.
Intellectual disability v9.206 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Early onset or syndromic epilepsy v8.79 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Fetal anomalies v6.129 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Severe microcephaly v8.21 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Intellectual disability v9.206 LDB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LDB1.
Fetal anomalies v6.129 LDB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LDB1.
Hydrocephalus v5.7 LDB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LDB1.
Fetal anomalies v6.129 BORCS5 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BORCS5.
Fetal anomalies v6.129 SENP7 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SENP7.
Fetal anomalies v6.129 SLC12A9 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SLC12A9.
Intellectual disability v9.206 KIF5B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: KIF5B.
Osteogenesis imperfecta v5.3 KIF5B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: KIF5B.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.28 TNNI1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: TNNI1.
Congenital myopathy v6.44 TNNI1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: TNNI1.
Intellectual disability v9.206 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Early onset or syndromic epilepsy v8.79 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Monogenic hearing loss v5.49 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
DDG2P v6.14 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Childhood onset hereditary spastic paraplegia v8.22 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Ataxia and cerebellar anomalies - narrow panel v8.36 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Early onset or syndromic epilepsy v8.79 RNU12 Ida Ertmanska commented on gene: RNU12: Comment on list classification: There is one large consanguineous pedigree reported in literature, with a biallelic RNU12 mutation segregating with early-onset ataxia. RNU12 should be rated Red for Early onset or syndromic epilepsy, until more evidence emerges.
Ataxia and cerebellar anomalies - narrow panel v8.36 RNU12 Ida Ertmanska commented on gene: RNU12: Comment on list classification: There is one large consanguineous pedigree reported in literature, with a biallelic RNU12 mutation segregating with early-onset ataxia. RNU12 should be rated Red for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges.
Early onset or syndromic epilepsy v8.79 RNU12 Ida Ertmanska gene: RNU12 was added
gene: RNU12 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 27863452; 33577674
Phenotypes for gene: RNU12 were set to ?Spinocerebellar ataxia, autosomal recessive 33, OMIM:620208
Review for gene: RNU12 was set to RED
Added comment: PMID: 27863452 Elsaid et al., 2017
Report of a large consanguineous pedigree with 6 individuals presenting with early-onset ataxia (onset <2 yrs old). Affected individuals were homozygous for RNU12 84C>U mutation. Method: WGS confirmed by Sanger. 2 other mutations segregates with disease in a recessive manner, affecting non-coding regions of genes POLDIP3 and PACSIN2 (uncertain significance).
Affected individuals showed a significant increase in RNU12 snRNA levels; expression of POLDIP3 and PACSIN2 did not differ between affected and unaffected members.
Phenotype spectrum: truncal ataxia 6/6, abnormal cerebellum 5/5 (5 assessed), hypotonia in infancy 5/6, mild learning difficulties 4/6, seizures (febrile / complex partial) 4/6, dysarthric speech 5/6, abnormal gait & falls 5/6.

Functional evidence: PMID: 33577674 Norppa and Frilander, 2021: Show that the 84C>U mutation leads to accelerated decay of the RNU12 snRNA, resulting in significantly reduced steady-state U12 snRNA levels (cell line model).

This gene is putatively linked to Spinocerebellar ataxia, autosomal recessive 33, MIM:620208 and linked to CDAGS syndrome, MIM:603116 (OMIM accessed 19th Dec 2025).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.36 RNU12 Ida Ertmanska gene: RNU12 was added
gene: RNU12 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 27863452; 33577674
Phenotypes for gene: RNU12 were set to ?Spinocerebellar ataxia, autosomal recessive 33, OMIM:620208
Review for gene: RNU12 was set to RED
Added comment: PMID: 27863452 Elsaid et al., 2017
Report of a large consanguineous pedigree with 6 individuals presenting with early-onset ataxia (onset <2 yrs old). Affected individuals were homozygous for RNU12 84C>U mutation. Method: WGS confirmed by Sanger. 2 other mutations segregates with disease in a recessive manner, affecting non-coding regions of genes POLDIP3 and PACSIN2 (uncertain significance).
Affected individuals showed a significant increase in RNU12 snRNA levels; expression of POLDIP3 and PACSIN2 did not differ between affected and unaffected members.
Phenotype spectrum: truncal ataxia 6/6, abnormal cerebellum 5/5 (5 assessed), hypotonia in infancy 5/6, mild learning difficulties 4/6, seizures (febrile / complex partial) 4/6, dysarthric speech 5/6, abnormal gait & falls 5/6.

Functional evidence: PMID: 33577674 Norppa and Frilander, 2021: Show that the 84C>U mutation leads to accelerated decay of the RNU12 snRNA, resulting in significantly reduced steady-state U12 snRNA levels (cell line model).

This gene is putatively linked to Spinocerebellar ataxia, autosomal recessive 33, MIM:620208 and linked to CDAGS syndrome, MIM:603116 (OMIM accessed 19th Dec 2025).
Sources: Literature
Hypertrophic cardiomyopathy v5.26 TBX1 Ida Ertmanska Publications for gene: TBX1 were set to PMID: 41130538
Hypertrophic cardiomyopathy v5.25 TBX1 Ida Ertmanska Phenotypes for gene: TBX1 were changed from Hypertrophic cardiomyopathy to Hypertrophic cardiomyopathy, HP:0001639
Hypertrophic cardiomyopathy v5.24 TBX1 Ida Ertmanska Classified gene: TBX1 as Red List (low evidence)
Hypertrophic cardiomyopathy v5.24 TBX1 Ida Ertmanska Gene: tbx1 has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy v5.23 TBX1 Ida Ertmanska reviewed gene: TBX1: Rating: RED; Mode of pathogenicity: None; Publications: 41130538; Phenotypes: Hypertrophic cardiomyopathy, HP:0001639; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.206 SOX3 Ida Ertmanska changed review comment from: PMID: 35295983 Li et al., 2022
Chinese boy found to have growth hormone deficiency, hypogonadotropic hypogonadism, and borderline intellectual disability (full-scale IQ = 72). WES revealed a hemizygous variant in SOX3 (c.287 delG, p.G96Afs*44), as well as a SEMA3A c.2198G>R (p.R733H) variant.

PMID: 35114986 Du et al., 2022
8yo Chinese boy with a 6 Mb duplication on Xq26.3q27.1 encompassing SOX (and 9 other genes). Presented with congenital hypopituitarism, short stature. Normal intelligence, total IQ = 92.

PMID: 29175558 Jelsig et al., 2018
Family with 3 affected male siblings, harbouring a hemizygous SOX3 variant NM_005634.2:c.449C > A; p.(Ser150Tyr). Phenotype included mild intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology, microcephaly and dental anomalies.

SOX3 is associated with Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, MIM:300123 in OMIM (accessed 19th Dec 2025).; to: PMID: 35295983 Li et al., 2022
Chinese boy found to have growth hormone deficiency, hypogonadotropic hypogonadism, and borderline intellectual disability (full-scale IQ = 72). WES revealed a hemizygous variant in SOX3 (c.287 delG, p.G96Afs*44), as well as a SEMA3A c.2198G>R (p.R733H) variant.

PMID: 35114986 Du et al., 2022
8yo Chinese boy with a 6 Mb duplication on Xq26.3q27.1 encompassing SOX (and 9 other genes). Presented with congenital hypopituitarism, short stature. Normal intelligence, total IQ = 92.

PMID: 29175558 Jelsig et al., 2018
Family with 3 affected male siblings, harbouring a hemizygous SOX3 variant NM_005634.2:c.449C > A; p.(Ser150Tyr). Phenotype included mild intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology, microcephaly and dental anomalies.

SOX3 is associated with Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, MIM:300123 and Panhypopituitarism, X-linked, MIM:312000 in OMIM (accessed 19th Dec 2025).
Intellectual disability v9.206 SOX3 Ida Ertmanska Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252 to Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123; X-linked intellectual disability with isolated growth hormone deficiency, MONDO:0019032
Intellectual disability v9.205 SOX3 Ida Ertmanska Publications for gene: SOX3 were set to
Intellectual disability v9.204 SOX3 Ida Ertmanska Mode of inheritance for gene: SOX3 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
Intellectual disability v9.203 SOX3 Ida Ertmanska edited their review of gene: SOX3: Added comment: Comment on list classification: While variants in SOX3 have been reported to cause a cognitive impairment, its severity does not meet the panel eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Based on available evidence, this gene should be rated Amber for Intellectual disability, until more evidence emerges.; Changed rating: AMBER; Changed phenotypes to: Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123, X-linked intellectual disability with isolated growth hormone deficiency, MONDO:0019032; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v9.203 SOX3 Ida Ertmanska reviewed gene: SOX3: Rating: ; Mode of pathogenicity: None; Publications: 29175558, 35114986, 35295983; Phenotypes: Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, OMIM:300123; Mode of inheritance: None
Mitochondrial disorders v9.38 MT-ATP8 Ida Ertmanska changed review comment from: As reviewed by Zornitza Stark, there are 3 individuals reported with primary mitochondrial disease and variants in MT-ATP8. Hence, this gene should remain Green for Mitochondrial disorders.; to: As reviewed by Zornitza Stark, there are 3 individuals reported with primary mitochondrial disease and variants in MT-ATP8. Hence, this gene should remain Green for Mitochondrial disorders.

This gene is not yet associated with a phenotype in OMIM (accessed 19th Dec 2025).
Mitochondrial disorders v9.38 MT-ATP8 Ida Ertmanska Phenotypes for gene: MT-ATP8 were changed from CARDIOMYOPATHY, INFANTILE HYPERTROPHIC; CARDIOMYOPATHY, APICAL HYPERTROPHIC, AND NEUROPATHY; BRAIN PSEUDOATROPHY, REVERSIBLE, VALPROATE-INDUCED, SUSCEPTIBILITY TO to Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency
Mitochondrial disorders v9.37 MT-ATP8 Ida Ertmanska Publications for gene: MT-ATP8 were set to
Mitochondrial disorders v9.36 MT-ATP8 Ida Ertmanska reviewed gene: MT-ATP8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy or pain disorder v7.31 KIF21A Ida Ertmanska Publications for gene: KIF21A were set to 39643435; 41282472
Hereditary neuropathy or pain disorder v7.30 KIF21A Ida Ertmanska Classified gene: KIF21A as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.30 KIF21A Ida Ertmanska Gene: kif21a has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.29 KIF21A Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: KIF21A.
Tag Q4_25_NHS_review tag was added to gene: KIF21A.
Hereditary neuropathy or pain disorder v7.29 KIF21A Ida Ertmanska commented on gene: KIF21A: Comment on list classification: There are 3 unrelated individuals with progressive peripheral neuropathy reported with de novo heterozygous missense variants localised in the second coiled‑coil domain of KIF21A. Variants in other KIF21A domains are not known to cause neuropathy. Based on available evidence, KIF21A should be promoted to Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.29 KIF21A Ida Ertmanska reviewed gene: KIF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22699964, 32141982, 37921537, 39643435, 41282472; Phenotypes: CFEOM, agenesis of the corpus callosum, peripheral neuropathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.78 EGFLAM Ida Ertmanska Phenotypes for gene: EGFLAM were changed from Congenital Stationary Night Blindness to Congenital stationary night blindness, HP:0007642
Retinal disorders v8.77 EGFLAM Ida Ertmanska Publications for gene: EGFLAM were set to PMID: 41343198
Retinal disorders v8.76 EGFLAM Ida Ertmanska Classified gene: EGFLAM as Amber List (moderate evidence)
Retinal disorders v8.76 EGFLAM Ida Ertmanska Gene: egflam has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.75 EGFLAM Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: EGFLAM.
Tag Q4_25_NHS_review tag was added to gene: EGFLAM.
Retinal disorders v8.75 EGFLAM Ida Ertmanska commented on gene: EGFLAM: Comment on list classification: As reviewed by Siying Lin, there are 3 individuals from 2 unrelated families reported with biallelic EGFLAM variants and Congenital stationary night blindness. In addition, a knockout mouse model supports the gene's association with a retinal phenotype. Based on available evidence, this gene should be promoted to Green for Retinal disorders.
Retinal disorders v8.75 EGFLAM Ida Ertmanska reviewed gene: EGFLAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 18641643, 41343198; Phenotypes: Congenital stationary night blindness, HP:0007642; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Tubulointerstitial kidney disease v3.14 APOA4 Ida Ertmanska Publications for gene: APOA4 were set to 21900878; 27262366; 33751222; 38096951; 39699959
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Tag Q4_25_NHS_review was removed from gene: APOA4.
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: APOA4.
Tag Q4_25_NHS_review tag was added to gene: APOA4.
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 28449784 Bois et al., 2017
13 patients with AApoAIV cardiac amyloidosis, mean age 75 years. Patients had cardiac dysfunction. Of 9 patients evaluated in detail, 8/9 had chronic kidney disease (various stages). Autopsy of 4 cases showed small vessel involvement and prominent medullary renal deposits Genetic analysis was performed, but 'did not identify definitive pathological mutations.'

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 distantly related families reported in literature with with chronic kidney disease, harbouring 2 different monoallelic missense variants. The variants segregated with disease in an autosomal dominant manner (PMID: 38096951). Other reports found that ApoA4 protein is the main component of amyloid deposits found in renal biopsies of patients with medullary amyloidosis. ApoA4 deposits have also been reported in cases of systemic amyloidosis, with renal and cardiac involvement. However, the affected individuals did not have pathogenic APOA4 mutations, suggesting variants in other genes may also lead to ApoA4 aggregation. Based on available evidence, this gene should be promoted to Green for Hereditary systemic amyloidosis.; to: Comment on list classification: There are 5 distantly related families reported in literature with with chronic kidney disease, harbouring 2 different monoallelic missense variants. The variants segregated with disease in an autosomal dominant manner (PMID: 38096951). Other reports found that ApoA4 protein is the main component of amyloid deposits found in renal biopsies of patients with medullary amyloidosis. ApoA4 deposits have also been reported in cases of systemic amyloidosis, with renal and cardiac involvement. However, the affected individuals did not have pathogenic APOA4 mutations, suggesting variants in other genes may also lead to ApoA4 aggregation. Based on available evidence, this gene should be promoted to Green for Tubulointerstitial kidney disease.
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska edited their review of gene: APOA4: Added comment: Comment on list classification: There are 5 distantly related families reported in literature with with chronic kidney disease, harbouring 2 different monoallelic missense variants. The variants segregated with disease in an autosomal dominant manner (PMID: 38096951). Other reports found that ApoA4 protein is the main component of amyloid deposits found in renal biopsies of patients with medullary amyloidosis. ApoA4 deposits have also been reported in cases of systemic amyloidosis, with renal and cardiac involvement. However, the affected individuals did not have pathogenic APOA4 mutations, suggesting variants in other genes may also lead to ApoA4 aggregation. Based on available evidence, this gene should be promoted to Green for Hereditary systemic amyloidosis.; Changed rating: GREEN; Changed publications to: 21900878, 27262366, 28449784, 33751222, 38096951, 39699959
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: APOA4.
Tag Q4_25_NHS_review tag was added to gene: APOA4.
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis, though only 26.7% of mice showed 'extensive' amyloid deposition. Variants in other genes may cause APOA4 to aggregate?

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 28449784 Bois et al., 2017
13 patients with AApoAIV cardiac amyloidosis, mean age 75 years. Patients had cardiac dysfunction. Of 9 patients evaluated in detail, 8/9 had chronic kidney disease (various stages). Autopsy of 4 cases showed small vessel involvement and prominent medullary renal deposits Genetic analysis was performed, but 'did not identify definitive pathological mutations.'

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis, though only 26.7% of mice showed 'extensive' amyloid deposition. Variants in other genes may cause APOA4 to aggregate?

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska edited their review of gene: APOA4: Added comment: Comment on list classification: There are 5 distantly related families reported in literature with with chronic kidney disease, harbouring 2 different monoallelic missense variants. The variants segregated with disease in an autosomal dominant manner (PMID: 38096951). Other reports found that ApoA4 protein is the main component of amyloid deposits found in renal biopsies of patients with medullary amyloidosis. Similarly, ApoA4 deposits have been reported in cases of cardiac amyloidosis. However, the affected individuals did not have pathogenic APOA4 mutations, suggesting variants in other genes may also lead to ApoA4 aggregation. Based on available evidence, this gene should be promoted to Green for Hereditary systemic amyloidosis.; Changed rating: GREEN; Changed publications to: 21900878, 27262366, 28449784, 33751222, 38096951, 39699959
Respiratory ciliopathies including non-CF bronchiectasis v4.54 CFAP221 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #279000) and the OMIM record was last accessed on 18 December 2025.
Respiratory ciliopathies including non-CF bronchiectasis v4.54 CFAP221 Achchuthan Shanmugasundram Phenotypes for gene: CFAP221 were changed from Ciliary dyskinesia, primary, 55, OMIM:279000 to Ciliary dyskinesia, primary, 55, OMIM:279000
Respiratory ciliopathies including non-CF bronchiectasis v4.53 CFAP221 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: CFAP221.
Respiratory ciliopathies including non-CF bronchiectasis v4.53 CFAP54 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: CFAP54.
Respiratory ciliopathies including non-CF bronchiectasis v4.53 NEK10 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #618781) and the OMIM record was last accessed on 18 December 2025.
Respiratory ciliopathies including non-CF bronchiectasis v4.53 NEK10 Achchuthan Shanmugasundram Phenotypes for gene: NEK10 were changed from Ciliary dyskinesia, primary, 44, OMIM:618781; ciliary dyskinesia, primary, 44, MONDO:0032914 to Ciliary dyskinesia, primary, 44, OMIM:618781; ciliary dyskinesia, primary, 44, MONDO:0032914
Respiratory ciliopathies including non-CF bronchiectasis v4.52 NEK10 Achchuthan Shanmugasundram Phenotypes for gene: NEK10 were changed from Ciliary dyskinesia, primary, 44, OMIM:618781, MONDO:0032914 to Ciliary dyskinesia, primary, 44, OMIM:618781; ciliary dyskinesia, primary, 44, MONDO:0032914
Respiratory ciliopathies including non-CF bronchiectasis v4.51 NEK10 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: NEK10.
Respiratory ciliopathies including non-CF bronchiectasis v4.51 CFAP74 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620197) and the OMIM record was last accessed on 18 December 2025.
Respiratory ciliopathies including non-CF bronchiectasis v4.51 CFAP74 Achchuthan Shanmugasundram Phenotypes for gene: CFAP74 were changed from Ciliary dyskinesia, primary, 49, without situs inversus, OMIM:620197 to Ciliary dyskinesia, primary, 49, without situs inversus, OMIM:620197; ciliary dyskinesia, primary, 49, without situs inversus, OMIM:620197
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP74 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: CFAP74.
Fetal anomalies v6.129 PHF5A Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: PHF5A.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 EFCAB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: EFCAB1.
Fetal anomalies v6.129 DHRSX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DHRSX.
Intellectual disability v9.203 RNU5B-1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621302) and the OMIM record was last accessed on 18 December 2025.
Intellectual disability v9.203 RNU5B-1 Achchuthan Shanmugasundram Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302; RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity, MONDO:1060179
Intellectual disability v9.202 RNU5B-1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU5B-1.
Early onset or syndromic epilepsy v8.78 RNU5B-1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621302) and the OMIM record was last accessed on 18 December 2025.
Early onset or syndromic epilepsy v8.78 RNU5B-1 Achchuthan Shanmugasundram Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302; RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity, MONDO:1060179
Early onset or syndromic epilepsy v8.77 RNU5B-1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU5B-1.
Fetal anomalies v6.129 RNU5B-1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU5B-1.
Fetal anomalies v6.129 C1orf127 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621080) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.129 C1orf127 Achchuthan Shanmugasundram Phenotypes for gene: C1orf127 were changed from Heterotaxy, visceral, 14, autosomal, OMIM:621080 to Heterotaxy, visceral, 14, autosomal, OMIM:621080; heterotaxy, visceral, 14, autosomal, MONDO:0976135
Fetal anomalies v6.128 C1orf127 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: C1orf127.
Laterality disorders and isomerism v4.9 C1orf127 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621080) and the OMIM record was last accessed on 18 December 2025.
Laterality disorders and isomerism v4.9 C1orf127 Achchuthan Shanmugasundram Phenotypes for gene: C1orf127 were changed from Heterotaxy, visceral, 14, autosomal, OMIM:621080 to Heterotaxy, visceral, 14, autosomal, OMIM:621080; heterotaxy, visceral, 14, autosomal, MONDO:0976135
Laterality disorders and isomerism v4.8 C1orf127 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: C1orf127.
Retinal disorders v8.75 RNU4-2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU4-2.
Congenital myopathy v6.44 MYMX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619941) and the OMIM record was last accessed on 18 December 2025.
Congenital myopathy v6.44 MYMX Achchuthan Shanmugasundram Phenotypes for gene: MYMX were changed from ?Carey-Fineman-Ziter syndrome 2, OMIM:619941 to Carey-Fineman-Ziter syndrome 2, OMIM:619941; Carey-Fineman-Ziter syndrome 2, MONDO:0100292
Congenital myopathy v6.43 MYMX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MYMX.
Multi locus imprinting disorders v1.16 NLRP5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620333) and the OMIM record was last accessed on 18 December 2025.
Multi locus imprinting disorders v1.16 NLRP5 Achchuthan Shanmugasundram Phenotypes for gene: NLRP5 were changed from Phenotype resulting from under expression: Biparental complete hydatidiform mole, Beckwith-Wiedemann Syndrome, Multi-locus imprinting disorder; Affected tissue: all to Oocyte/zygote/embryo maturation arrest 19, OMIM:620333; oocyte/zygote/embryo maturation arrest 19, MONDO:0957231
Monogenic short stature v1.29 NLRP5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620333) and the OMIM record was last accessed on 18 December 2025.
Monogenic short stature v1.29 NLRP5 Achchuthan Shanmugasundram Phenotypes for gene: NLRP5 were changed from IUGR; Short stature; Failure to thrive; body asymmetry; multilocus imprinting disturbances to Oocyte/zygote/embryo maturation arrest 19, OMIM:620333; oocyte/zygote/embryo maturation arrest 19, MONDO:0957231
Multi locus imprinting disorders v1.15 NLRP5 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: NLRP5.
Monogenic short stature v1.28 NLRP2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620332) and the OMIM record was last accessed on 18 December 2025.
Monogenic short stature v1.28 NLRP2 Achchuthan Shanmugasundram Phenotypes for gene: NLRP2 were changed from Maternal effect gene- causing phenotypes that include IUGR to Oocyte/zygote/embryo maturation arrest 18, OMIM:620332; oocyte/zygote/embryo maturation arrest 18, MONDO:0957230
Multi locus imprinting disorders v1.15 NLRP2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620332) and the OMIM record was last accessed on 18 December 2025.
Multi locus imprinting disorders v1.15 NLRP2 Achchuthan Shanmugasundram Phenotypes for gene: NLRP2 were changed from Beckwith-Wiedemann syndrome due to imprinting defect of 11p15 MONDO:0016475 to Oocyte/zygote/embryo maturation arrest 18, OMIM:620332; oocyte/zygote/embryo maturation arrest 18, MONDO:0957230; Beckwith-Wiedemann syndrome due to imprinting defect of 11p15, MONDO:0016475
Multi locus imprinting disorders v1.14 NLRP2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: NLRP2.
Multi locus imprinting disorders v1.14 NLRP2 Achchuthan Shanmugasundram Tag watchlist was removed from gene: NLRP2.
Tag gene-checked was removed from gene: NLRP2.
Segmental overgrowth disorders - Deep sequencing v4.4 NLRP2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620332) and the OMIM record was last accessed on 18 December 2025.
Segmental overgrowth disorders - Deep sequencing v4.4 NLRP2 Achchuthan Shanmugasundram Phenotypes for gene: NLRP2 were changed from Beckwith-Wiedemann syndrome due to imprinting defect of 11p15 MONDO:0016475 to Oocyte/zygote/embryo maturation arrest 18, OMIM:620332; oocyte/zygote/embryo maturation arrest 18, MONDO:0957230; Beckwith-Wiedemann syndrome due to imprinting defect of 11p15, MONDO:0016475
DDG2P v6.14 LEF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621224) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.14 LEF1 Achchuthan Shanmugasundram Phenotypes for gene: LEF1 were changed from LEF1-related ectodermal dysplasia and limb malformation to LEF1-related ectodermal dysplasia and limb malformation; Ectodermal dysplasia 17 with or without limb malformations, OMIM:621224; ectodermal dysplasia 17 with or without limb malformations, MONDO:0979228
DDG2P v6.13 LEF1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: LEF1.
Ectodermal dysplasia v4.20 LEF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621224) and the OMIM record was last accessed on 18 December 2025.
Ectodermal dysplasia v4.20 LEF1 Achchuthan Shanmugasundram Phenotypes for gene: LEF1 were changed from ectodermal dysplasia syndrome, MONDO:0019287 to Ectodermal dysplasia 17 with or without limb malformations, OMIM:621224; ectodermal dysplasia 17 with or without limb malformations, MONDO:0979228
Ectodermal dysplasia v4.19 LEF1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: LEF1.
Intellectual disability v9.202 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:62138 to Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:621384
Intellectual disability v9.201 PAN2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621384) and the OMIM record was last accessed on 18 December 2025.
Intellectual disability v9.201 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from Global developmental delay; Intellectual disability; Sensorineural hearing impairment; Abnormality of the genitourinary system; Abnormality of the cardiovascular system; Abnormality of blood and blood-forming tissues; EEG abnormality; Seizures; Anorectal anomaly; Abnormality of the skeletal system; Abnormality of the eye; Abnormality of head or neck to Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:62138
Intellectual disability v9.200 PAN2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: PAN2.
DDG2P v6.13 PAN2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621384) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.13 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from PAN2-related neurodevelopmental disorder with multiple congenital anomalies to PAN2-related neurodevelopmental disorder with multiple congenital anomalies; Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:621384
DDG2P v6.12 PAN2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: PAN2.
Fetal anomalies v6.128 PAN2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621384) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.128 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from syndromic disease MONDO:0002254 to Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:621384
Fetal anomalies v6.127 PAN2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: PAN2.
Clefting v6.19 AMOTL1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621192) and the OMIM record was last accessed on 18 December 2025.
Clefting v6.19 AMOTL1 Achchuthan Shanmugasundram Phenotypes for gene: AMOTL1 were changed from cleft lip/palate MONDO:0016044; imperforate anus; dysmorphism to Craniofaciocardiohepatic syndrome, OMIM:621192; craniofaciocardiohepatic syndrome, MONDO:0978295
Clefting v6.18 AMOTL1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: AMOTL1.
DDG2P v6.12 AMOTL1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621192) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.12 AMOTL1 Achchuthan Shanmugasundram Phenotypes for gene: AMOTL1 were changed from tall stature; cardiac anomalies; orofacial clefting; AMOTL1-related orofacial clefting, cardiac anomalies, and tall stature to AMOTL1-related orofacial clefting, cardiac anomalies, and tall stature; Craniofaciocardiohepatic syndrome, OMIM:621192; craniofaciocardiohepatic syndrome, MONDO:0978295
DDG2P v6.11 AMOTL1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: AMOTL1.
Fetal anomalies v6.127 AMOTL1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621192) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.127 AMOTL1 Achchuthan Shanmugasundram Phenotypes for gene: AMOTL1 were changed from Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related to Craniofaciocardiohepatic syndrome, OMIM:621192; craniofaciocardiohepatic syndrome, MONDO:0978295
Fetal anomalies v6.126 AMOTL1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: AMOTL1.
Intellectual disability v9.200 GON4L Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621212) and the OMIM record was last accessed on 18 December 2025.
Intellectual disability v9.200 GON4L Achchuthan Shanmugasundram Phenotypes for gene: GON4L were changed from prenatal-onset growth impairment and developmental delay to Li-Takada-Miyake syndrome, OMIM:621212; Li-Takada-Miyake syndrome, MONDO:0978303
DDG2P v6.11 GON4L Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621212) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.11 GON4L Achchuthan Shanmugasundram Phenotypes for gene: GON4L were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Li-Takada-Miyake syndrome, OMIM:621212; Li-Takada-Miyake syndrome, MONDO:0978303
Fetal anomalies v6.126 GON4L Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621212) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.126 GON4L Achchuthan Shanmugasundram Phenotypes for gene: GON4L were changed from complex neurodevelopmental disorder, MONDO:0100038 to Li-Takada-Miyake syndrome, OMIM:621212; Li-Takada-Miyake syndrome, MONDO:0978303
Fetal anomalies v6.125 GON4L Achchuthan Shanmugasundram Tag gene-checked was removed from gene: GON4L.
Skeletal ciliopathies v6.4 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Skeletal ciliopathies v6.4 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from No OMIM phenotype; Oro-facio-digital syndrome type IX (Adly (2014) Hum Mutat 35, 36) to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Skeletal ciliopathies v6.3 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Neurological ciliopathies v6.12 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Neurological ciliopathies v6.12 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from No OMIM phenotype; Oro-facio-digital syndrome type IX (Adly (2014) Hum Mutat 35, 36) to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Neurological ciliopathies v6.11 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Ophthalmological ciliopathies v5.10 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Ophthalmological ciliopathies v5.10 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Ophthalmological ciliopathies v5.9 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Structural eye disease v4.36 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Structural eye disease v4.35 TBC1D32 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
DDG2P v6.10 TBC1D32 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
DDG2P v6.10 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from TBC1D32-related ciliopathy; Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795 to TBC1D32-related ciliopathy; Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Fetal anomalies v6.125 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Fetal anomalies v6.124 TBC1D32 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Rare multisystem ciliopathy disorders v1.179 TBC1D32 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #258865 & #621307) and the OMIM records were last accessed on 18 December 2025.
Rare multisystem ciliopathy disorders v1.179 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Alsahan-Harris syndrome, OMIM:621307; Alsahan-Harris syndrome, MONDO:0979871
Rare multisystem ciliopathy disorders v1.178 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Rare multisystem ciliopathy disorders v1.178 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Rare multisystem ciliopathy disorders v1.177 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Structural eye disease v4.35 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Structural eye disease v4.35 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome 9, 258865 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Structural eye disease v4.34 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Retinal disorders v8.75 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621280) and the OMIM record was last accessed on 18 December 2025.
Retinal disorders v8.75 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from retinitis pigmentosa, MONDO:0019200 to Retinitis pigmentosa 100, OMIM:621280; retinitis pigmentosa, MONDO:0019200
DDG2P v6.9 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
DDG2P v6.9 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
DDG2P v6.9 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from TBC1D32-related ciliopathy to TBC1D32-related ciliopathy; Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Fetal anomalies v6.124 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Fetal anomalies v6.124 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from OFD IX to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Fetal anomalies v6.123 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Malformations of cortical development v7.18 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Malformations of cortical development v7.18 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Malformations of cortical development v7.17 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Pituitary hormone deficiency v4.3 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Pituitary hormone deficiency v4.3 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Syndromic Hypopituitarism; orofaciodigital syndrome to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795; Syndromic Hypopituitarism
Pituitary hormone deficiency v4.2 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Thoracic dystrophies v1.24 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Hydrocephalus v5.7 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome IX, OMIM:258865; Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; orofaciodigital syndrome IX, MONDO:0009795
Thoracic dystrophies v1.23 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Thoracic dystrophies v1.23 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from OFD to Orofaciodigital syndrome IX, OMIM:258865; Orofaciodigital syndrome, MONDO:0015375
Thoracic dystrophies v1.22 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Hydrocephalus v5.6 TBC1D32 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TBC1D32.
Hydrocephalus v5.6 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #258865) and the OMIM record was last accessed on 18 December 2025.
Hydrocephalus v5.6 TBC1D32 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D32 were changed from Orofaciodigital syndrome, MONDO:0015375 to Orofaciodigital syndrome IX, OMIM:258865; Orofaciodigital syndrome, MONDO:0015375
Hypertrophic cardiomyopathy v5.23 TRIM63 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: TRIM63.
Hypertrophic cardiomyopathy v5.23 TRIM63 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621270) and the OMIM record was last accessed on 18 December 2025.
Hypertrophic cardiomyopathy v5.23 TRIM63 Achchuthan Shanmugasundram Phenotypes for gene: TRIM63 were changed from Hypertrophic cardiomyopathy, MONDO:0005045; restrictive cardiomyopathy, MONDO:0005201 to Cardiomyopathy, familial hypertrophic, 31, OMIM:621270; cardiomyopathy, familial hypertrophic, 31, MONDO:0979573
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska Phenotypes for gene: APOA4 were changed from tubulointerstitial kidney disease; Chronic kidney disease to Tubulointerstitial kidney disease, autosomal dominant 6, OMIM: 621106; tubulointerstitial kidney disease, autosomal dominant 6, MONDO:0976234
Tubulointerstitial kidney disease v3.12 APOA4 Ida Ertmanska Publications for gene: APOA4 were set to PMID 38096951
Tubulointerstitial kidney disease v3.11 APOA4 Ida Ertmanska Classified gene: APOA4 as Amber List (moderate evidence)
Tubulointerstitial kidney disease v3.11 APOA4 Ida Ertmanska Gene: apoa4 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.29 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary ataxia with onset in adulthood v8.15 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v9.36 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska edited their review of gene: APOA4: Changed rating: AMBER
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Tag Q4_25_promote_green was removed from gene: APOA4.
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton Deleted their review
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton Deleted their review
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis, though only 26.7% of mice showed 'extensive' amyloid deposition. Variants in other genes may cause APOA4 to aggregate?

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton Deleted their review
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton Deleted their comment
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton changed review comment from: Request mode of inheritance changed to biallelic only.
In Sheffield we do not report single hits in SPG7 due to limited evidence of a monoallelic association for SPG7. We have performed a case control study using local data in Sheffield and determined no association for the common p.(Ala510Val) variant as a single hit for the disease.
Evidence in the literature is extremely limited for a monoallelic MOI, and we suggest these have been reported erroneously due to the high frequency of p.(Ala510Val) in the population.
MOI in OMIM was recently changed from AD/AR to AR only.; to: Request mode of inheritance changed to biallelic only.
In Sheffield we do not report single hits in SPG7 due to limited evidence of a monoallelic association for SPG7. We have performed a case control study using local data in Sheffield and determined no association for the common p.(Ala510Val) variant as a single hit for the disease.
Evidence in the literature is extremely limited for a monoallelic MOI, and we suggest these have been reported erroneously due to the high frequency of p.(Ala510Val) in the population.
MOI in OMIM was recently changed from AD/AR to AR only.
Ataxia and cerebellar anomalies - narrow panel v8.35 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v8.35 SPG7 Lauren Turton Deleted their review
Adult onset hereditary spastic paraplegia v6.3 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Adult onset hereditary spastic paraplegia v6.3 SPG7 Lauren Turton Deleted their review
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton Deleted their review
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Classified gene: APOA4 as Amber List (moderate evidence)
Hereditary systemic amyloidosis v1.27 APOA4 Ida Ertmanska Gene: apoa4 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton Deleted their review
Hereditary systemic amyloidosis v1.26 APOA4 Ida Ertmanska gene: APOA4 was added
gene: APOA4 was added to Hereditary systemic amyloidosis. Sources: Literature
Q4_25_promote_green tags were added to gene: APOA4.
Mode of inheritance for gene: APOA4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: APOA4 were set to 21900878; 27262366; 33751222; 38096951; 39699959
Phenotypes for gene: APOA4 were set to Tubulointerstitial kidney disease, autosomal dominant 6, OMIM: 621106; tubulointerstitial kidney disease, autosomal dominant 6, MONDO:0976234; AApoAIV amyloidosis, MONDO:0018589
Review for gene: APOA4 was set to GREEN
Added comment: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton Deleted their comment
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton Deleted their review
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton changed review comment from: Request mode of inheritance changed to biallelic only.
In Sheffield we do not report single hits in SPG7 due to limited evidence of a monoallelic association for SPG7. We have performed a case control study using local data in Sheffield and determined no association for the common p.(Ala510Val) variant as a single hit for the disease.
Evidence in the literature is extremely limited for a monoallelic MOI, and we suggest these have been reported erroneously due to the high frequency of p.(Ala510Val) in the population.
MOI in OMIM was recently changed from AD/AR to AR only.; to: Request mode of inheritance changed to biallelic only.
In Sheffield we do not report single hits in SPG7 due to limited evidence of a monoallelic association for SPG7. We have performed a case control study using local data in Sheffield and determined no association for the common p.(Ala510Val) variant as a single hit for the disease.
Evidence in the literature is extremely limited for a monoallelic MOI, and we suggest these have been reported erroneously due to the high frequency of p.(Ala510Val) in the population.
MOI in OMIM was recently changed from AD/AR to AR only.
Possible mitochondrial disorder - nuclear genes v4.17 SPG7 Lauren Turton reviewed gene: SPG7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Likely inborn error of metabolism v8.83 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Adult onset neurodegenerative disorder v8.9 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Adult onset hereditary spastic paraplegia v6.3 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v8.35 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Childhood onset hereditary spastic paraplegia v8.22 SPG7 Lauren Turton reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska edited their review of gene: APOA4: Changed publications to: 21900878, 27262366, 33751222, 38096951, 39699959
Generalised arterial calcification in infancy v1.3 ENPP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #208000) and the OMIM record was last accessed on 18 December 2025.
Generalised arterial calcification in infancy v1.3 ENPP1 Achchuthan Shanmugasundram Phenotypes for gene: ENPP1 were changed from to Arterial calcification, generalized, of infancy, 1, OMIM:208000; arterial calcification, generalized, of infancy, 1, MONDO:0008817
Generalised arterial calcification in infancy v1.2 ABCC6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #61447) and the OMIM record was last accessed on 18 December 2025.
Generalised arterial calcification in infancy v1.2 ABCC6 Achchuthan Shanmugasundram Phenotypes for gene: ABCC6 were changed from to Arterial calcification, generalized, of infancy, 2, OMIM:614473; arterial calcification, generalized, of infancy, 2, MONDO:0013768
Gaucher disease v1.2 GBA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #230800, #230900, #231000, #231005 & #608013) and the OMIM records were last accessed on 18 December 2025.
Gaucher disease v1.2 GBA Achchuthan Shanmugasundram Phenotypes for gene: GBA were changed from to Gaucher disease, type I, OMIM:230800; Gaucher disease, type II, OMIM:230900; Gaucher disease, type III, OMIM:231000; Gaucher disease, type IIIC, OMIM:231005; Gaucher disease, perinatal lethal, OMIM:608013
Fumarate hydratase-related tumour syndromes v1.2 FH Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #150800) and the OMIM record was last accessed on 18 December 2025.
Fumarate hydratase-related tumour syndromes v1.2 FH Achchuthan Shanmugasundram Phenotypes for gene: FH were changed from to Leiomyomatosis and renal cell cancer, OMIM:150800; hereditary leiomyomatosis and renal cell cancer, MONDO:0007888
Familial dysalbuminaemic hyperthyroxinaemia v1.2 ALB Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #615999) and the OMIM record was last accessed on 18 December 2025.
Familial dysalbuminaemic hyperthyroxinaemia v1.2 ALB Achchuthan Shanmugasundram Phenotypes for gene: ALB were changed from to [Dysalbuminemic hyperthyroxinemia], OMIM:615999; hyperthyroxinemia, familial dysalbuminemic, MONDO:0014448
Factor XIII deficiency v1.3 F13B Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613235) and the OMIM record was last accessed on 18 December 2025.
Factor XIII deficiency v1.3 F13B Achchuthan Shanmugasundram Phenotypes for gene: F13B were changed from to Factor XIIIB deficiency, OMIM:613235; factor XIII, b subunit, deficiency of, MONDO:0013190
Factor XIII deficiency v1.2 F13A1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613225) and the OMIM record was last accessed on 18 December 2025.
Factor XIII deficiency v1.2 F13A1 Achchuthan Shanmugasundram Phenotypes for gene: F13A1 were changed from to Factor XIIIA deficiency, OMIM:613225; factor XIII, A subunit, deficiency of, MONDO:0013187
Factor XI deficiency v1.2 F11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #612416) and the OMIM record was last accessed on 18 December 2025.
Factor XI deficiency v1.2 F11 Achchuthan Shanmugasundram Phenotypes for gene: F11 were changed from to Factor XI deficiency, autosomal dominant, OMIM:612416; Factor XI deficiency, autosomal recessive, OMIM:612416; congenital factor XI deficiency, MONDO:0012897
Factor X deficiency v1.2 F10 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227600) and the OMIM record was last accessed on 18 December 2025.
Factor X deficiency v1.2 F10 Achchuthan Shanmugasundram Phenotypes for gene: F10 were changed from to Factor X deficiency, OMIM:227600; congenital factor X deficiency, MONDO:0009212
Factor VIII deficiency v1.2 F8 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #306700) and the OMIM record was last accessed on 18 December 2025.
Factor VIII deficiency v1.2 F8 Achchuthan Shanmugasundram Phenotypes for gene: F8 were changed from to Hemophilia A, OMIM:306700; hemophilia A, MONDO:0010602
Factor VII deficiency v1.2 F7 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227500) and the OMIM record was last accessed on 18 December 2025.
Factor VII deficiency v1.2 F7 Achchuthan Shanmugasundram Phenotypes for gene: F7 were changed from to Factor VII deficiency, OMIM:227500; congenital factor VII deficiency, MONDO:0009211
Factor V deficiency v1.2 F5 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227400) and the OMIM record was last accessed on 18 October 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227400) and the OMIM record was last accessed on 18 December 2025.
Factor V deficiency v1.2 F5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #227400) and the OMIM record was last accessed on 18 October 2025.
Factor V deficiency v1.2 F5 Achchuthan Shanmugasundram Phenotypes for gene: F5 were changed from to Factor V deficiency, OMIM:227400; congenital factor V deficiency, MONDO:0009210
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska changed review comment from: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).; to: PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis - variants in other genes may cause APOA4 to aggregate.

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska edited their review of gene: APOA4: Changed publications to: 21900878 27262366, 33751222, 38096951, 39699959
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska reviewed gene: APOA4: Rating: AMBER; Mode of pathogenicity: None; Publications: 38096951; Phenotypes: Tubulointerstitial kidney disease, autosomal dominant 6, OMIM: 621106, tubulointerstitial kidney disease, autosomal dominant 6, MONDO:0976234; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Factor IX deficiency v1.2 F9 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #300807 & #306900) and the OMIM records were last accessed on 17 December 2025.
Factor IX deficiency v1.2 F9 Achchuthan Shanmugasundram Phenotypes for gene: F9 were changed from to Thrombophilia, X-linked, due to factor IX defect, OMIM:300807; Hemophilia B, OMIM:306900; hemophilia B, MONDO:0010604; thrombophilia, X-linked, due to factor 9 defect, MONDO:0010432
Factor II deficiency v1.2 F2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #613679) and the OMIM record was last accessed on 17 December 2025.
Factor II deficiency v1.2 F2 Achchuthan Shanmugasundram Phenotypes for gene: F2 were changed from to Dysprothrombinemia, OMIM:613679; Hypoprothrombinemia, OMIM:613679; congenital prothrombin deficiency, MONDO:0013361
Facioscapulohumeral muscular dystrophy - extended testing v1.2 SMCHD1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #158901) and the OMIM record was last accessed on 17 December 2025.
Facioscapulohumeral muscular dystrophy - extended testing v1.2 SMCHD1 Achchuthan Shanmugasundram Phenotypes for gene: SMCHD1 were changed from to Facioscapulohumeral muscular dystrophy 2, digenic, OMIM:158901; facioscapulohumeral muscular dystrophy 2, MONDO:0008031
Fabry disease v1.2 GLA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #301500) and the OMIM record was last accessed on 17 December 2025.
Fabry disease v1.2 GLA Achchuthan Shanmugasundram Phenotypes for gene: GLA were changed from to Fabry disease, OMIM:301500; Fabry disease, cardiac variant, OMIM:301500; Fabry disease, MONDO:0010526
Elastin-related phenotypes v1.2 ELN Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #123700 & #185500) and the OMIM records were last accessed on 17 December 2025.
Elastin-related phenotypes v1.2 ELN Achchuthan Shanmugasundram Phenotypes for gene: ELN were changed from to Cutis laxa, autosomal dominant, OMIM:123700; Supravalvar aortic stenosis, OMIM:185500; cutis laxa, autosomal dominant 1, MONDO:0007411; supravalvular aortic stenosis, MONDO:0008504
Duchenne or Becker muscular dystrophy v1.2 DMD Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #310200 & #300376) and the OMIM records were last accessed on 17 December 2025.
Duchenne or Becker muscular dystrophy v1.2 DMD Achchuthan Shanmugasundram Phenotypes for gene: DMD were changed from to Duchenne muscular dystrophy, OMIM:310200; Becker muscular dystrophy, OMIM:300376; Duchenne muscular dystrophy, MONDO:0010679; Becker muscular dystrophy, MONDO:0010311
DICER1-related cancer predisposition v1.2 DICER1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #138800 & #601200) and the OMIM records were last accessed on 17 December 2025.
DICER1-related cancer predisposition v1.2 DICER1 Achchuthan Shanmugasundram Phenotypes for gene: DICER1 were changed from to Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800; Pleuropulmonary blastoma, OMIM:601200; DICER1-related tumor predisposition, MONDO:0100216
Cystinosis v1.2 CTNS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #219800) and the OMIM record was last accessed on 17 December 2025.
Cystinosis v1.2 CTNS Achchuthan Shanmugasundram Phenotypes for gene: CTNS were changed from to Cystinosis, atypical nephropathic, OMIM:219800; Cystinosis, nephropathic, OMIM:219800; nephropathic cystinosis, MONDO:0100151
Cystic fibrosis diagnostic test v1.2 CFTR Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #219700) and the OMIM record was last accessed on 17 December 2025.
Cystic fibrosis diagnostic test v1.2 CFTR Achchuthan Shanmugasundram Phenotypes for gene: CFTR were changed from to Cystic fibrosis, OMIM:219700; cystic fibrosis, MONDO:0009061
Congenital adrenal hyperplasia diagnostic test v1.2 CYP21A2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #201910) and the OMIM record was last accessed on 17 December 2025.
Congenital adrenal hyperplasia diagnostic test v1.2 CYP21A2 Achchuthan Shanmugasundram Phenotypes for gene: CYP21A2 were changed from to Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency, OMIM:201910; Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency, OMIM:201910; classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, MONDO:0008728
Combined vitamin K-dependent clotting factor deficiency v1.3 VKORC1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #607473) and the OMIM record was last accessed on 17 December 2025.
Combined vitamin K-dependent clotting factor deficiency v1.3 VKORC1 Achchuthan Shanmugasundram Phenotypes for gene: VKORC1 were changed from to Vitamin K-dependent clotting factors, combined deficiency of, type 2, OMIM:607473; vitamin K-dependent clotting factors, combined deficiency of, type 2, MONDO:0011837
Combined vitamin K-dependent clotting factor deficiency v1.2 GGCX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #277450) and the OMIM record was last accessed on 17 December 2025.
Combined vitamin K-dependent clotting factor deficiency v1.2 GGCX Achchuthan Shanmugasundram Phenotypes for gene: GGCX were changed from to Vitamin K-dependent clotting factors, combined deficiency of, 1, OMIM:277450; vitamin K-dependent clotting factors, combined deficiency of, type 1, MONDO:0010187
Central congenital hypoventilation v1.6 PHOX2B Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #209880) and the OMIM record was last accessed on 17 December 2025.
Central congenital hypoventilation v1.6 PHOX2B Achchuthan Shanmugasundram Phenotypes for gene: PHOX2B were changed from to Congenital central hypoventilation syndrome, OMIM:209880; central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, MONDO:0800026
Hereditary diffuse gastric cancer v2.4 CTNNA1 Achchuthan Shanmugasundram Phenotypes for gene: CTNNA1 were changed from to CTNNA1-related diffuse gastric and lobular breast cancer syndrome, MONDO:0100256
Hereditary diffuse gastric cancer v2.3 CDH1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #137215) and the OMIM record was last accessed on 17 December 2025.
Hereditary diffuse gastric cancer v2.3 CDH1 Achchuthan Shanmugasundram Phenotypes for gene: CDH1 were changed from Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215 to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215; CDH1-related diffuse gastric and lobular breast cancer syndrome, MONDO:0100488
Carney complex v1.2 PRKAR1A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #160980) and the OMIM record was last accessed on 17 December 2025.
Carney complex v1.2 PRKAR1A Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1A were changed from to Carney complex, OMIM:160980; Carney complex, type 1, MONDO:0008057
Calcium-sensing receptor phenotypes v1.2 CASR Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #145980, #239200 & #601198) and these OMIM records were last accessed on 17 December 2025.
Calcium-sensing receptor phenotypes v1.2 CASR Achchuthan Shanmugasundram Phenotypes for gene: CASR were changed from to Hypocalciuric hypercalcemia, type I, OMIM:145980; Hyperparathyroidism, neonatal, OMIM:239200; Hypocalcemia, autosomal dominant, OMIM:601198; Hypocalcemia, autosomal dominant, with Bartter syndrome, OMIM:601198; familial hypocalciuric hypercalcemia 1, MONDO:0007791; neonatal severe primary hyperparathyroidism, MONDO:0009397; autosomal dominant hypocalcemia 1, MONDO:0011013
CADASIL v1.5 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #125310) and the OMIM record was last accessed on 17 December 2025.
CADASIL v1.5 NOTCH3 Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310 to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310; cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, MONDO:0000914
Blepharophimosis ptosis and epicanthus inversus v1.2 FOXL2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #110100) and the OMIM record was last accessed on 17 December 2025.
Blepharophimosis ptosis and epicanthus inversus v1.2 FOXL2 Achchuthan Shanmugasundram Phenotypes for gene: FOXL2 were changed from to Blepharophimosis, ptosis, and epicanthus inversus, OMIM:110100; blepharophimosis, ptosis, and epicanthus inversus syndrome, MONDO:0007201
Beckwith-Wiedemann syndrome v1.2 CDKN1C Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #130650) and the OMIM record was last accessed on 17 December 2025.
Beckwith-Wiedemann syndrome v1.2 CDKN1C Achchuthan Shanmugasundram Phenotypes for gene: CDKN1C were changed from to Beckwith-Wiedemann syndrome, OMIM:130650; Beckwith-Wiedemann syndrome, MONDO:0007534
Barth syndrome v1.3 TAZ Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #302060) and the OMIM record was last accessed on 17 December 2025.
Barth syndrome v1.3 TAZ Achchuthan Shanmugasundram Phenotypes for gene: TAZ were changed from to Barth syndrome, OMIM:302060; Barth syndrome, MONDO:0010543
BAP1 associated tumour predisposition syndrome v1.2 BAP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #614327) and the OMIM record was last accessed on 17 December 2025.
BAP1 associated tumour predisposition syndrome v1.2 BAP1 Achchuthan Shanmugasundram Phenotypes for gene: BAP1 were changed from to Tumor predisposition syndrome, OMIM:614327; BAP1-related tumor predisposition syndrome, MONDO:0013692
Autoimmune lymphoproliferative syndrome with defective apoptosis v1.2 FAS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #601859) and the OMIM record was last accessed on 17 December 2025.
Autoimmune lymphoproliferative syndrome with defective apoptosis v1.2 FAS Achchuthan Shanmugasundram Phenotypes for gene: FAS were changed from to Autoimmune lymphoproliferative syndrome, OMIM:601859; autoimmune lymphoproliferative syndrome type 1, MONDO:0011158
Ataxia telangiectasia - mutation testing v1.2 ATM Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #208900) and the OMIM record was last accessed on 17 December 2025.
Ataxia telangiectasia - mutation testing v1.2 ATM Achchuthan Shanmugasundram Phenotypes for gene: ATM were changed from to Ataxia telangiectasia, OMIM:208900; ataxia telangiectasia, MONDO:0008840
APC associated Polyposis v1.2 APC Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #135290, #175100 & #619182) and these OMIM records were last accessed on 17 December 2025.
APC associated Polyposis v1.2 APC Achchuthan Shanmugasundram Phenotypes for gene: APC were changed from to Desmoid disease, hereditary, OMIM:135290; Adenomatous polyposis coli, OMIM:175100; Brain tumor-polyposis syndrome 2, OMIM:175100; Gardner syndrome, OMIM:175100; Gastric adenocarcinoma and proximal polyposis of the stomach, OMIM:619182; desmoid tumor, MONDO:0007608; gastric adenocarcinoma and proximal polyposis of the stomach, MONDO:0017790; familial adenomatous polyposis 1, MONDO:0021056
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.7 FOXF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #265380) and the OMIM record was last accessed on 17 December 2025.
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.7 FOXF1 Achchuthan Shanmugasundram Phenotypes for gene: FOXF1 were changed from to Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380; alveolar capillary dysplasia with misalignment of pulmonary veins, MONDO:0009934
Alstrom syndrome v1.2 ALMS1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #203800) and the OMIM record was last accessed on 17 December 2025.
Alstrom syndrome v1.2 ALMS1 Achchuthan Shanmugasundram Phenotypes for gene: ALMS1 were changed from to Alstrom syndrome, OMIM:203800; Alstrom syndrome, MONDO:0008763
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.9 PRKAR1A Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #101800) and the OMIM record was last accessed on 17 December 2025.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.9 PRKAR1A Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1A were changed from to Acrodysostosis type 1, OMIM:101800; Acrodysostosis 1 with or without hormone resistance, MONDO:0007044
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.8 PDE4D Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #614613) and the OMIM record was last accessed on 17 December 2025.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.8 PDE4D Achchuthan Shanmugasundram Phenotypes for gene: PDE4D were changed from to Acrodysostosis 2, with or without hormone resistance, OMIM:614613; acrodysostosis 2 with or without hormone resistance, MONDO:0013822
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.7 GNAS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #103580, #603233, #612462 & #612463). These OMIM records were last accessed on 17 December 2025.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.7 GNAS Achchuthan Shanmugasundram Phenotypes for gene: GNAS were changed from to Pseudohypoparathyroidism Ia, OMIM:103580; Pseudohypoparathyroidism Ib, OMIM:603233; Pseudohypoparathyroidism Ic, OMIM:612462; Pseudopseudohypoparathyroidism, OMIM:612463; pseudohypoparathyroidism type 1A, MONDO:0007078; pseudohypoparathyroidism type 1B, MONDO:0011301; pseudohypoparathyroidism type 1C, MONDO:0012911; pseudopseudohypoparathyroidism, MONDO:0012912
Agammaglobulinaemia with absent BTK expression v1.2 BTK Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: OMIM records accessed on 17 December 2025.; to: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #300755 & #307200) and OMIM records were last accessed on 17 December 2025.
Agammaglobulinaemia with absent BTK expression v1.2 BTK Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM records accessed on 17 December 2025.
Agammaglobulinaemia with absent BTK expression v1.2 BTK Achchuthan Shanmugasundram Phenotypes for gene: BTK were changed from to Agammaglobulinemia, X-linked 1, OMIM:300755; Isolated growth hormone deficiency, type III, with agammaglobulinemia, OMIM:307200; Bruton-type agammaglobulinemia, MONDO:0010421; isolated growth hormone deficiency type III, MONDO:0010615
Fetal anomalies v6.123 PAICS Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype (Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859) accessed on 17-12-2025
Fetal anomalies v6.123 PAICS Arina Puzriakova Phenotypes for gene: PAICS were changed from Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426; Polyhydramnios; multiple congenital abnormalities; early neonatal death to Phosphoribosylaminoimidazole carboxylase deficiency, OMIM:619859; Polyhydramnios; multiple congenital abnormalities; early neonatal death
Early onset or syndromic epilepsy v8.77 ATP2B1 Simon Thomas reviewed gene: ATP2B1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 40834682; Phenotypes: generalized epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.77 PPP2R5C Arina Puzriakova Phenotypes for gene: PPP2R5C were changed from neurodevelopmental disorder to Houge-Janssens syndrome 4, OMIM:621185
Intellectual disability v9.199 PPP2R5C Arina Puzriakova Phenotypes for gene: PPP2R5C were changed from neurodevelopmental disorder to Houge-Janssens syndrome 4, OMIM:621185
Fetal anomalies v6.122 MIA3 Arina Puzriakova Publications for gene: MIA3 were set to 32101163; 40119123; 33778321
Fetal anomalies v6.121 MIA3 Arina Puzriakova commented on gene: MIA3: Another fetal case - PMID: 40130161 (2025) - Homozygous c.2768T>G, p.(Leu923*) was detected in a fetus from a Slovenian family who presented with short bones of extremities (7 percentile), fibular aplasia, bilateral radial aplasia, tibial aplasia, hypoplastic nasal bone, delayed ossification, and congenital contractures.
Skeletal dysplasia v8.26 MIA3 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to green at the next GMS panel update - at least 5 unrelated individuals with biallelic variants in this gene and skeletal dysplasia. Supported by animal models.; to: Comment on list classification: There is sufficient evidence to promote this gene to green at the next GMS panel update - at least 6 unrelated individuals with biallelic variants in this gene and skeletal dysplasia. Supported by animal models.
Skeletal dysplasia v8.26 MIA3 Arina Puzriakova Publications for gene: MIA3 were set to 32101163; 33778321; 40948380; 40119123; 21606205; 34680893
Skeletal dysplasia v8.25 MIA3 Arina Puzriakova edited their review of gene: MIA3: Changed publications to: 32101163, 33778321, 40948380, 40119123, 40130161, 21606205, 34680893
Skeletal dysplasia v8.25 MIA3 Arina Puzriakova changed review comment from: At least four additional cases with biallelic variants in this gene and a severe skeletal dysplasia.

PMID: 33778321 (2021) - Indian family with third degree consanguinity, with a history of three pregnancy terminations due to clinical suspicion of lethal osteogenesis imperfecta and one full‐term pregnancy. The proband was a fetus with a lethal skeletal dysplasia and fetal hydrops. WES revealed a homozygous frameshift (c.2770_2773del, p.(Leu924Serfs*)) in MIA3 (also known as TANGO1). Segregation analysis confirmed both parents are heterozygote carriers.

PMID: 40948380 (2025) - Homozygous c.354+2T>G (p.Val90_Asp118del) was identified in an 3 year old male born to Iranian consanguineous parents. The phenotype consisted of short limbs, short stature, hypotonia at birth and delayed walking.

PMID: 40119123 (2025) - Homozygous c.354+2T>G (p.Val90_Asp118del) in a 5 year old Egyptian male and homozygous c.113G>T (p.Cys38Phe) in a second Egyptian patient aged 1 year and 9 months old with severe short limbs, short stature, metaphyseal dysplasia, dysmorphic facies, lax joints, dentinogenesis imperfecta. Previously reported extra-skeletal manifestations (hearing loss, retinopathy, hydronephrosis, microalbuminuria, diabetes, primary obesity, and intellectual disability) were not observed. Both individuals were born to consanguineous parents.

MIA3 KO mice show neonatal lethality due to insufficient bone mineralization (PMID: 21606205). Skeletal phenotype also seen in dogs with homozygous splice variant (PMID: 34680893).; to: At least four additional cases with biallelic variants in this gene and a severe skeletal dysplasia.

PMID: 33778321 (2021) - Indian family with third degree consanguinity, with a history of three pregnancy terminations due to clinical suspicion of lethal osteogenesis imperfecta and one full‐term pregnancy. The proband was a fetus with a lethal skeletal dysplasia and fetal hydrops. WES revealed a homozygous frameshift c.2770_2773del, p.(Leu924Serfs*) in MIA3 (also known as TANGO1). Segregation analysis confirmed both parents are heterozygote carriers.

PMID: 40948380 (2025) - Homozygous c.354+2T>G (p.Val90_Asp118del) was identified in an 3 year old male born to Iranian consanguineous parents. The phenotype consisted of short limbs, short stature, hypotonia at birth and delayed walking.

PMID: 40119123 (2025) - Homozygous c.354+2T>G p.(Val90_Asp118del) in a 5 year old Egyptian male and homozygous c.113G>T p.(Cys38Phe) in a second Egyptian patient aged 1 year and 9 months old with severe short limbs, short stature, metaphyseal dysplasia, dysmorphic facies, lax joints, dentinogenesis imperfecta. Previously reported extra-skeletal manifestations (hearing loss, retinopathy, hydronephrosis, microalbuminuria, diabetes, primary obesity, and intellectual disability) were not observed. Both individuals were born to consanguineous parents.

PMID: 40130161 (2025) - Homozygous c.2768T>G, p.(Leu923*) was detected in a fetus from a Slovenian family who presented with short bones of extremities (7 percentile), fibular aplasia, bilateral radial aplasia, tibial aplasia, hypoplastic nasal bone, delayed ossification, and congenital contractures.

MIA3 KO mice show neonatal lethality due to insufficient bone mineralization (PMID: 21606205). Skeletal phenotype also seen in dogs with homozygous splice variant (PMID: 34680893).
Skeletal dysplasia v8.25 MIA3 Arina Puzriakova Publications for gene: MIA3 were set to 32101163
Skeletal dysplasia v8.24 MIA3 Arina Puzriakova Classified gene: MIA3 as Amber List (moderate evidence)
Skeletal dysplasia v8.24 MIA3 Arina Puzriakova Gene: mia3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v8.23 MIA3 Arina Puzriakova Classified gene: MIA3 as Red List (low evidence)
Skeletal dysplasia v8.23 MIA3 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to green at the next GMS panel update - at least 5 unrelated individuals with biallelic variants in this gene and skeletal dysplasia. Supported by animal models.
Skeletal dysplasia v8.23 MIA3 Arina Puzriakova Gene: mia3 has been classified as Red List (Low Evidence).
Skeletal dysplasia v8.22 MIA3 Arina Puzriakova edited their review of gene: MIA3: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v8.22 MIA3 Arina Puzriakova Tag Q4_25_promote_green tag was added to gene: MIA3.
Skeletal dysplasia v8.22 MIA3 Arina Puzriakova reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32101163, 33778321, 40948380, 40119123, 21606205, 34680893; Phenotypes: Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.121 ZEB1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: ZEB1.
Tag Q3_25_NHS_review was removed from gene: ZEB1.
Fetal anomalies v6.121 WDR47 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: WDR47.
Tag Q3_25_NHS_review was removed from gene: WDR47.
Fetal anomalies v6.121 UNC13D Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: UNC13D.
Tag Q3_25_NHS_review was removed from gene: UNC13D.
Fetal anomalies v6.121 TCP1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: TCP1.
Tag Q3_25_NHS_review was removed from gene: TCP1.
Fetal anomalies v6.121 STX5 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: STX5.
Tag Q3_25_NHS_review was removed from gene: STX5.
Fetal anomalies v6.121 SRPK3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SRPK3.
Tag Q3_25_NHS_review was removed from gene: SRPK3.
Fetal anomalies v6.121 SPTA1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SPTA1.
Tag Q3_25_NHS_review was removed from gene: SPTA1.
Fetal anomalies v6.121 SPOUT1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SPOUT1.
Tag Q3_25_NHS_review was removed from gene: SPOUT1.
Fetal anomalies v6.121 SLC35A3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SLC35A3.
Tag Q3_25_NHS_review was removed from gene: SLC35A3.
Fetal anomalies v6.121 SLC12A9 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SLC12A9.
Tag Q3_25_NHS_review was removed from gene: SLC12A9.
Fetal anomalies v6.121 SENP7 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: SENP7.
Tag Q3_25_NHS_review was removed from gene: SENP7.
Fetal anomalies v6.121 RPL26 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: RPL26.
Tag Q3_25_NHS_review was removed from gene: RPL26.
Fetal anomalies v6.121 RNU5B-1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: RNU5B-1.
Tag Q3_25_NHS_review was removed from gene: RNU5B-1.
Fetal anomalies v6.121 RIPPLY2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: RIPPLY2.
Tag Q3_25_NHS_review was removed from gene: RIPPLY2.
Fetal anomalies v6.121 RAB11B Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: RAB11B.
Tag Q3_25_NHS_review was removed from gene: RAB11B.
Fetal anomalies v6.121 PUS3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PUS3.
Tag Q3_25_NHS_review was removed from gene: PUS3.
Fetal anomalies v6.121 PTEN Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PTEN.
Tag Q3_25_NHS_review was removed from gene: PTEN.
Fetal anomalies v6.121 PSKH1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PSKH1.
Tag Q3_25_NHS_review was removed from gene: PSKH1.
Fetal anomalies v6.121 PPFIBP1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PPFIBP1.
Tag Q3_25_NHS_review was removed from gene: PPFIBP1.
Fetal anomalies v6.121 PPFIA3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PPFIA3.
Tag Q3_25_NHS_review was removed from gene: PPFIA3.
Fetal anomalies v6.121 PLAA Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PLAA.
Tag Q3_25_NHS_review was removed from gene: PLAA.
Fetal anomalies v6.121 PIGW Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PIGW.
Tag Q3_25_NHS_review was removed from gene: PIGW.
Optic neuropathy v5.38 NDUFA10 Ida Ertmanska Mode of pathogenicity for gene: NDUFA10 was changed from Other to None
Fetal anomalies v6.121 PIGP Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PIGP.
Tag Q3_25_NHS_review was removed from gene: PIGP.
Optic neuropathy v5.37 NDUFA1 Ida Ertmanska Mode of pathogenicity for gene: NDUFA1 was changed from None to None
Optic neuropathy v5.36 NDUFA1 Ida Ertmanska Mode of pathogenicity for gene: NDUFA1 was changed from None to None
Optic neuropathy v5.35 NDUFA10 Ida Ertmanska Phenotypes for gene: NDUFA10 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 22, OMIM:618243; mitochondrial complex I deficiency, nuclear type 22, MONDO:0032626; Optic neuropathy, HP:0001138
Optic neuropathy v5.34 NDUFA1 Ida Ertmanska edited their review of gene: NDUFA1: Changed phenotypes to: Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020, Optic neuropathy, HP:0001138
Optic neuropathy v5.34 NDUFA10 Ida Ertmanska Publications for gene: NDUFA10 were set to PMID: 41234160
Optic neuropathy v5.33 NDUFA10 Ida Ertmanska Classified gene: NDUFA10 as Amber List (moderate evidence)
Optic neuropathy v5.33 NDUFA10 Ida Ertmanska Gene: ndufa10 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.32 NDUFA10 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: NDUFA10.
Tag Q4_25_NHS_review tag was added to gene: NDUFA10.
Optic neuropathy v5.32 NDUFA10 Ida Ertmanska changed review comment from: Comment on list classification: There are 4 individuals from 3 unrelated families with homozygous NDUFA10 variants and optic atrophy (isolated or syndromic).; to: Comment on list classification: There are 4 individuals from 3 unrelated families with homozygous NDUFA10 variants and optic atrophy (isolated or syndromic). Based on the available evidence, this gene should be promoted to Green for Optic neuropathy.
Fetal anomalies v6.121 PIGG Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PIGG.
Tag Q3_25_NHS_review was removed from gene: PIGG.
Optic neuropathy v5.32 NDUFA10 Ida Ertmanska edited their review of gene: NDUFA10: Added comment: Comment on list classification: There are 4 individuals from 3 unrelated families with homozygous NDUFA10 variants and optic atrophy (isolated or syndromic).; Changed publications to: 31130284, 36270260, 41234160; Changed phenotypes to: Mitochondrial complex I deficiency, nuclear type 22, OMIM:618243, mitochondrial complex I deficiency, nuclear type 22, MONDO:0032626
Fetal anomalies v6.121 PI4KA Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PI4KA.
Tag Q3_25_NHS_review was removed from gene: PI4KA.
Fetal anomalies v6.121 PHF5A Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PHF5A.
Tag Q3_25_NHS_review was removed from gene: PHF5A.
Fetal anomalies v6.121 PAK2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PAK2.
Tag Q3_25_NHS_review was removed from gene: PAK2.
Optic neuropathy v5.32 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated male probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated male probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome (PMID: 25356405, PMID: 29506883).
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

Authors highlight the clinical variability between LSS patients harbouring the same variant.

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).
Fetal anomalies v6.121 PAICS Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: PAICS.
Tag Q3_25_NHS_review was removed from gene: PAICS.
Fetal anomalies v6.121 ODC1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: ODC1.
Tag Q3_25_NHS_review was removed from gene: ODC1.
Fetal anomalies v6.121 NEXN Arina Puzriakova changed review comment from: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group. MOI has also been updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as per the review.; to: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group. MOI has also been updated from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BIALLELIC, autosomal or pseudoautosomal' as per the review.
Fetal anomalies v6.121 NR2F1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: NR2F1.
Tag Q3_25_NHS_review was removed from gene: NR2F1.
Optic neuropathy v5.32 NDUFA10 Ida Ertmanska reviewed gene: NDUFA10: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 22, OMIM:618243; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.121 NODAL Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: NODAL.
Tag Q3_25_demote_red was removed from gene: NODAL.
Fetal anomalies v6.121 NEXN Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: NEXN.
Tag Q3_25_NHS_review was removed from gene: NEXN.
Fetal anomalies v6.121 NEPRO Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: NEPRO.
Tag Q3_25_NHS_review was removed from gene: NEPRO.
Fetal anomalies v6.121 NDUFB7 Achchuthan Shanmugasundram Tag Q1_25_ promote_green was removed from gene: NDUFB7.
Tag Q3_25_NHS_review was removed from gene: NDUFB7.
Fetal anomalies v6.121 MYH9 Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: MYH9.
Tag Q3_25_demote_red was removed from gene: MYH9.
Fetal anomalies v6.121 MSL2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MSL2.
Tag Q3_25_NHS_review was removed from gene: MSL2.
Fetal anomalies v6.121 MIA3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MIA3.
Tag Q3_25_NHS_review was removed from gene: MIA3.
Fetal anomalies v6.121 MED11 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MED11.
Tag Q3_25_NHS_review was removed from gene: MED11.
Fetal anomalies v6.121 MAPK1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MAPK1.
Tag Q3_25_NHS_review was removed from gene: MAPK1.
Fetal anomalies v6.121 MAGED2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: MAGED2.
Tag Q3_25_NHS_review was removed from gene: MAGED2.
Fetal anomalies v6.121 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: LSS.
Tag Q3_25_NHS_review was removed from gene: LSS.
Fetal anomalies v6.121 LGI3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: LGI3.
Tag Q3_25_NHS_review was removed from gene: LGI3.
Fetal anomalies v6.121 LDB1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: LDB1.
Tag Q3_25_NHS_review was removed from gene: LDB1.
Fetal anomalies v6.121 LAGE3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: LAGE3.
Tag Q3_25_NHS_review was removed from gene: LAGE3.
Fetal anomalies v6.121 ITGAV Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: ITGAV.
Tag Q3_25_NHS_review was removed from gene: ITGAV.
Fetal anomalies v6.121 IFT27 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: IFT27.
Tag Q3_25_NHS_review was removed from gene: IFT27.
Fetal anomalies v6.121 HNRNPU Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: HNRNPU.
Tag Q3_25_NHS_review was removed from gene: HNRNPU.
Fetal anomalies v6.121 HDAC3 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: HDAC3.
Tag Q3_25_NHS_review was removed from gene: HDAC3.
Fetal anomalies v6.121 GNS Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: GNS.
Tag Q3_25_demote_amber was removed from gene: GNS.
Fetal anomalies v6.121 GNAI2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: GNAI2.
Tag Q3_25_NHS_review was removed from gene: GNAI2.
Fetal anomalies v6.121 GEMIN4 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: GEMIN4.
Tag Q3_25_NHS_review was removed from gene: GEMIN4.
Fetal anomalies v6.121 GALT Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: GALT.
Tag Q3_25_NHS_review was removed from gene: GALT.
Fetal anomalies v6.121 FLVCR1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: FLVCR1.
Fetal anomalies v6.121 FAAP100 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: FAAP100.
Tag Q3_25_NHS_review was removed from gene: FAAP100.
Fetal anomalies v6.121 EXOSC8 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: EXOSC8.
Tag Q3_25_NHS_review was removed from gene: EXOSC8.
Fetal anomalies v6.121 EXOC6B Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: EXOC6B.
Tag Q3_25_NHS_review was removed from gene: EXOC6B.
Fetal anomalies v6.121 EFL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: EFL1.
Tag Q3_25_NHS_review was removed from gene: EFL1.
Fetal anomalies v6.121 EEFSEC Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: EEFSEC.
Tag Q3_25_NHS_review was removed from gene: EEFSEC.
Skeletal dysplasia v8.22 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Ondontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269 to Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.121 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Ondontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269 to Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.120 C1orf127 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: C1orf127.
Tag Q2_25_ NHS_review was removed from gene: C1orf127.
Optic neuropathy v5.32 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated male probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).
Optic neuropathy v5.32 NDUFA1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated patients with hemizygous variants in NDUFA1, with mitochondrial disease symptoms including optic atrophy. Based on the available evidence, NDUFA1 should be promoted to Green for Optic neuropathy at the next GMS update.; to: Comment on list classification: As reviewed by Neringa Jurkute, there are 3 unrelated patients with hemizygous variants in NDUFA1, with mitochondrial disease symptoms including optic atrophy. Based on the available evidence, NDUFA1 should be promoted to Green for Optic neuropathy at the next GMS update.
Optic neuropathy v5.32 NDUFA1 Ida Ertmanska Mode of pathogenicity for gene: NDUFA1 was changed from Other to None
Optic neuropathy v5.31 NDUFA1 Ida Ertmanska Publications for gene: NDUFA1 were set to PMID: 41234160
Optic neuropathy v5.30 NDUFA1 Ida Ertmanska Phenotypes for gene: NDUFA1 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020; Optic neuropathy, HP:0001138
Optic neuropathy v5.29 NDUFA1 Ida Ertmanska Classified gene: NDUFA1 as Amber List (moderate evidence)
Optic neuropathy v5.29 NDUFA1 Ida Ertmanska Gene: ndufa1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: NDUFA1.
Tag Q4_25_NHS_review tag was added to gene: NDUFA1.
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska commented on gene: NDUFA1: Comment on list classification: There are 3 unrelated patients with hemizygous variants in NDUFA1, with mitochondrial disease symptoms including optic atrophy. Based on the available evidence, NDUFA1 should be promoted to Green for Optic neuropathy at the next GMS update.
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences; Pale optic disk temporal bilaterally.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy; Temporal optic nerve pallor.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; Optic nerve pallor (OS>OD).

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis

This gene is associated with XLR Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020 (accessed 16th Dec 2025).
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome (pleiotropy?).
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome.
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.
Three probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome (pleiotropy?).
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy ofcerebellar vermis; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

3 unrelated probands carried NDUFA1 variants:
Families H and I (independent families): c.28T>C p.(Ser10Pro); variant not in gnomAD v4.1.0, though 1 allele reported for p.Ser10Thr (same residue); Revel = 0.15.
Patient H II-1: insidious onset at 2yo; Pendular nystagmus, Abnormal basal ganglia MRI; signal intensity, delayed ability to walk; MRI: Bilateral pallidal and dentati hyperintensity in TR sequences.
Patient I II-1: Insidious onset at 3yo: Mild neurosensory hearing impairment; MRI finding: optic nerve atrophy.

Family J: c.55C>T p.(Pro19Ser) - previously reported in two published cases of Leigh syndrome (pleiotropy?).
Patient J II-1: insidious onset at 5yo; Nystagmus, Polyneuropathy, Intellectual disability (borderline), Mild neurosensory hearing impairment, Sensory ataxia; MRI: Optic nerve atrophy, very mild atrophy of cerebellar vermis
Optic neuropathy v5.28 NDUFA1 Ida Ertmanska reviewed gene: NDUFA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 12, OMIM:301020; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - narrow panel v8.35 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel at the next GMS update.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges.
Intellectual disability v9.198 TSEN34 Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability at the next GMS update.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.198 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 16th Dec 2025).
Ataxia and cerebellar anomalies - narrow panel v8.35 TSEN34 Ida Ertmanska Phenotypes for gene: TSEN34 were changed from Pontocerebellar hypoplasia type 2C, OMIM:612390 to Pontocerebellar hypoplasia type 2C, OMIM:612390; pontocerebellar hypoplasia type 2C, MONDO:0012891
Ataxia and cerebellar anomalies - narrow panel v8.34 TSEN34 Ida Ertmanska Publications for gene: TSEN34 were set to 18711368; 20952379; 27370523
Intellectual disability v9.198 TSEN34 Ida Ertmanska Phenotypes for gene: TSEN34 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4 to Pontocerebellar hypoplasia type 2C, OMIM:612390; pontocerebellar hypoplasia type 2C, MONDO:0012891
Intellectual disability v9.197 TSEN34 Ida Ertmanska Publications for gene: TSEN34 were set to 0
Intellectual disability v9.196 TSEN34 Ida Ertmanska Tag Q4_25_demote_amber tag was added to gene: TSEN34.
Intellectual disability v9.196 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Intellectual disability v9.196 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical. No mention of cognitive ability.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Intellectual disability v9.196 TSEN34 Ida Ertmanska edited their review of gene: TSEN34: Changed rating: AMBER
Intellectual disability v9.196 TSEN34 Ida Ertmanska commented on gene: TSEN34: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. In addition, there is no mention Hence, TSEN34 should be demoted to Amber for Intellectual disability at the next GMS update.
Intellectual disability v9.196 TSEN34 Ida Ertmanska reviewed gene: TSEN34: Rating: RED; Mode of pathogenicity: None; Publications: 20952379, 27370523, 32476018, 37544645; Phenotypes: Pontocerebellar hypoplasia type 2C, OMIM:612390, pontocerebellar hypoplasia type 2C, MONDO:0012891; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska edited their review of gene: TSEN34: Changed publications to: 20952379, 27370523, 32476018, 37544645
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska edited their review of gene: TSEN34: Changed phenotypes to: Pontocerebellar hypoplasia type 2C, OMIM:612390, pontocerebellar hypoplasia type 2C, MONDO:0012891
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.
Patient details from PMID:18711368: Patient hg1, male, phenotype: progressive microcephaly, chorea/dystonia, visual impairment, spontaneous breath; MRI typical.


PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief report of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief mention of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant/clinical details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska changed review comment from: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief report of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant details.

Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).; to: PMID: 20952379 Namavar et al., 2011
Reported one Pontocerebellar hypoplasia type 2C patient with a homozygous p.R58W variant in TSEN34 and epileptic seizures. PCH2 patient with seizures and TSEN34 variant reported in (most likely the same patient as in PMID:18711368 Budde et al., 2008). Sequenced exon-intron boundaries of TSEN54, TSEN34, TSEN2, TSEN15, RARS2 and VRK1 only.

PMID: 27370523 Balbi, Taicher & Litman, 2016
Brief report of a 2-year-old female child diagnosed with TSEN34-related pontocerebellar hypoplasia Type 2 - no variant details.

Functional evidence:
PMID: 32476018 Hayne et al., 2020 / PMID: 37544645 Hayne et al., 2023
Human tRNA splicing endonuclease (TSEN) is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15), and it co-purifies with CLP1. Other TSEN subunits and CLP1 are all known to cause PCH. The TSEN34 R58W mutation eliminates a salt bridge between R58 and E218, affecting protein stability.

Additional info:
Variant NM_001077446.4(TSEN34):c.862_865dup (p.Leu289fs) was reported as Likely Pathogenic for Pontocerebellar hypoplasia type 2C in ClinVar by Mendelics (source: clinical testing).

This gene is putatively linked to AR Pontocerebellar hypoplasia type 2C, MIM:612390 (OMIM accessed 15th Dec 2025).
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska commented on gene: TSEN34: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel at the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska Tag Q4_25_demote_amber tag was added to gene: TSEN34.
Ataxia and cerebellar anomalies - narrow panel v8.33 TSEN34 Ida Ertmanska Phenotypes for gene: TSEN34 were changed from Pontocerebellar hypoplasia type 2C,612390; Pontocerebellar Hypoplasia type 2C; Pontocerebellar hypoplasia 2C (612390); Pontocerebellar Hypoplasia to Pontocerebellar hypoplasia type 2C, OMIM:612390
Ataxia and cerebellar anomalies - narrow panel v8.32 TSEN34 Ida Ertmanska Publications for gene: TSEN34 were set to PMID: 18711368
Ataxia and cerebellar anomalies - narrow panel v8.31 TSEN34 Ida Ertmanska edited their review of gene: TSEN34: Changed rating: AMBER
Ataxia and cerebellar anomalies - narrow panel v8.31 TSEN34 Ida Ertmanska reviewed gene: TSEN34: Rating: RED; Mode of pathogenicity: None; Publications: 20952379, 27370523; Phenotypes: Pontocerebellar hypoplasia type 2C, OMIM:612390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v6.7 TK2 Ida Ertmanska Publications for gene: TK2 were set to 11687801 18021809 19736010 16831967 36146520
Congenital muscular dystrophy v6.6 TK2 Ida Ertmanska Phenotypes for gene: TK2 were changed from Congenital muscular dystrophy; mitochondrial disease; limb girdle muscular dystrophy to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301
Congenital muscular dystrophy v6.5 TK2 Ida Ertmanska Classified gene: TK2 as Amber List (moderate evidence)
Congenital muscular dystrophy v6.5 TK2 Ida Ertmanska Gene: tk2 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v6.4 TK2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TK2.
Tag Q4_25_NHS_review tag was added to gene: TK2.
Congenital muscular dystrophy v6.4 TK2 Ida Ertmanska edited their review of gene: TK2: Added comment: Comment on list classification: There are numerous patients reported in literature with biallelic variants in TK2 and mitochondrial myopathy. More than 25 cases have been reported with rapidly progressive infantile-onset (<1year of age) muscle weakness, usually leading to respiratory failure before age 3. Based on available evidence TK2 should be promoted to Green for Congenital muscular dystrophy at the next GMS update.; Changed publications to: 18819985, 38544965, 40098049
Congenital muscular dystrophy v6.4 TK2 Ida Ertmanska reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560, mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.28 TK2 Ida Ertmanska Publications for gene: TK2 were set to 22345218 23303857 24198295 31092255 25948719
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.27 TK2 Ida Ertmanska Phenotypes for gene: TK2 were changed from mitochondrial disease; limb girdle muscular dystrophy; congenital muscular dystrophy to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.26 TK2 Ida Ertmanska Classified gene: TK2 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.26 TK2 Ida Ertmanska Gene: tk2 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TK2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TK2.
Tag Q4_25_NHS_review tag was added to gene: TK2.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TK2 Ida Ertmanska changed review comment from: PMID: 24198295 Alston et al., 2013
A 74-year-old woman with sensorineural hearing loss, progressive muscle weakness and rapidly progressive respiratory failure. Compound het TK2 variants c.103C>T (p.Gln35*) and c.582G>T (p.Lys194Asn).

PMID: 35280287 Manini et al., 2022
55yo Italian woman; ptosis and dysphonia with onset at 8yo, dysphagia at 20yo, slowly progressive limb weakness reported in adulthood; compound het TK2 mutations: c.278A>G, p.Asn93Ser and c.543del, p.Leu182Phefs*11; mtDNA depletion demonstrated by qPCR in muscle tissue.

PMID: 37527940 Morganroth et al., 2023
Report of a 40yo male patient with muscle weakness (limb girdle weakness, chronic progressive external ophthalmoplegia, dysphagia) and respiratory failure; developed limb girdle weakness at 21yo; homozygous for TK2 c.604_606del (p.K202del). Mother confirmed a heterozygous carrier.

PMID: 38544965 Ceballos et al., 2024
Cohort of 53 Spanish patients with biallelic variants in TK2. 40% of patients presented with disease before 12yo. 50/53 patients had a diagnosis of mitochondrial myopathy based on muscle biopsy findings.

PMID: 40098049 Li et al., 2025
Female patient with early-onset lipid storage myopathy (onset at 8 months old); compound het variatns in TK2: c.311G > A (p.Arg104His) and a deletion spanning TK2 exons 5-10 (g.66545871_66565372del); COX negative fibers and accumulation of lipid droplets noted on biceps biopsy; detected decrease in TK2 protein and mtDNA copy number in patient muscle samples.
Based on literature review of 50 TK2-related myopathy cases, authors note that the same TK2 variant may cause variable onset and severity of disease between patients. Variable presentation of limb girdle muscle weakness, ptosis, respiratory failure, and facial weakness; range of congenital to adult disease onset.

TK2 is associated with AR Mitochondrial DNA depletion syndrome 2 (myopathic type), MIM:609560 and putatively associated with AR Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, MIM:617069 (OMIM accessed 15th Dec 2025).; to: PMID: 24198295 Alston et al., 2013
A 74-year-old woman with sensorineural hearing loss, progressive muscle weakness and rapidly progressive respiratory failure. Compound het TK2 variants c.103C>T (p.Gln35*) and c.582G>T (p.Lys194Asn).

PMID: 35280287 Manini et al., 2022
55yo Italian woman; ptosis and dysphonia with onset at 8yo, dysphagia at 20yo, slowly progressive limb weakness reported in adulthood; compound het TK2 mutations: c.278A>G, p.Asn93Ser and c.543del, p.Leu182Phefs*11; mtDNA depletion demonstrated by qPCR in muscle tissue.

PMID: 37527940 Morganroth et al., 2023
Report of a 40yo male patient with muscle weakness (limb girdle weakness, chronic progressive external ophthalmoplegia, dysphagia) and respiratory failure; developed limb girdle weakness at 21yo; homozygous for TK2 c.604_606del (p.K202del). Mother confirmed to be a heterozygous carrier.

PMID: 38544965 Ceballos et al., 2024
Cohort of 53 Spanish patients with biallelic variants in TK2. 40% of patients presented with disease before 12yo. 50/53 patients had a diagnosis of mitochondrial myopathy based on muscle biopsy findings.

PMID: 40098049 Li et al., 2025
Female patient with early-onset lipid storage myopathy (onset at 8 months old); compound het variants in TK2: c.311G > A (p.Arg104His) and a deletion spanning TK2 exons 5-10 (g.66545871_66565372del); COX negative fibers and accumulation of lipid droplets noted on biceps biopsy; detected decrease in TK2 protein and mtDNA copy number in patient muscle samples.
Based on literature review of 50 TK2-related myopathy cases, authors note that the same TK2 variant may cause variable onset and severity of disease between patients. Variable presentation of limb girdle muscle weakness, ptosis, respiratory failure, and facial weakness; range of congenital to adult disease onset.

TK2 is associated with AR Mitochondrial DNA depletion syndrome 2 (myopathic type), MIM:609560 and putatively associated with AR Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, MIM:617069 (OMIM accessed 15th Dec 2025).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TK2 Ida Ertmanska commented on gene: TK2: Comment on list classification: There are numerous individuals reported in literature with biallelic TK2 variants and mitochondrial myopathy. Affected individuals may present with disease of variable severity and age of onset. The phenotype range includes progressive muscle weakness, ptosis, chronic progressive external ophthalmoplegia (CPEO), and respiratory failure. Based on available evidence, this gene should be promoted to Green for Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TK2 Ida Ertmanska reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24198295, 35280287, 37527940, 38544965, 40098049; Phenotypes: Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560, mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.120 DST Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: DST.
Tag Q3_25_NHS_review was removed from gene: DST.
Fetal anomalies v6.120 DSE Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: DSE.
Tag Q3_25_NHS_review was removed from gene: DSE.
Fetal anomalies v6.120 DHX9 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: DHX9.
Tag Q3_25_NHS_review was removed from gene: DHX9.
Fetal anomalies v6.120 DHRSX Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: DHRSX.
Tag Q3_25_NHS_review was removed from gene: DHRSX.
Fetal anomalies v6.120 CTGF Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: CTGF.
Tag Q3_25_NHS_review was removed from gene: CTGF.
Fetal anomalies v6.120 COQ2 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: COQ2.
Tag Q3_25_NHS_review was removed from gene: COQ2.
Fetal anomalies v6.120 COMP Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: COMP.
Tag Q3_25_NHS_review was removed from gene: COMP.
Fetal anomalies v6.120 COL25A1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: COL25A1.
Tag Q3_25_NHS_review was removed from gene: COL25A1.
Fetal anomalies v6.120 CELSR1 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: CELSR1.
Tag Q3_25_NHS_review was removed from gene: CELSR1.
Fetal anomalies v6.120 CDK5 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: CDK5.
Tag Q3_25_NHS_review was removed from gene: CDK5.
Fetal anomalies v6.120 C12orf66 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: C12orf66.
Tag Q3_25_NHS_review was removed from gene: C12orf66.
Fetal anomalies v6.120 BORCS5 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: BORCS5.
Tag Q3_25_NHS_review was removed from gene: BORCS5.
Fetal anomalies v6.120 BHLHE22 Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: BHLHE22.
Tag Q3_25_NHS_review was removed from gene: BHLHE22.
Fetal anomalies v6.120 ARL6IP1 Achchuthan Shanmugasundram Tag Q3_24_NHS_review was removed from gene: ARL6IP1.
Tag Q3_25_promote_green was removed from gene: ARL6IP1.
Fetal anomalies v6.120 ARL2BP Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: ARL2BP.
Tag Q3_25_NHS_review was removed from gene: ARL2BP.
Fetal anomalies v6.120 AGT Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: AGT.
Tag Q3_25_NHS_review was removed from gene: AGT.
Fetal anomalies v6.120 AGRN Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: AGRN.
Tag Q3_25_NHS_review was removed from gene: AGRN.
Bleeding and platelet disorders v4.2 RAP1B Carl Fratter gene: RAP1B was added
gene: RAP1B was added to Bleeding and platelet disorders. Sources: Expert Review
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAP1B were set to PMID: 32627184; 35451551; 37850357
Phenotypes for gene: RAP1B were set to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies (OMIM #620654)
Penetrance for gene: RAP1B were set to unknown
Mode of pathogenicity for gene: RAP1B 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: RAP1B was set to GREEN
Added comment: Specific gain-of-function missense variants have been associated with this disorder to date.
RAP1B is already included as a green gene on other panels, including the R91 cytopenia panel.
It would be appropriate to add this gene to the R90 panel, as other syndromic thrombocytopenia associated genes are included on this panel. This opinion is supported by the Central&South GLH haemostasis genomics MDT.
Sources: Expert Review
Fetal anomalies v6.120 ZEB1 Achchuthan Shanmugasundram reviewed gene: ZEB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 WDR47 Achchuthan Shanmugasundram reviewed gene: WDR47: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 UNC13D Achchuthan Shanmugasundram edited their review of gene: UNC13D: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 TCP1 Achchuthan Shanmugasundram reviewed gene: TCP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 STX5 Achchuthan Shanmugasundram edited their review of gene: STX5: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 SRPK3 Achchuthan Shanmugasundram reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 SPTA1 Achchuthan Shanmugasundram edited their review of gene: SPTA1: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 SPOUT1 Achchuthan Shanmugasundram reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 SLC35A3 Achchuthan Shanmugasundram reviewed gene: SLC35A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 SLC12A9 Achchuthan Shanmugasundram reviewed gene: SLC12A9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 SENP7 Achchuthan Shanmugasundram reviewed gene: SENP7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 RPL26 Achchuthan Shanmugasundram reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 RNU5B-1 Achchuthan Shanmugasundram reviewed gene: RNU5B-1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 RIPPLY2 Achchuthan Shanmugasundram reviewed gene: RIPPLY2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 RAB11B Achchuthan Shanmugasundram edited their review of gene: RAB11B: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 PUS3 Achchuthan Shanmugasundram reviewed gene: PUS3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PTEN Achchuthan Shanmugasundram reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PSKH1 Achchuthan Shanmugasundram reviewed gene: PSKH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PPFIBP1 Achchuthan Shanmugasundram reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PPFIA3 Achchuthan Shanmugasundram reviewed gene: PPFIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PLAA Achchuthan Shanmugasundram edited their review of gene: PLAA: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 PIGW Achchuthan Shanmugasundram reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PIGP Achchuthan Shanmugasundram reviewed gene: PIGP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PIGG Achchuthan Shanmugasundram edited their review of gene: PIGG: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 PI4KA Achchuthan Shanmugasundram edited their review of gene: PI4KA: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 PHF5A Achchuthan Shanmugasundram reviewed gene: PHF5A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PDE12 Achchuthan Shanmugasundram edited their review of gene: PDE12: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GMS reviewers commented as follows: The concern from the panel for this one is that the two prenatal presentations are very different. There is no link between brain anomalies and hydrops. The panel want to see more evidence that the gene is causing a prenatal pehnotype and there is not another cuase of these abnormalities in these families.; Changed rating: AMBER
Fetal anomalies v6.120 PAK2 Achchuthan Shanmugasundram reviewed gene: PAK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 PAICS Achchuthan Shanmugasundram reviewed gene: PAICS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 ODC1 Achchuthan Shanmugasundram reviewed gene: ODC1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 NR2F1 Achchuthan Shanmugasundram reviewed gene: NR2F1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 NODAL Achchuthan Shanmugasundram reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 NEXN Achchuthan Shanmugasundram edited their review of gene: NEXN: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 NEPRO Achchuthan Shanmugasundram reviewed gene: NEPRO: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 NDUFB7 Achchuthan Shanmugasundram reviewed gene: NDUFB7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MYH9 Achchuthan Shanmugasundram reviewed gene: MYH9: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MSL2 Achchuthan Shanmugasundram reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MIA3 Achchuthan Shanmugasundram reviewed gene: MIA3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MED11 Achchuthan Shanmugasundram reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 MAPK1 Achchuthan Shanmugasundram edited their review of gene: MAPK1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 MAGED2 Achchuthan Shanmugasundram reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 LSS Achchuthan Shanmugasundram reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 LGI3 Achchuthan Shanmugasundram reviewed gene: LGI3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 LDB1 Achchuthan Shanmugasundram reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 LAGE3 Achchuthan Shanmugasundram edited their review of gene: LAGE3: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 ITGAV Achchuthan Shanmugasundram edited their review of gene: ITGAV: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 IFT27 Achchuthan Shanmugasundram edited their review of gene: IFT27: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 HNRNPU Achchuthan Shanmugasundram reviewed gene: HNRNPU: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 HDAC3 Achchuthan Shanmugasundram reviewed gene: HDAC3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 GNS Achchuthan Shanmugasundram reviewed gene: GNS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 GNAI2 Achchuthan Shanmugasundram reviewed gene: GNAI2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 GEMIN4 Achchuthan Shanmugasundram reviewed gene: GEMIN4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 GALT Achchuthan Shanmugasundram reviewed gene: GALT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 FLVCR1 Achchuthan Shanmugasundram reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 FLII Achchuthan Shanmugasundram reviewed gene: FLII: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 FAAP100 Achchuthan Shanmugasundram reviewed gene: FAAP100: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 EXOSC8 Achchuthan Shanmugasundram edited their review of gene: EXOSC8: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 EXOC6B Achchuthan Shanmugasundram reviewed gene: EXOC6B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 EFL1 Achchuthan Shanmugasundram reviewed gene: EFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 EEFSEC Achchuthan Shanmugasundram reviewed gene: EEFSEC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 DST Achchuthan Shanmugasundram reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 DSE Achchuthan Shanmugasundram reviewed gene: DSE: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 DHX9 Achchuthan Shanmugasundram reviewed gene: DHX9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 DHRSX Achchuthan Shanmugasundram reviewed gene: DHRSX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 CTGF Achchuthan Shanmugasundram reviewed gene: CTGF: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 COQ2 Achchuthan Shanmugasundram reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 COMP Achchuthan Shanmugasundram reviewed gene: COMP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 COL25A1 Achchuthan Shanmugasundram edited their review of gene: COL25A1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 CELSR1 Achchuthan Shanmugasundram edited their review of gene: CELSR1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 CDK5 Achchuthan Shanmugasundram reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 C1orf127 Achchuthan Shanmugasundram reviewed gene: C1orf127: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 C12orf66 Achchuthan Shanmugasundram reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 BORCS5 Achchuthan Shanmugasundram reviewed gene: BORCS5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 BHLHE22 Achchuthan Shanmugasundram reviewed gene: BHLHE22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 ARL6IP1 Achchuthan Shanmugasundram reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 ARL2BP Achchuthan Shanmugasundram reviewed gene: ARL2BP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v6.120 AGT Achchuthan Shanmugasundram edited their review of gene: AGT: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Fetal anomalies v6.120 AGRN Achchuthan Shanmugasundram reviewed gene: AGRN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska commented on gene: PNPT1: Comment on list classification: There are at least 4 unrelated families with adult-onset Spinocerebellar ataxia and heterozygous PNPT1 variants. While some carriers were very mildly affected or reported unaffected, there is good evidence of PNPT1 variants cosegregating with ataxia, supporting an autosomal dominant inheritance mode. Based on available evidence, this gene should be promoted to Green for Hereditary ataxia with onset in adulthood.
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska changed review comment from: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).; to: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. The PNPT1 splice variant introduces a premature stop codon (p.Gln672SerfsTer6) - confirmed by RT-PCR. OXPHOS enzyme activities were normal,
Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska changed review comment from: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).
The authors pose that heterozygous variants cause lower penetrance and variable expressivity, which may explain later onset and milder phenotype than in homozygous cases.

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s).; to: PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).
Hereditary ataxia with onset in adulthood v8.15 PNPT1 Ida Ertmanska Phenotypes for gene: PNPT1 were changed from to Spinocerebellar ataxia 25, OMIM:608703
Hereditary ataxia with onset in adulthood v8.14 PNPT1 Ida Ertmanska Publications for gene: PNPT1 were set to
Hereditary ataxia with onset in adulthood v8.13 PNPT1 Ida Ertmanska Classified gene: PNPT1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v8.13 PNPT1 Ida Ertmanska Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v8.12 PNPT1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: PNPT1.
Tag Q4_25_NHS_review tag was added to gene: PNPT1.
Hereditary ataxia with onset in adulthood v8.12 PNPT1 Ida Ertmanska reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35411967, 39924761; Phenotypes: Spinocerebellar ataxia 25, OMIM:608703; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.119 ZEB1 Arina Puzriakova Source Expert Review Green was added to ZEB1.
Source NHS GMS was added to ZEB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 WDR47 Arina Puzriakova Source Expert Review Green was added to WDR47.
Source NHS GMS was added to WDR47.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 UNC13D Arina Puzriakova Source Expert Review Green was added to UNC13D.
Source NHS GMS was added to UNC13D.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 TCP1 Arina Puzriakova Source Expert Review Green was added to TCP1.
Source NHS GMS was added to TCP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 STX5 Arina Puzriakova Source Expert Review Green was added to STX5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SRPK3 Arina Puzriakova Source Expert Review Green was added to SRPK3.
Source NHS GMS was added to SRPK3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SPTA1 Arina Puzriakova Source Expert Review Green was added to SPTA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SPOUT1 Arina Puzriakova Source Expert Review Green was added to SPOUT1.
Source NHS GMS was added to SPOUT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SLC35A3 Arina Puzriakova Source Expert Review Green was added to SLC35A3.
Source NHS GMS was added to SLC35A3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SLC12A9 Arina Puzriakova Source Expert Review Green was added to SLC12A9.
Source NHS GMS was added to SLC12A9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 SENP7 Arina Puzriakova Source Expert Review Green was added to SENP7.
Source NHS GMS was added to SENP7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 RPL26 Arina Puzriakova Source Expert Review Green was added to RPL26.
Source NHS GMS was added to RPL26.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 RNU5B-1 Arina Puzriakova Source Expert Review Green was added to RNU5B-1.
Source NHS GMS was added to RNU5B-1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 RIPPLY2 Arina Puzriakova Source Expert Review Green was added to RIPPLY2.
Source NHS GMS was added to RIPPLY2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 RAB11B Arina Puzriakova Source Expert Review Green was added to RAB11B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PUS3 Arina Puzriakova Source Expert Review Green was added to PUS3.
Source NHS GMS was added to PUS3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PTEN Arina Puzriakova Source Expert Review Green was added to PTEN.
Source NHS GMS was added to PTEN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PSKH1 Arina Puzriakova Source Expert Review Green was added to PSKH1.
Source NHS GMS was added to PSKH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PPFIBP1 Arina Puzriakova Source Expert Review Green was added to PPFIBP1.
Source NHS GMS was added to PPFIBP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PPFIA3 Arina Puzriakova Source Expert Review Green was added to PPFIA3.
Source NHS GMS was added to PPFIA3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PLAA Arina Puzriakova Source Expert Review Green was added to PLAA.
Source NHS GMS was added to PLAA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PIGW Arina Puzriakova Source Expert Review Green was added to PIGW.
Source NHS GMS was added to PIGW.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PIGP Arina Puzriakova Source Expert Review Green was added to PIGP.
Source NHS GMS was added to PIGP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PIGG Arina Puzriakova Source Expert Review Green was added to PIGG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PI4KA Arina Puzriakova Source Expert Review Green was added to PI4KA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PHF5A Arina Puzriakova Source Expert Review Green was added to PHF5A.
Source NHS GMS was added to PHF5A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PAK2 Arina Puzriakova Source Expert Review Green was added to PAK2.
Source NHS GMS was added to PAK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 PAICS Arina Puzriakova Source Expert Review Green was added to PAICS.
Source NHS GMS was added to PAICS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 ODC1 Arina Puzriakova Source Expert Review Green was added to ODC1.
Source NHS GMS was added to ODC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 NR2F1 Arina Puzriakova Source Expert Review Green was added to NR2F1.
Source NHS GMS was added to NR2F1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 NODAL Arina Puzriakova Source Expert Review Red was added to NODAL.
Source NHS GMS was added to NODAL.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Fetal anomalies v6.119 NEXN Arina Puzriakova Source Expert Review Green was added to NEXN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 NEPRO Arina Puzriakova Source Expert Review Green was added to NEPRO.
Source NHS GMS was added to NEPRO.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MYH9 Arina Puzriakova Source Expert Review Red was added to MYH9.
Source NHS GMS was added to MYH9.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Fetal anomalies v6.119 MSL2 Arina Puzriakova Source Expert Review Green was added to MSL2.
Source NHS GMS was added to MSL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MIA3 Arina Puzriakova Source Expert Review Green was added to MIA3.
Source NHS GMS was added to MIA3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MED11 Arina Puzriakova Source Expert Review Green was added to MED11.
Source NHS GMS was added to MED11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MAPK1 Arina Puzriakova Source Expert Review Green was added to MAPK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 MAGED2 Arina Puzriakova Source Expert Review Green was added to MAGED2.
Source NHS GMS was added to MAGED2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 LSS Arina Puzriakova Source Expert Review Green was added to LSS.
Source NHS GMS was added to LSS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 LGI3 Arina Puzriakova Source Expert Review Green was added to LGI3.
Source NHS GMS was added to LGI3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 LDB1 Arina Puzriakova Source Expert Review Green was added to LDB1.
Source NHS GMS was added to LDB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 LAGE3 Arina Puzriakova Source Expert Review Green was added to LAGE3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 ITGAV Arina Puzriakova Source Expert Review Green was added to ITGAV.
Source NHS GMS was added to ITGAV.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 IFT27 Arina Puzriakova Source Expert Review Green was added to IFT27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 HNRNPU Arina Puzriakova Source Expert Review Green was added to HNRNPU.
Source NHS GMS was added to HNRNPU.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 HDAC3 Arina Puzriakova Source Expert Review Green was added to HDAC3.
Source NHS GMS was added to HDAC3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 GNS Arina Puzriakova Source Expert Review Amber was added to GNS.
Source NHS GMS was added to GNS.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Fetal anomalies v6.119 GNAI2 Arina Puzriakova Source Expert Review Green was added to GNAI2.
Source NHS GMS was added to GNAI2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 GEMIN4 Arina Puzriakova Source Expert Review Green was added to GEMIN4.
Source NHS GMS was added to GEMIN4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 GALT Arina Puzriakova Source Expert Review Green was added to GALT.
Source NHS GMS was added to GALT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 FLVCR1 Arina Puzriakova Source Expert Review Green was added to FLVCR1.
Source NHS GMS was added to FLVCR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 FAAP100 Arina Puzriakova Source Expert Review Green was added to FAAP100.
Source NHS GMS was added to FAAP100.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 EXOSC8 Arina Puzriakova Source Expert Review Green was added to EXOSC8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 EXOC6B Arina Puzriakova Source Expert Review Green was added to EXOC6B.
Source NHS GMS was added to EXOC6B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 EFL1 Arina Puzriakova Source Expert Review Green was added to EFL1.
Source NHS GMS was added to EFL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 EEFSEC Arina Puzriakova Source Expert Review Green was added to EEFSEC.
Source NHS GMS was added to EEFSEC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 DST Arina Puzriakova Source Expert Review Green was added to DST.
Source NHS GMS was added to DST.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 DSE Arina Puzriakova Source Expert Review Green was added to DSE.
Source NHS GMS was added to DSE.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 DHX9 Arina Puzriakova Source Expert Review Green was added to DHX9.
Source NHS GMS was added to DHX9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 DHRSX Arina Puzriakova Source Expert Review Green was added to DHRSX.
Source NHS GMS was added to DHRSX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 CTGF Arina Puzriakova Source Expert Review Green was added to CTGF.
Source NHS GMS was added to CTGF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 COQ2 Arina Puzriakova Source Expert Review Green was added to COQ2.
Source NHS GMS was added to COQ2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 COMP Arina Puzriakova Source Expert Review Green was added to COMP.
Source NHS GMS was added to COMP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 COL25A1 Arina Puzriakova Source Expert Review Green was added to COL25A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 CELSR1 Arina Puzriakova Source Expert Review Green was added to CELSR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 CDK5 Arina Puzriakova Source Expert Review Green was added to CDK5.
Source NHS GMS was added to CDK5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 C1orf127 Arina Puzriakova Source Expert Review Green was added to C1orf127.
Source NHS GMS was added to C1orf127.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 C12orf66 Arina Puzriakova Source Expert Review Green was added to C12orf66.
Source NHS GMS was added to C12orf66.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 BORCS5 Arina Puzriakova Source Expert Review Green was added to BORCS5.
Source NHS GMS was added to BORCS5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 BHLHE22 Arina Puzriakova Source Expert Review Green was added to BHLHE22.
Source NHS GMS was added to BHLHE22.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 ARL6IP1 Arina Puzriakova Source Expert Review Green was added to ARL6IP1.
Source NHS GMS was added to ARL6IP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 ARL2BP Arina Puzriakova Source Expert Review Green was added to ARL2BP.
Source NHS GMS was added to ARL2BP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 AGT Arina Puzriakova Source Expert Review Green was added to AGT.
Source NHS GMS was added to AGT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 AGRN Arina Puzriakova Source Expert Review Green was added to AGRN.
Source NHS GMS was added to AGRN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.119 NDUFB7 Arina Puzriakova Source Expert Review Green was added to NDUFB7.
Source NHS GMS was added to NDUFB7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v6.118 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Green List (high evidence)
Fetal anomalies v6.118 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Green List (High Evidence).
Fetal anomalies v6.117 DMPK_CTG Arina Puzriakova Tag Q3_25_promote_green was removed from STR: DMPK_CTG.
Tag Q3_25_NHS_review was removed from STR: DMPK_CTG.
Fetal anomalies v6.117 DMPK_CTG Arina Puzriakova commented on STR: DMPK_CTG: The rating of this STR has been updated to Green following NHS Genomic Medicine Service approval.
Fetal anomalies v6.117 XYLT1_GCC Arina Puzriakova commented on STR: XYLT1_GCC: R21 Clinical Oversight Group comment: Agree that this should be approved by the STR group first
Amelogenesis imperfecta v4.24 LTBP3 Ida Ertmanska commented on gene: LTBP3
Intellectual disability v9.196 ANKS1B Ida Ertmanska Phenotypes for gene: ANKS1B were changed from complex neurodevelopmental disorder, MONDO:0100038 to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.195 ANKS1B Ida Ertmanska Phenotypes for gene: ANKS1B were changed from Developmental delay; Intellectual disability; Autism; Speech and language delay to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.195 ANKS1B Ida Ertmanska Classified gene: ANKS1B as Amber List (moderate evidence)
Intellectual disability v9.195 ANKS1B Ida Ertmanska Gene: anks1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD. 4/9 patients had some abnormalities reported on MRI (thin corpus callosum, enlarged ventricles).

Functional evidence: PMID: 38129387 Cho et al., 2023
'Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function'

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).; to: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a complex neurodevelopmental disorder, with normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).

Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.

9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD. 4/9 patients had some abnormalities reported on MRI (thin corpus callosum, enlarged ventricles).

Functional evidence: PMID: 38129387 Cho et al., 2023
'Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function'

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).; to: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD. 4/9 patients had some abnormalities reported on MRI (thin corpus callosum, enlarged ventricles).

Functional evidence: PMID: 38129387 Cho et al., 2023
'Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function'

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: Comment on list classification: Affected individuals had normal intellect or slightly below average, which does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Hence, ANKS1B should remain Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: Individuals with monogenic heterozygous microdeletions in ANSK1B had normal intellect or slightly below average, which does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Hence, ANKS1B should remain Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.194 ANKS1B Ida Ertmanska changed review comment from: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).; to: PMID: 31388001 Carbonell et al., 2019
Report of 2 unrelated families (EIN-1 and EIN-2), with 6 affected members. The individuals presented with a pattern of developmental delays, oculomotor and oromotor irregularities, dysmetria, impaired fine-motor dexterity, and problems with balance and gait. The individuals had normal ntelligence (FSIQ = 85-105), except patient EIN-2-1 (FSIQ = 81, slightly below average).
Also reported 10 individuals from other sources (Decipher, University of Toronto, GeneMatcher), with microdeletions in ANKS1B.
9 individuals from 7 families with monogenic deletions in ANKS1B are described in Table 1. 1 family was South Asian and 6 had Caucasian ancestry. Craniofacial dysmorphism was reported in 5/7 families. 3/9 patients were diagnosed with ID, however the severity is not specified, and two of the individuals were under 5 years of age - diagnosis is difficult before age 5. 6/9 individuals had developmental delay, 5/9 had ASD, and 4/9 had ADHD.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Dec 2025).
Intellectual disability v9.194 ANKS1B Ida Ertmanska edited their review of gene: ANKS1B: Added comment: Comment on list classification: Affected individuals had normal intellect or slightly below average, which does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Hence, ANKS1B should remain Amber for Intellectual disability until more evidence emerges.; Changed rating: AMBER; Changed publications to: 31388001, 38129387; Changed phenotypes to: complex neurodevelopmental disorder, MONDO:0100038; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.194 ANKS1B Ida Ertmanska commented on gene: ANKS1B
Intellectual disability v9.194 LDB1 Arina Puzriakova Classified gene: LDB1 as Amber List (moderate evidence)
Intellectual disability v9.194 LDB1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Although ventriculomegaly and/or hydrocephalus are the primary feature of the disorder, at least seven unrelated individuals have been reported with GDD and several also exhibited hypotonia. Taking this into account and the broader syndromic presentation, it would be appropriate to include this gene on the R27 Paediatric disorders and R69 Hypotonic infant super panels, both of which incorporate Intellectual disability as a component panel.
Intellectual disability v9.194 LDB1 Arina Puzriakova Gene: ldb1 has been classified as Amber List (Moderate Evidence).
Hydrocephalus v5.5 LDB1 Arina Puzriakova Classified gene: LDB1 as Amber List (moderate evidence)
Hydrocephalus v5.5 LDB1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - more than 10 unrelated individuals with de novo variants in this gene and ventriculomegaly and/or hydrocephalus.
Hydrocephalus v5.5 LDB1 Arina Puzriakova Gene: ldb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.193 LDB1 Arina Puzriakova gene: LDB1 was added
gene: LDB1 was added to Intellectual disability. Sources: Literature
Q4_25_promote_green tags were added to gene: LDB1.
Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB1 were set to 39680505; 38091987; 33077954
Phenotypes for gene: LDB1 were set to Congenital hydrocephalus, MONDO:0016349
Review for gene: LDB1 was set to GREEN
Added comment: - Allington et al. 2024 (PMID: 39680505) investigate a cohort of 2697 trios with congenital primary cerebral ventriculomegaly using WES. Eight unrelated individuals identified with de novo variants in LDB1 (7 LOF, 1 predicted damaging missense) - exhibiting perinatally diagnosed cerebral ventriculomegaly, including neurosurgically treated congenital hydrocephalus. Additionally, 5/8 GDD, 3/8 autism, 2/8 delayed gross motor development, 2/8 had congenital heart defects (inc. coarctation, PDA), 2/8 camptodactyly.

Additional case was identified from GeneMatcher with a de novo frameshift variants in LDB1. Phenotypes include severe ventriculomegaly, absence of well formed gyri, severe limb contractures and camptodactyly. Search of Decipher/DDD also revealed 4 pathogenic de novo variants in LDB1 and associated binding partners in individuals congenital ventriculomegaly.

- Torene et al. 2023 (PMID: 38091987) identified three individuals with protein truncating variants. Two individuals with de novo variants both had ventriculomegaly, hypotonia, GDD, craniofacial abnormalities. The third individual inherited the variants from an asymptomatic mother, and displayed developmental delay, hypotonia, congenital heart defects and a small hypoplastic hippocampi but did not have ventriculomegaly or craniofacial anomalies.

- Jin et al. 2020 (PMID: 33077954) also report an individual with a de novo LOF variant in this gene who had congenital hydrocephalus but details on this case are otherwise limited.
Sources: Literature
Hydrocephalus v5.4 LDB1 Arina Puzriakova gene: LDB1 was added
gene: LDB1 was added to Hydrocephalus. Sources: Literature
Q4_25_promote_green tags were added to gene: LDB1.
Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB1 were set to 39680505; 38091987; 33077954
Phenotypes for gene: LDB1 were set to Congenital hydrocephalus, MONDO:0016349
Review for gene: LDB1 was set to GREEN
Added comment: - Allington et al. 2024 (PMID: 39680505) investigate a cohort of 2697 trios with congenital primary cerebral ventriculomegaly using WES. Eight unrelated individuals identified with de novo variants in LDB1 (7 LOF, 1 predicted damaging missense) - exhibiting perinatally diagnosed cerebral ventriculomegaly, including neurosurgically treated congenital hydrocephalus. Additionally, 5/8 GDD, 3/8 autism, 2/8 delayed gross motor development, 2/8 had congenital heart defects (inc. coarctation, PDA), 2/8 camptodactyly.

Additional case was identified from GeneMatcher with a de novo frameshift variants in LDB1. Phenotypes include severe ventriculomegaly, absence of well formed gyri, severe limb contractures and camptodactyly. Search of Decipher/DDD also revealed 4 pathogenic de novo variants in LDB1 and associated binding partners in individuals congenital ventriculomegaly.

- Torene et al. 2023 (PMID: 38091987) identified three individuals with protein truncating variants. Two individuals with de novo variants both had ventriculomegaly, hypotonia, GDD, craniofacial abnormalities. The third individual inherited the variants from an asymptomatic mother, and displayed developmental delay, hypotonia, congenital heart defects and a small hypoplastic hippocampi but did not have ventriculomegaly or craniofacial anomalies.

- Jin et al. 2020 (PMID: 33077954) also report an individual with a de novo LOF variant in this gene who had congenital hydrocephalus but details on this case are otherwise limited.
Sources: Literature
Possible mitochondrial disorder - nuclear genes v4.17 TOMM7 Ida Ertmanska reviewed gene: TOMM7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.17 NDUFB7 Ida Ertmanska reviewed gene: NDUFB7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.17 MRPL39 Ida Ertmanska reviewed gene: MRPL39: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.17 COX14 Ida Ertmanska reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.17 BTD Ida Ertmanska commented on gene: BTD
Possible mitochondrial disorder - nuclear genes v4.17 ANO10 Ida Ertmanska reviewed gene: ANO10: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Possible mitochondrial disorder - nuclear genes v4.16 BTD Ida Ertmanska Tag Q2_25_expert_review was removed from gene: BTD.
Tag Q2_25_ demote_amber was removed from gene: BTD.
Possible mitochondrial disorder - nuclear genes v4.16 ANO10 Ida Ertmanska Tag Q2_25_expert_review was removed from gene: ANO10.
Tag Q2_25_ demote_amber was removed from gene: ANO10.
Possible mitochondrial disorder - nuclear genes v4.16 COX14 Ida Ertmanska Tag Q2_25_expert_review was removed from gene: COX14.
Tag Q2_25_ demote_amber was removed from gene: COX14.
Possible mitochondrial disorder - nuclear genes v4.16 MRPL39 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: MRPL39.
Possible mitochondrial disorder - nuclear genes v4.16 NDUFB7 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: NDUFB7.
Possible mitochondrial disorder - nuclear genes v4.16 TOMM7 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: TOMM7.
Tag Q3_24_NHS_review was removed from gene: TOMM7.
Possible mitochondrial disorder - nuclear genes v4.16 TOMM7 Ida Ertmanska Source Expert Review Green was added to TOMM7.
Source NHS GMS was added to TOMM7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Possible mitochondrial disorder - nuclear genes v4.16 NDUFB7 Ida Ertmanska Source Expert Review Green was added to NDUFB7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Possible mitochondrial disorder - nuclear genes v4.16 MRPL39 Ida Ertmanska Source Expert Review Green was added to MRPL39.
Source NHS GMS was added to MRPL39.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Possible mitochondrial disorder - nuclear genes v4.16 COX14 Ida Ertmanska Source Expert Review Amber was added to COX14.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v4.16 ANO10 Ida Ertmanska Source Expert Review Amber was added to ANO10.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Non-acute porphyrias v1.33 HMBS Ida Ertmanska commented on gene: HMBS: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before changing the mode of inheritance.
Non-acute porphyrias v1.33 HMBS Ida Ertmanska Tag to_be_confirmed_NHSE tag was added to gene: HMBS.
Monogenic hearing loss v5.49 MT-TS2 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-TS2.
Monogenic hearing loss v5.49 MT-TL1 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-TL1.
Monogenic hearing loss v5.49 MT-TK Ida Ertmanska Tag technical-limitations tag was added to gene: MT-TK.
Monogenic hearing loss v5.49 MT-CO1 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-CO1.
Monogenic hearing loss v5.49 TUBB4B Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: TUBB4B.
Monogenic hearing loss v5.49 XPA Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: XPA.
Monogenic hearing loss v5.49 RFC4 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: RFC4.
Monogenic hearing loss v5.49 MT-TS2 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TS2.
Tag Q2_25_expert_review was removed from gene: MT-TS2.
Tag Q2_25_ NHS_review was removed from gene: MT-TS2.
Monogenic hearing loss v5.49 MT-TL1 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TL1.
Tag Q2_25_expert_review was removed from gene: MT-TL1.
Tag Q2_25_ NHS_review was removed from gene: MT-TL1.
Monogenic hearing loss v5.49 MT-TK Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TK.
Tag Q2_25_expert_review was removed from gene: MT-TK.
Tag Q2_25_ NHS_review was removed from gene: MT-TK.
Monogenic hearing loss v5.49 MT-CO1 Ida Ertmanska Tag Q2_25_expert_review was removed from gene: MT-CO1.
Tag Q1_25_ promote_green was removed from gene: MT-CO1.
Tag Q2_25_ NHS_review was removed from gene: MT-CO1.
Monogenic hearing loss v5.49 MRPL49 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MRPL49.
Monogenic hearing loss v5.49 LHX3 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: LHX3.
Monogenic hearing loss v5.49 HGF Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: HGF.
Tag Q1_25_ expert_review was removed from gene: HGF.
Monogenic hearing loss v5.49 GJB6 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: GJB6.
Tag Q2_25_expert_review was removed from gene: GJB6.
Tag Q2_25_ NHS_review was removed from gene: GJB6.
Monogenic hearing loss v5.49 DAP3 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: DAP3.
Monogenic hearing loss v5.49 ATP6V1B1 Ida Ertmanska Tag Q2_25_ MOI was removed from gene: ATP6V1B1.
Tag Q2_25_ NHS_review was removed from gene: ATP6V1B1.
Monogenic hearing loss v5.49 XPA Ida Ertmanska reviewed gene: XPA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 TUBB4B Ida Ertmanska reviewed gene: TUBB4B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 RFC4 Ida Ertmanska reviewed gene: RFC4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 MT-TS2 Ida Ertmanska commented on gene: MT-TS2
Monogenic hearing loss v5.49 MT-TL1 Ida Ertmanska commented on gene: MT-TL1
Monogenic hearing loss v5.49 MT-TK Ida Ertmanska commented on gene: MT-TK
Monogenic hearing loss v5.49 MT-CO1 Ida Ertmanska commented on gene: MT-CO1
Monogenic hearing loss v5.49 MRPL49 Ida Ertmanska reviewed gene: MRPL49: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 LHX3 Ida Ertmanska reviewed gene: LHX3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 HGF Ida Ertmanska reviewed gene: HGF: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 GJB6 Ida Ertmanska reviewed gene: GJB6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 DAP3 Ida Ertmanska reviewed gene: DAP3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic hearing loss v5.49 ATP6V1B1 Ida Ertmanska commented on gene: ATP6V1B1
Monogenic hearing loss v5.48 XPA Ida Ertmanska Source Expert Review Green was added to XPA.
Source NHS GMS was added to XPA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 TUBB4B Ida Ertmanska Source Expert Review Green was added to TUBB4B.
Source NHS GMS was added to TUBB4B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 RFC4 Ida Ertmanska Source Expert Review Green was added to RFC4.
Source NHS GMS was added to RFC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 MRPL49 Ida Ertmanska Source Expert Review Green was added to MRPL49.
Source NHS GMS was added to MRPL49.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 LHX3 Ida Ertmanska Source Expert Review Green was added to LHX3.
Source NHS GMS was added to LHX3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 HGF Ida Ertmanska Source Expert Review Green was added to HGF.
Source NHS GMS was added to HGF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 GJB6 Ida Ertmanska Source Expert Review Green was added to GJB6.
Source NHS GMS was added to GJB6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 DAP3 Ida Ertmanska Source Expert Review Green was added to DAP3.
Source NHS GMS was added to DAP3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic hearing loss v5.48 ATP6V1B1 Ida Ertmanska Source NHS GMS was added to ATP6V1B1.
Mode of inheritance for gene ATP6V1B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thrombocythaemia v1.11 SH2B3 Eleanor Williams changed review comment from: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported. ; to: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported. Heterozygous mother of one homozgyous proband is reported to have had Thrombocytosis from adolescence.
Thrombocythaemia v1.11 SH2B3 Eleanor Williams changed review comment from: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for.; to: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for. Some heterozygous unaffected parents reported.
Thrombocythaemia v1.11 SH2B3 Eleanor Williams Publications for gene: SH2B3 were set to 28484264; 27237057; 23908464; 40481232
Thrombocythaemia v1.10 SH2B3 Eleanor Williams commented on gene: SH2B3: PMID: 41325922 Iaquinta et al 2025 - report of 3 individuals with the same germline heterozygous SH2B3 c.232G>A, p.Glu78Lys variant. They screened 330 patients with myeloproliferative neoplasms with a 73 gene panel. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis and one presented with primary myelofibrosis that evolved to acute myeloid leukemia (AML). The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. Distant familial relatedness was not explored. The variant is rare in gnomAD v4.1.0 with a frequency of 0.001097. The authors conclude that heterozygosity alone appears insufficient to drive disease, but supports a low-penetrance predisposition role.

PMID: 40481232 Leardini et al 2025 - 10 children from 9 families with SH2B3-associated neonatal myeloproliferative disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in 8 and in 2 patients with monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. 9 different variants reported. This was a international, multicenter, retrospective study on paediatric patients with germline variants in SH2B3. Two patients were previously reported in PMID: 38152053. Patients ranged in age from 0–4.0 years. The VAF in blood for patient P8.1 who carries a germline monoallelic variant, was close to 100%, suggesting a near-complete replacement of normal hematopoiesis by the mutant clone. Note: additional somatic driver mutations in other genes were not looked for.
Thrombophilia with a likely monogenic cause v2.9 PLG Eleanor Williams Tag Q2_25_expert_review was removed from gene: PLG.
Tag Q2_25_ demote_amber was removed from gene: PLG.
Thrombophilia with a likely monogenic cause v2.9 PLG Eleanor Williams reviewed gene: PLG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thrombophilia with a likely monogenic cause v2.8 PLG Eleanor Williams Source Expert Review Amber was added to PLG.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Thrombocythaemia v1.10 SH2B3 Eleanor Williams Added comment: Comment on phenotypes: Phenotype accessed in OMIM on 11th Dec 2025
Thrombocythaemia v1.10 SH2B3 Eleanor Williams Phenotypes for gene: SH2B3 were changed from Thrombocythemia, somatic, 187950 to Thrombocythemia, somatic, OMIM:187950
Congenital myopathy v6.43 MYMX Achchuthan Shanmugasundram Tag Q4_24_promote_green was removed from gene: MYMX.
Congenital myopathy v6.43 RFC4 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: RFC4.
Congenital myopathy v6.43 CIAO1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: CIAO1.
Tag Q3_24_NHS_review was removed from gene: CIAO1.
Congenital myopathy v6.43 MT-TW Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TW.
Tag Q2_25_expert_review was removed from gene: MT-TW.
Tag Q2_25_ NHS_review was removed from gene: MT-TW.
Congenital myopathy v6.43 MT-TN Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TN.
Tag Q2_25_expert_review was removed from gene: MT-TN.
Tag Q2_25_ NHS_review was removed from gene: MT-TN.
Congenital myopathy v6.43 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TL1.
Tag Q2_25_expert_review was removed from gene: MT-TL1.
Tag Q2_25_ NHS_review was removed from gene: MT-TL1.
Congenital myopathy v6.43 MT-TK Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TK.
Tag Q2_25_expert_review was removed from gene: MT-TK.
Tag Q2_25_ NHS_review was removed from gene: MT-TK.
Congenital myopathy v6.43 MT-TE Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MT-TE.
Tag Q2_25_expert_review was removed from gene: MT-TE.
Tag Q2_25_ NHS_review was removed from gene: MT-TE.
Thrombocythaemia v1.9 SH2B3 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: SH2B3.
Tag Q2_25_expert_review was removed from gene: SH2B3.
Tag Q2_25_ NHS_review was removed from gene: SH2B3.
Thrombocythaemia v1.9 SH2B3 Eleanor Williams Added comment: Comment on publications: Adding the PubMed ID of 40481232 for Leardini et al 2025
Thrombocythaemia v1.9 SH2B3 Eleanor Williams Publications for gene: SH2B3 were set to 28484264; 27237057; 23908464
Congenital myopathy v6.43 TNNI1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: TNNI1.
Thrombocythaemia v1.8 SH2B3 Eleanor Williams changed review comment from: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval. NW : Other was chosen to capture somatic variants, but is it appropriate to look for those on the R406 panel? MOI should probably be biallelic/monoallelic?NW: Other was chosen to capture somatic variants, but is it appropriate to look for those on the R406 panel? MOI should probably be biallelic/monoallelic?; to: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Congenital myopathy v6.43 TNNI1 Achchuthan Shanmugasundram reviewed gene: TNNI1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Congenital myopathy v6.43 SRPK3 Achchuthan Shanmugasundram reviewed gene: SRPK3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Congenital myopathy v6.43 RFC4 Achchuthan Shanmugasundram commented on gene: RFC4: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Congenital myopathy v6.43 MYMX Achchuthan Shanmugasundram commented on gene: MYMX: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Congenital myopathy v6.43 MT-TW Achchuthan Shanmugasundram edited their review of gene: MT-TW: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 MT-TN Achchuthan Shanmugasundram edited their review of gene: MT-TN: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 MT-TL1 Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 MT-TK Achchuthan Shanmugasundram edited their review of gene: MT-TK: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 MT-TE Achchuthan Shanmugasundram edited their review of gene: MT-TE: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. GLH review concluded that mitochondrial myopathies are not good fit for this panel. R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing would be the more appropriate test.; Changed rating: RED
Congenital myopathy v6.43 CIAO1 Achchuthan Shanmugasundram reviewed gene: CIAO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thrombocythaemia v1.8 SH2B3 Eleanor Williams reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thrombocythaemia v1.7 SH2B3 Eleanor Williams Source Expert Review Green was added to SH2B3.
Mode of inheritance for gene SH2B3 was changed from Other to BIALLELIC, autosomal or pseudoautosomal
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 TNNI1 Achchuthan Shanmugasundram Source Expert Review Green was added to TNNI1.
Source NHS GMS was added to TNNI1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 SRPK3 Achchuthan Shanmugasundram Source Expert Review Green was added to SRPK3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 RFC4 Achchuthan Shanmugasundram Source Expert Review Green was added to RFC4.
Source NHS GMS was added to RFC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 MYMX Achchuthan Shanmugasundram Source Expert Review Green was added to MYMX.
Source NHS GMS was added to MYMX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v6.42 MT-TW Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TW.
Source NHS GMS was added to MT-TW.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 MT-TN Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TN.
Source NHS GMS was added to MT-TN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 MT-TL1 Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TL1.
Source NHS GMS was added to MT-TL1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 MT-TK Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TK.
Source NHS GMS was added to MT-TK.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 MT-TE Achchuthan Shanmugasundram Source Expert Review Red was added to MT-TE.
Source NHS GMS was added to MT-TE.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Congenital myopathy v6.42 CIAO1 Achchuthan Shanmugasundram Source Expert Review Green was added to CIAO1.
Source NHS GMS was added to CIAO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thoracic aortic aneurysm or dissection (GMS) v4.4 SMAD6 Eleanor Williams Tag Q2_25_ demote_red was removed from gene: SMAD6.
Tag Q2_25_expert_review was removed from gene: SMAD6.
Tag Q2_25_ NHS_review was removed from gene: SMAD6.
Thoracic aortic aneurysm or dissection (GMS) v4.4 SMAD6 Eleanor Williams reviewed gene: SMAD6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v4.3 SMAD6 Eleanor Williams Source Expert Review Red was added to SMAD6.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Optic neuropathy v5.28 MT-TS2 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TS2.
Tag Q2_25_expert_review was removed from gene: MT-TS2.
Tag Q2_25_ NHS_review was removed from gene: MT-TS2.
Tag technical-limitations tag was added to gene: MT-TS2.
Optic neuropathy v5.28 MT-TL1 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TL1.
Tag Q2_25_expert_review was removed from gene: MT-TL1.
Tag Q2_25_ NHS_review was removed from gene: MT-TL1.
Tag technical-limitations tag was added to gene: MT-TL1.
Optic neuropathy v5.28 MT-ND2 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-ND2.
Optic neuropathy v5.28 MT-ND3 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-ND3.
Optic neuropathy v5.28 MT-ND4L Ida Ertmanska Tag technical-limitations tag was added to gene: MT-ND4L.
Optic neuropathy v5.28 MT-ND5 Ida Ertmanska Tag technical-limitations tag was added to gene: MT-ND5.
Optic neuropathy v5.28 MT-TK Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-TK.
Tag Q2_25_expert_review was removed from gene: MT-TK.
Tag Q2_25_ NHS_review was removed from gene: MT-TK.
Tag technical-limitations tag was added to gene: MT-TK.
Optic neuropathy v5.28 MT-ND5 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-ND5.
Tag Q2_25_expert_review was removed from gene: MT-ND5.
Tag Q2_25_ NHS_review was removed from gene: MT-ND5.
Optic neuropathy v5.28 MT-ND4L Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-ND4L.
Tag Q2_25_expert_review was removed from gene: MT-ND4L.
Tag Q2_25_ NHS_review was removed from gene: MT-ND4L.
Severe early-onset obesity v5.20 STX16 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: STX16.
Optic neuropathy v5.28 MT-ND3 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-ND3.
Tag Q2_25_expert_review was removed from gene: MT-ND3.
Tag Q2_25_ NHS_review was removed from gene: MT-ND3.
Optic neuropathy v5.28 MT-ND2 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: MT-ND2.
Tag Q2_25_expert_review was removed from gene: MT-ND2.
Tag Q2_25_ NHS_review was removed from gene: MT-ND2.
Severe early-onset obesity v5.20 STX16 Eleanor Williams reviewed gene: STX16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v5.28 MT-ND2 Ida Ertmanska changed review comment from: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber. The GMS reviewers commented as follows: More appropriate for specialist mitochondrial lab to test for this - 1) Alternative panel test available for this gene (R42.2 - Leber hereditary optic neuropathy). 2). May not be technically feasible for all laboratories to include this gene on the panel.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber. The GMS reviewers commented as follows: More appropriate for specialist mitochondrial lab to test for this - 1) Alternative panel test available for this gene (R42.2 - Leber hereditary optic neuropathy); 2). May not be technically feasible for all laboratories to include this gene on the panel.
Severe early-onset obesity v5.19 STX16 Eleanor Williams Source Expert Review Green was added to STX16.
Source NHS GMS was added to STX16.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v5.28 MIEF1 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: MIEF1.
Tag Q3_24_NHS_review was removed from gene: MIEF1.
Optic neuropathy v5.28 BORCS8 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: BORCS8.
Optic neuropathy v5.28 MT-TS2 Ida Ertmanska commented on gene: MT-TS2
Optic neuropathy v5.28 MT-TL1 Ida Ertmanska commented on gene: MT-TL1
Optic neuropathy v5.28 MT-TK Ida Ertmanska commented on gene: MT-TK
Optic neuropathy v5.28 MT-ND5 Ida Ertmanska commented on gene: MT-ND5
Optic neuropathy v5.28 MT-ND4L Ida Ertmanska commented on gene: MT-ND4L
Optic neuropathy v5.28 MT-ND3 Ida Ertmanska commented on gene: MT-ND3
Optic neuropathy v5.28 MT-ND2 Ida Ertmanska commented on gene: MT-ND2
Optic neuropathy v5.28 MIEF1 Ida Ertmanska reviewed gene: MIEF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Optic neuropathy v5.28 BORCS8 Ida Ertmanska reviewed gene: BORCS8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Segmental overgrowth disorders - Deep sequencing v4.3 PADI6 Eleanor Williams Tag Q2_25_ demote_red was removed from gene: PADI6.
Tag Q2_25_expert_review was removed from gene: PADI6.
Segmental overgrowth disorders - Deep sequencing v4.3 PADI6 Achchuthan Shanmugasundram reviewed gene: PADI6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Segmental overgrowth disorders - Deep sequencing v4.2 PADI6 Eleanor Williams Source Expert Review Red was added to PADI6.
Source NHS GMS was added to PADI6.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Optic neuropathy v5.27 MIEF1 Ida Ertmanska Source Expert Review Green was added to MIEF1.
Source NHS GMS was added to MIEF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Optic neuropathy v5.27 BORCS8 Ida Ertmanska Source Expert Review Green was added to BORCS8.
Source NHS GMS was added to BORCS8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Multi locus imprinting disorders v1.14 ZFP57 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: ZFP57.
Tag to_be_confirmed_NHSE tag was added to gene: ZFP57.
Multi locus imprinting disorders v1.14 ZFP57 Ida Ertmanska commented on gene: ZFP57
Non-acute porphyrias v1.33 HMBS Ida Ertmanska Tag Q2_25_ demote_red was removed from gene: HMBS.
Tag Q2_25_ MOI was removed from gene: HMBS.
Tag Q2_25_expert_review was removed from gene: HMBS.
Non-acute porphyrias v1.33 HMBS Ida Ertmanska commented on gene: HMBS
Respiratory ciliopathies including non-CF bronchiectasis v4.50 WFDC2 Eleanor Williams Tag Q3_24_promote_green was removed from gene: WFDC2.
Tag Q3_24_NHS_review was removed from gene: WFDC2.
Tag to_be_confirmed_NHSE tag was added to gene: WFDC2.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TUBB4B Eleanor Williams Tag dd_review was removed from gene: TUBB4B.
Tag Q1_25_ promote_green was removed from gene: TUBB4B.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TTC12 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: TTC12.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TP73 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: TP73.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 NEK10 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: NEK10.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 GAS2L2 Eleanor Williams Tag Q3_24_promote_green was removed from gene: GAS2L2.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 EFCAB1 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: EFCAB1.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 DNAJB13 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: DNAJB13.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 DAW1 Eleanor Williams Tag Q2_25_ demote_red was removed from gene: DAW1.
Tag Q2_25_expert_review was removed from gene: DAW1.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP74 Eleanor Williams Tag Q1_25_ NHS_review was removed from gene: CFAP74.
Tag Q1_25_ promote_green was removed from gene: CFAP74.
Tag Q1_25_ expert_review was removed from gene: CFAP74.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP54 Eleanor Williams Tag Q1_25_ NHS_review was removed from gene: CFAP54.
Tag Q1_25_ promote_green was removed from gene: CFAP54.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP221 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: CFAP221.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CEP164 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: CEP164.
Respiratory ciliopathies including non-CF bronchiectasis v4.50 WFDC2 Eleanor Williams commented on gene: WFDC2
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TUBB4B Eleanor Williams reviewed gene: TUBB4B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TTC12 Eleanor Williams reviewed gene: TTC12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 TP73 Eleanor Williams reviewed gene: TP73: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 NEK10 Eleanor Williams reviewed gene: NEK10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 GAS2L2 Eleanor Williams edited their review of gene: GAS2L2: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Respiratory ciliopathies including non-CF bronchiectasis v4.50 EFCAB1 Eleanor Williams reviewed gene: EFCAB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 DNAJB13 Eleanor Williams reviewed gene: DNAJB13: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 DAW1 Eleanor Williams reviewed gene: DAW1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP74 Eleanor Williams reviewed gene: CFAP74: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP54 Eleanor Williams reviewed gene: CFAP54: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CFAP221 Eleanor Williams reviewed gene: CFAP221: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.50 CEP164 Eleanor Williams reviewed gene: CEP164: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Respiratory ciliopathies including non-CF bronchiectasis v4.49 TUBB4B Eleanor Williams Source NHS GMS was added to TUBB4B.
Source Expert Review Green was added to TUBB4B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 TTC12 Eleanor Williams Source NHS GMS was added to TTC12.
Source Expert Review Green was added to TTC12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 TP73 Eleanor Williams Source NHS GMS was added to TP73.
Source Expert Review Green was added to TP73.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 NEK10 Eleanor Williams Source NHS GMS was added to NEK10.
Source Expert Review Green was added to NEK10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 GAS2L2 Eleanor Williams Source NHS GMS was added to GAS2L2.
Source Expert Review Green was added to GAS2L2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 EFCAB1 Eleanor Williams Source NHS GMS was added to EFCAB1.
Source Expert Review Green was added to EFCAB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 DNAJB13 Eleanor Williams Source Expert Review Green was added to DNAJB13.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 DAW1 Eleanor Williams Source Expert Review Red was added to DAW1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 CFAP74 Eleanor Williams Source NHS GMS was added to CFAP74.
Source Expert Review Green was added to CFAP74.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 CFAP54 Eleanor Williams Source Expert Review Green was added to CFAP54.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 CFAP221 Eleanor Williams Source NHS GMS was added to CFAP221.
Source Expert Review Green was added to CFAP221.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v4.49 CEP164 Eleanor Williams Source NHS GMS was added to CEP164.
Source Expert Review Green was added to CEP164.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypertrophic cardiomyopathy v5.22 MT-TV Arina Puzriakova commented on gene: MT-TV
Hypertrophic cardiomyopathy v5.22 MT-TL1 Arina Puzriakova commented on gene: MT-TL1
Hypertrophic cardiomyopathy v5.22 MT-ND5 Arina Puzriakova commented on gene: MT-ND5
Hypertrophic cardiomyopathy v5.22 KLHL24 Arina Puzriakova reviewed gene: KLHL24: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypertrophic cardiomyopathy v5.22 ALPK3 Arina Puzriakova commented on gene: ALPK3: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Hypertrophic cardiomyopathy v5.21 MT-TV Arina Puzriakova Classified gene: MT-TV as No list
Hypertrophic cardiomyopathy v5.21 MT-TV Arina Puzriakova Gene: mt-tv has been removed from the panel.
Hypertrophic cardiomyopathy v5.20 MT-TV Arina Puzriakova Tag curated_removed tag was added to gene: MT-TV.
Hypertrophic cardiomyopathy v5.20 MT-TV Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MT-TV.
Tag Q2_25_expert_review was removed from gene: MT-TV.
Tag Q2_25_ NHS_review was removed from gene: MT-TV.
Hypertrophic cardiomyopathy v5.20 MT-TL1 Arina Puzriakova Classified gene: MT-TL1 as No list
Hypertrophic cardiomyopathy v5.20 MT-TL1 Arina Puzriakova Gene: mt-tl1 has been removed from the panel.
Hypertrophic cardiomyopathy v5.19 MT-TL1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MT-TL1.
Tag Q2_25_expert_review was removed from gene: MT-TL1.
Tag Q2_25_ NHS_review was removed from gene: MT-TL1.
Tag curated_removed tag was added to gene: MT-TL1.
Hypertrophic cardiomyopathy v5.19 MT-ND5 Arina Puzriakova Classified gene: MT-ND5 as No list
Hypertrophic cardiomyopathy v5.19 MT-ND5 Arina Puzriakova Gene: mt-nd5 has been removed from the panel.
Hypertrophic cardiomyopathy v5.18 MT-ND5 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MT-ND5.
Tag Q2_25_expert_review was removed from gene: MT-ND5.
Tag Q2_25_ NHS_review was removed from gene: MT-ND5.
Tag curated_removed tag was added to gene: MT-ND5.
Renal tubulopathies v5.10 OCRL Eleanor Williams Tag Q2_25_ promote_green was removed from gene: OCRL.
Tag Q2_25_ NHS_review was removed from gene: OCRL.
Monogenic short stature v1.27 SPOUT1 Ida Ertmanska reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 SMC5 Ida Ertmanska reviewed gene: SMC5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 SLF2 Ida Ertmanska reviewed gene: SLF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 SLC13A1 Ida Ertmanska reviewed gene: SLC13A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 RSPRY1 Ida Ertmanska reviewed gene: RSPRY1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 RNPC3 Ida Ertmanska reviewed gene: RNPC3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 RECQL4 Ida Ertmanska reviewed gene: RECQL4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 PAPPA2 Ida Ertmanska commented on gene: PAPPA2
Monogenic short stature v1.27 MSTO1 Ida Ertmanska commented on gene: MSTO1
Monogenic short stature v1.27 GH1 Ida Ertmanska reviewed gene: GH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.27 FBXO22 Ida Ertmanska reviewed gene: FBXO22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypertrophic cardiomyopathy v5.18 KLHL24 Arina Puzriakova Tag Q3_24_promote_green was removed from gene: KLHL24.
Tag Q3_24_NHS_review was removed from gene: KLHL24.
Hypertrophic cardiomyopathy v5.18 ALPK3 Arina Puzriakova Tag Q3_24_NHS_review was removed from gene: ALPK3.
Tag Q3_24_MOI was removed from gene: ALPK3.
Hypertrophic cardiomyopathy v5.18 KLHL24 Arina Puzriakova Source Expert Review Green was added to KLHL24.
Source NHS GMS was added to KLHL24.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypertrophic cardiomyopathy v5.18 ALPK3 Arina Puzriakova Mode of inheritance for gene ALPK3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v3.17 NDUFB7 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: NDUFB7.
Mitochondrial disorder with complex I deficiency v3.17 NDUFB7 Arina Puzriakova commented on gene: NDUFB7: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Mitochondrial disorder with complex I deficiency v3.16 NDUFB7 Arina Puzriakova Source Expert Review Green was added to NDUFB7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe insulin resistance and lipodystrophy syndromes v4.64 PLA2G16 Arina Puzriakova Tag Q3_24_promote_green was removed from gene: PLA2G16.
Severe insulin resistance and lipodystrophy syndromes v4.64 PLA2G16 Achchuthan Shanmugasundram reviewed gene: PLA2G16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe insulin resistance and lipodystrophy syndromes v4.63 PLA2G16 Arina Puzriakova Source NHS GMS was added to PLA2G16.
Source Expert Review Green was added to PLA2G16.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 TNNI1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: TNNI1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 SNUPN Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SNUPN.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 JAG2 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: JAG2.
Tag Q2_25_ NHS_review was removed from gene: JAG2.
Intellectual disability v9.192 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Congenital myaesthenic syndrome v5.6 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Congenital myopathy v6.41 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Congenital muscular dystrophy v6.4 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Arthrogryposis v9.15 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 CIAO1 Arina Puzriakova Tag Q3_24_promote_green was removed from gene: CIAO1.
Tag Q3_24_NHS_review was removed from gene: CIAO1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.25 CIAO1 Arina Puzriakova Phenotypes for gene: CIAO1 were changed from CIAO1 associated neuromuscular disorder to Multiple mitochondrial dysfunctions syndrome 10, OMIM:620960
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 ACTN2 Arina Puzriakova Tag Q2_25_ MOI was removed from gene: ACTN2.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 TNNI1 Arina Puzriakova commented on gene: TNNI1: The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 SNUPN Arina Puzriakova reviewed gene: SNUPN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 JAG2 Arina Puzriakova reviewed gene: JAG2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 CIAO1 Arina Puzriakova reviewed gene: CIAO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.24 ACTN2 Arina Puzriakova commented on gene: ACTN2
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 TNNI1 Arina Puzriakova Source NHS GMS was added to TNNI1.
Source Expert Review Green was added to TNNI1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 SNUPN Arina Puzriakova Source NHS GMS was added to SNUPN.
Source Expert Review Green was added to SNUPN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 JAG2 Arina Puzriakova Source Expert Review Green was added to JAG2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 CIAO1 Arina Puzriakova Source NHS GMS was added to CIAO1.
Source Expert Review Green was added to CIAO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.23 ACTN2 Arina Puzriakova Mode of inheritance for gene ACTN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neonatal diabetes v5.9 RNU4ATAC Anna-Marie Johnson gene: RNU4ATAC was added
gene: RNU4ATAC was added to Neonatal diabetes. Sources: Literature
Mode of inheritance for gene: RNU4ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU4ATAC were set to MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
Phenotypes for gene: RNU4ATAC were set to neonatal diabetes; developmental delay; microcephaly; skeletal abnormalities; hypothyroidism; humoral immune defect; hepatic disorder; growth failure; failure to thrive; atopic dermatitis
Penetrance for gene: RNU4ATAC were set to Complete
Mode of pathogenicity for gene: RNU4ATAC was set to Other
Review for gene: RNU4ATAC was set to GREEN
Added comment: RNU4ATAC is a non-protein-coding gene and a component of the minor spliceosome, a protein-RNA complex mediating splicing of ~700 genes containing U12/minor-type introns. Johnson et al report RNU4ATAC as a novel disease gene causing monogenic autoimmune diabetes (median onset: 20 weeks) with additional immune dysregulation; whole genome sequencing of 7 unrelated individuals identified homozygous or compound heterozygous variants in RNU4ATAC, all known causes of monogenic diabetes had already been excluded. Sanger sequencing of the RNU4ATAC gene in patients with neonatal diabetes of unknown cause identified a further 5 unrelated individuals with biallelic variants in RNU4ATAC. RNA-seq from 3 unrelated individuals confirmed intron retention in comparison to controls. Multi-omic analysis of patient samples revealed a profound B cell developmental defect. This is the first report of pathogenic variants in non-coding genes causing monogenic diabetes, and also extends the phenotype of RNU4ATACopathies.
Sources: Literature
Neonatal diabetes v5.9 RNU6ATAC Anna-Marie Johnson gene: RNU6ATAC was added
gene: RNU6ATAC was added to Neonatal diabetes. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to MedRxiv preprint Johnson et al., 2025 https://doi.org/10.1101/2025.09.12.25335567
Phenotypes for gene: RNU6ATAC were set to neonatal diabetes; hypothyroidism; humoral immunue defect; hepatic disorder; growth failure; failure to thrive; skeletal abnormalities; atopic dermatitis; vitiligo; alopecia
Penetrance for gene: RNU6ATAC were set to Complete
Mode of pathogenicity for gene: RNU6ATAC was set to Other
Review for gene: RNU6ATAC was set to GREEN
Added comment: RNU6ATAC is a non-protein-coding gene and a component of the minor spliceosome, a protein-RNA complex mediating splicing of ~700 genes containing U12/minor-type introns. Johnson et al report RNU6ATAC as a novel disease gene causing monogenic autoimmune diabetes (median onset: 17 weeks) with additional immune dysregulation; whole genome sequencing of 4 individuals from 4 families identified 4 different biallelic pathogenic variants in the RNU6ATAC gene, all known causes of monogenic diabetes had already been excluded. Sanger sequencing of affected siblings from family A and D confirmed co segregation (1 additional case in family A, 2 in family D). RNA-seq from Family D confirmed intron retention in comparison to controls. Multi-omic analysis of patient samples revealed a profound B cell developmental defect.
Sources: Literature
Laterality disorders and isomerism v4.8 C1orf127 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: C1orf127.
Tag Q2_25_ NHS_review was removed from gene: C1orf127.
Laterality disorders and isomerism v4.8 AL117258.1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: AL117258.1.
Laterality disorders and isomerism v4.8 C1orf127 Arina Puzriakova commented on gene: C1orf127: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Laterality disorders and isomerism v4.8 AL117258.1 Arina Puzriakova reviewed gene: AL117258.1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Laterality disorders and isomerism v4.7 C1orf127 Arina Puzriakova Source NHS GMS was added to C1orf127.
Source Expert Review Green was added to C1orf127.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Laterality disorders and isomerism v4.7 AL117258.1 Arina Puzriakova Source NHS GMS was added to AL117258.1.
Source Expert Review Green was added to AL117258.1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Iron metabolism disorders - NOT common HFE mutations v3.3 CYBRD1 Arina Puzriakova Tag Q4_24_expert_review was removed from gene: CYBRD1.
Tag Q4_24_demote_red was removed from gene: CYBRD1.
Iron metabolism disorders - NOT common HFE mutations v3.3 CYBRD1 Arina Puzriakova reviewed gene: CYBRD1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Iron metabolism disorders - NOT common HFE mutations v3.2 CYBRD1 Arina Puzriakova Source Expert Review Red was added to CYBRD1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Inherited polyposis and early onset colorectal cancer - germline testing v3.10 MBD4 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: MBD4.
Tag Q2_25_ NHS_review was removed from gene: MBD4.
Inherited polyposis and early onset colorectal cancer - germline testing v3.10 MBD4 Arina Puzriakova edited their review of gene: MBD4: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Inherited polyposis and early onset colorectal cancer - germline testing v3.9 MBD4 Arina Puzriakova Source Expert Review Green was added to MBD4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.9 DNMT3A Arina Puzriakova Phenotypes for gene: DNMT3A were changed from Heyn-Sproul-Jackson syndrome, OMIM: 618724 to Heyn-Sproul-Jackson syndrome, OMIM:618724
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.8 DNMT3A Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: DNMT3A.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.8 DNMT3A Arina Puzriakova reviewed gene: DNMT3A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.7 DNMT3A Arina Puzriakova Source NHS GMS was added to DNMT3A.
Source Expert Review Green was added to DNMT3A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Inherited ovarian cancer (without breast cancer) v4.8 LLGL2 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: LLGL2.
Tag Q2_25_ NHS_review was removed from gene: LLGL2.
Tag to_be_confirmed_NHSE tag was added to gene: LLGL2.
Inherited ovarian cancer (without breast cancer) v4.8 LLGL2 Arina Puzriakova commented on gene: LLGL2
Monogenic short stature v1.26 SPOUT1 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: SPOUT1.
Monogenic short stature v1.26 SMC5 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: SMC5.
Monogenic short stature v1.26 SLF2 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: SLF2.
Monogenic short stature v1.26 SLC13A1 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: SLC13A1.
Monogenic short stature v1.26 RSPRY1 Ida Ertmanska Tag Q1_25_ promote_green was removed from gene: RSPRY1.
Monogenic short stature v1.26 RNPC3 Ida Ertmanska Tag Q2_25_ demote_red was removed from gene: RNPC3.
Tag Q2_25_expert_review was removed from gene: RNPC3.
Tag Q2_25_ phenotype was removed from gene: RNPC3.
Ectodermal dysplasia v4.19 FOSL2 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: FOSL2.
Monogenic short stature v1.26 RECQL4 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: RECQL4.
Tag Q3_24_NHS_review was removed from gene: RECQL4.
Ectodermal dysplasia v4.19 TWIST2 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: TWIST2.
Monogenic short stature v1.26 MSTO1 Ida Ertmanska Tag Q3_24_NHS_review was removed from gene: MSTO1.
Tag Q3_24_MOI was removed from gene: MSTO1.
Monogenic short stature v1.26 GH1 Ida Ertmanska Tag Q1_25_ NHS_review was removed from gene: GH1.
Tag Q1_25_ promote_green was removed from gene: GH1.
Monogenic short stature v1.26 FBXO22 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: FBXO22.
Ectodermal dysplasia v4.19 TWIST2 Achchuthan Shanmugasundram reviewed gene: TWIST2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Ectodermal dysplasia v4.19 FOSL2 Achchuthan Shanmugasundram commented on gene: FOSL2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Ectodermal dysplasia v4.18 TWIST2 Achchuthan Shanmugasundram Source NHS GMS was added to TWIST2.
Source Expert Review Green was added to TWIST2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Ectodermal dysplasia v4.18 FOSL2 Achchuthan Shanmugasundram Source NHS GMS was added to FOSL2.
Source Expert Review Green was added to FOSL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dilated and arrhythmogenic cardiomyopathy v3.10 MYLK3 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: MYLK3.
Tag Q2_25_expert_review was removed from gene: MYLK3.
Tag Q2_25_ NHS_review was removed from gene: MYLK3.
Dilated and arrhythmogenic cardiomyopathy v3.10 MYLK3 Achchuthan Shanmugasundram commented on gene: MYLK3
Mitochondrial disorder with complex IV deficiency v4.11 COX14 Ida Ertmanska Tag Q2_25_expert_review was removed from gene: COX14.
Tag Q2_25_ demote_amber was removed from gene: COX14.
Mitochondrial disorder with complex IV deficiency v4.11 COX14 Ida Ertmanska reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Mitochondrial disorder with complex IV deficiency v4.10 COX14 Ida Ertmanska Source Expert Review Amber was added to COX14.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Rare anaemia v3.15 RPL27 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: RPL27.
Tag Q2_25_ NHS_review was removed from gene: RPL27.
Rare anaemia v3.15 RPL27 Ida Ertmanska reviewed gene: RPL27: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare anaemia v3.14 RPL27 Ida Ertmanska Source Expert Review Green was added to RPL27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.30 RPL27 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: RPL27.
Tag Q2_25_ NHS_review was removed from gene: RPL27.
Cytopenia - NOT Fanconi anaemia v4.30 RPL17 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: RPL17.
Cytopenia - NOT Fanconi anaemia v4.30 FASLG Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: FASLG.
Cytopenia - NOT Fanconi anaemia v4.30 FAS Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: FAS.
Pigmentary skin disorders v4.10 BLM Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: BLM.
Pigmentary skin disorders v4.10 BLM Ida Ertmanska reviewed gene: BLM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v4.30 RPL27 Achchuthan Shanmugasundram edited their review of gene: RPL27: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v4.30 RPL17 Achchuthan Shanmugasundram commented on gene: RPL17: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Cytopenia - NOT Fanconi anaemia v4.30 FASLG Achchuthan Shanmugasundram commented on gene: FASLG: The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Cytopenia - NOT Fanconi anaemia v4.30 FAS Achchuthan Shanmugasundram commented on gene: FAS: The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Pigmentary skin disorders v4.9 BLM Ida Ertmanska Source NHS GMS was added to BLM.
Source Expert Review Green was added to BLM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.29 RPL27 Achchuthan Shanmugasundram Source Expert Review Green was added to RPL27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.29 RPL17 Achchuthan Shanmugasundram Source Expert Review Green was added to RPL17.
Source NHS GMS was added to RPL17.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.29 FASLG Achchuthan Shanmugasundram Source Expert Review Green was added to FASLG.
Source NHS GMS was added to FASLG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v4.29 FAS Achchuthan Shanmugasundram Source Expert Review Green was added to FAS.
Source NHS GMS was added to FAS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Primary lymphoedema v4.20 TIE1 Ida Ertmanska Tag Q2_25_ promote_green was removed from gene: TIE1.
Primary lymphoedema v4.20 TIE1 Ida Ertmanska reviewed gene: TIE1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary lymphoedema v4.19 TIE1 Ida Ertmanska Source NHS GMS was added to TIE1.
Source Expert Review Green was added to TIE1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Osteogenesis imperfecta v5.3 KIF5B Ida Ertmanska Tag Q3_24_promote_green was removed from gene: KIF5B.
Osteogenesis imperfecta v5.3 KIF5B Ida Ertmanska reviewed gene: KIF5B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Osteogenesis imperfecta v5.2 KIF5B Ida Ertmanska Source NHS GMS was added to KIF5B.
Source Expert Review Green was added to KIF5B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v5.4 ATP6V1B1 Ida Ertmanska Tag Q2_25_ MOI was removed from gene: ATP6V1B1.
Tag Q2_25_ NHS_review was removed from gene: ATP6V1B1.
Nephrocalcinosis or nephrolithiasis v5.4 ATP6V1B1 Ida Ertmanska commented on gene: ATP6V1B1
Nephrocalcinosis or nephrolithiasis v5.3 ATP6V1B1 Ida Ertmanska Source NHS GMS was added to ATP6V1B1.
Mode of inheritance for gene ATP6V1B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myaesthenic syndrome v5.5 CIAO1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: CIAO1.
Tag Q3_24_NHS_review was removed from gene: CIAO1.
Tag to_be_confirmed_NHSE tag was added to gene: CIAO1.
Congenital myaesthenic syndrome v5.5 CIAO1 Achchuthan Shanmugasundram commented on gene: CIAO1
Congenital muscular dystrophy v6.3 CIAO1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: CIAO1.
Tag Q3_24_NHS_review was removed from gene: CIAO1.
Congenital muscular dystrophy v6.3 CIAO1 Achchuthan Shanmugasundram reviewed gene: CIAO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Congenital muscular dystrophy v6.2 CIAO1 Achchuthan Shanmugasundram Source Expert Review Green was added to CIAO1.
Source NHS GMS was added to CIAO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Inherited breast cancer and ovarian cancer v2.17 BARD1 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: BARD1.
Tag Q2_25_ NHS_review was removed from gene: BARD1.
Inherited breast cancer and ovarian cancer v2.17 BARD1 Arina Puzriakova edited their review of gene: BARD1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval. Additional comments from reviewing GLHs: Propose that BARD1 are treated in the same way as ATM/CHEK2 (truncating variants only etc); Changed rating: GREEN
Inherited breast cancer and ovarian cancer v2.16 BARD1 Arina Puzriakova Source Expert Review Green was added to BARD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital adrenal hypoplasia v4.8 ABCD1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: ABCD1.
Congenital adrenal hypoplasia v4.8 ABCD1 Achchuthan Shanmugasundram reviewed gene: ABCD1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Congenital adrenal hypoplasia v4.7 ABCD1 Achchuthan Shanmugasundram Source NHS GMS was added to ABCD1.
Source Expert Review Green was added to ABCD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypogonadotropic hypogonadism (GMS) v4.3 RNF216 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: RNF216.
Hypogonadotropic hypogonadism (GMS) v4.3 FEZF1 Arina Puzriakova Tag Q3_24_promote_green was removed from gene: FEZF1.
Hypogonadotropic hypogonadism (GMS) v4.3 RNF216 Arina Puzriakova reviewed gene: RNF216: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypogonadotropic hypogonadism (GMS) v4.3 FEZF1 Arina Puzriakova reviewed gene: FEZF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypogonadotropic hypogonadism (GMS) v4.2 RNF216 Arina Puzriakova Source Expert Review Green was added to RNF216.
Source NHS GMS was added to RNF216.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypogonadotropic hypogonadism (GMS) v4.2 FEZF1 Arina Puzriakova Source Expert Review Green was added to FEZF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cholestasis v3.14 PSKH1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: PSKH1.
Cholestasis v3.14 RINT1 Achchuthan Shanmugasundram Tag Q2_25_ demote_red was removed from gene: RINT1.
Tag Q2_25_expert_review was removed from gene: RINT1.
Renal tubulopathies v5.10 CLCN5 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: CLCN5.
Tag Q2_25_ NHS_review was removed from gene: CLCN5.
Renal tubulopathies v5.10 ATP6V1B1 Eleanor Williams Tag Q2_25_ MOI was removed from gene: ATP6V1B1.
Tag Q2_25_ NHS_review was removed from gene: ATP6V1B1.
Cholestasis v3.14 RINT1 Achchuthan Shanmugasundram edited their review of gene: RINT1: Added comment: The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.; Changed rating: RED
Cholestasis v3.14 PSKH1 Achchuthan Shanmugasundram commented on gene: PSKH1: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Cholestasis v3.13 RINT1 Achchuthan Shanmugasundram Source NHS GMS was added to RINT1.
Source Expert Review Red was added to RINT1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Cholestasis v3.13 PSKH1 Achchuthan Shanmugasundram Source NHS GMS was added to PSKH1.
Source Expert Review Green was added to PSKH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.26 PAPPA2 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: PAPPA2.
Tag Q3_24_NHS_review was removed from gene: PAPPA2.
Tag Q3_24_expert_review was removed from gene: PAPPA2.
Tag to_be_confirmed_NHSE tag was added to gene: PAPPA2.
Monogenic short stature v1.26 SPOUT1 Ida Ertmanska reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 SMC5 Ida Ertmanska reviewed gene: SMC5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 SLF2 Ida Ertmanska reviewed gene: SLF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 SLC13A1 Ida Ertmanska reviewed gene: SLC13A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 RSPRY1 Ida Ertmanska reviewed gene: RSPRY1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 RNPC3 Ida Ertmanska reviewed gene: RNPC3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 RECQL4 Ida Ertmanska reviewed gene: RECQL4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 PAPPA2 Ida Ertmanska commented on gene: PAPPA2
Monogenic short stature v1.26 MSTO1 Ida Ertmanska commented on gene: MSTO1
Monogenic short stature v1.26 GH1 Ida Ertmanska reviewed gene: GH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 FBXO22 Ida Ertmanska reviewed gene: FBXO22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Renal tubulopathies v5.10 OCRL Eleanor Williams commented on gene: OCRL: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Renal tubulopathies v5.10 CLCN5 Eleanor Williams commented on gene: CLCN5: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Renal tubulopathies v5.10 ATP6V1B1 Eleanor Williams commented on gene: ATP6V1B1: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Renal tubulopathies v5.9 OCRL Eleanor Williams Source Expert Review Green was added to OCRL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Renal tubulopathies v5.9 CLCN5 Eleanor Williams Source Expert Review Green was added to CLCN5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Renal tubulopathies v5.9 ATP6V1B1 Eleanor Williams Mode of inheritance for gene ATP6V1B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary Erythrocytosis v2.16 JAK2 Arina Puzriakova Phenotypes for gene: JAK2 were changed from Hereditary erythrocytosis to Hereditary erythrocytosis; Erythrocytosis, somatic, OMIM:133100
Hereditary Erythrocytosis v2.15 JAK2 Arina Puzriakova Tag Q1_25_ NHS_review was removed from gene: JAK2.
Tag Q1_25_ promote_green was removed from gene: JAK2.
Cerebral vascular malformations v4.9 CBL Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: CBL.
Tag Q2_25_expert_review was removed from gene: CBL.
Tag Q2_25_ NHS_review was removed from gene: CBL.
Hereditary Erythrocytosis v2.15 SH2B3 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SH2B3.
Tag Q2_25_expert_review was removed from gene: SH2B3.
Tag Q2_25_ NHS_review was removed from gene: SH2B3.
Hereditary Erythrocytosis v2.15 SH2B3 Arina Puzriakova commented on gene: SH2B3: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GMS reviewers commented as follows: All GLH providers for this specialty agree that this should not be promoted to green rating - no definitive evidence for germline association with erythrocytosis
Hereditary Erythrocytosis v2.15 JAK2 Arina Puzriakova edited their review of gene: JAK2: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Hereditary Erythrocytosis v2.14 JAK2 Arina Puzriakova Source Expert Review Green was added to JAK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 SPOUT1 Ida Ertmanska Source Expert Review Green was added to SPOUT1.
Source NHS GMS was added to SPOUT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 SMC5 Ida Ertmanska Source Expert Review Green was added to SMC5.
Source NHS GMS was added to SMC5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 SLF2 Ida Ertmanska Source Expert Review Green was added to SLF2.
Source NHS GMS was added to SLF2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 SLC13A1 Ida Ertmanska Source Expert Review Green was added to SLC13A1.
Source NHS GMS was added to SLC13A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 RSPRY1 Ida Ertmanska Source Expert Review Green was added to RSPRY1.
Source NHS GMS was added to RSPRY1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 RNPC3 Ida Ertmanska Source Expert Review Red was added to RNPC3.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Monogenic short stature v1.25 RECQL4 Ida Ertmanska Source Expert Review Green was added to RECQL4.
Source NHS GMS was added to RECQL4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 MSTO1 Ida Ertmanska Mode of inheritance for gene MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Monogenic short stature v1.25 GH1 Ida Ertmanska Source Expert Review Green was added to GH1.
Source NHS GMS was added to GH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 FBXO22 Ida Ertmanska Source Expert Review Green was added to FBXO22.
Source NHS GMS was added to FBXO22.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cerebral vascular malformations v4.9 ANO1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: ANO1.
Tag Q2_25_expert_review was removed from gene: ANO1.
Tag Q2_25_ NHS_review was removed from gene: ANO1.
Cerebral vascular malformations v4.9 CBL Achchuthan Shanmugasundram commented on gene: CBL: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Cerebral vascular malformations v4.9 ANO1 Achchuthan Shanmugasundram reviewed gene: ANO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cerebral vascular malformations v4.8 CBL Achchuthan Shanmugasundram Source Expert Review Green was added to CBL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cerebral vascular malformations v4.8 ANO1 Achchuthan Shanmugasundram Source NHS GMS was added to ANO1.
Source Expert Review Green was added to ANO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autosomal recessive primary hypertrophic osteoarthropathy v1.16 SLCO2A1 Achchuthan Shanmugasundram Tag Q2_25_ MOI was removed from gene: SLCO2A1.
Familial tumours of the nervous system v2.7 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from {Melanoma and neural system tumor syndrome}, OMIM:155755; MELANOMA; PANCREATIC CANCER; ASTROCYTOMA; GLIOBLASTOMA; SCHWANNOMA; NEUROFIBROMA; MENINGIOMA; MALIGNANT PERIPHERAL NERVE SHEATH TUMOURS to {Melanoma and neural system tumor syndrome}, OMIM:155755; Astrocytoma; Glioblastoma; Schwannoma; Neurofibroma; Meningioma; Malignant peripheral nerve sheath tumours
Autosomal recessive primary hypertrophic osteoarthropathy v1.16 SLCO2A1 Achchuthan Shanmugasundram commented on gene: SLCO2A1
Autosomal recessive primary hypertrophic osteoarthropathy v1.15 SLCO2A1 Achchuthan Shanmugasundram Mode of inheritance for gene SLCO2A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Familial tumours of the nervous system v2.6 CDKN2A Arina Puzriakova Publications for gene: CDKN2A were set to PMID 24884915; 8317504; 9622062; 10797439; 17440112; 26794401; 29263814; 28699883; 28754699; 35422439; 38936911
Familial tumours of the nervous system v2.5 CDKN2A Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: CDKN2A.
Tag Q2_25_ NHS_review was removed from gene: CDKN2A.
Familial tumours of the nervous system v2.5 CDKN2A Arina Puzriakova edited their review of gene: CDKN2A: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Familial tumours of the nervous system v2.4 CDKN2A Arina Puzriakova Source NHS GMS was added to CDKN2A.
Source Expert Review Green was added to CDKN2A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Osteopetrosis v1.37 TYROBP Eleanor Williams Tag Q3_24_NHS_review was removed from gene: TYROBP.
Tag Q3_24_demote_red was removed from gene: TYROBP.
Tag Q3_24_expert_review was removed from gene: TYROBP.
Autoinflammatory disorders v2.34 TBK1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: TBK1.
Tag Q2_25_ NHS_review was removed from gene: TBK1.
Osteopetrosis v1.37 TYROBP Eleanor Williams edited their review of gene: TYROBP: Added comment: The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.; Changed rating: RED
Osteopetrosis v1.36 TYROBP Eleanor Williams Source Expert Review Red was added to TYROBP.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Autoinflammatory disorders v2.34 RIPK1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: RIPK1.
Tag Q2_25_ NHS_review was removed from gene: RIPK1.
Autoinflammatory disorders v2.34 RELA Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: RELA.
Tag Q2_25_ NHS_review was removed from gene: RELA.
Autoinflammatory disorders v2.34 POMP Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: POMP.
Tag Q2_25_ NHS_review was removed from gene: POMP.
Autoinflammatory disorders v2.34 IKBKG Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: IKBKG.
Tag Q2_25_ NHS_review was removed from gene: IKBKG.
Autoinflammatory disorders v2.34 ELF4 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: ELF4.
Tag Q2_25_ NHS_review was removed from gene: ELF4.
Autoinflammatory disorders v2.34 COPA Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: COPA.
Tag Q2_25_ NHS_review was removed from gene: COPA.
Autoinflammatory disorders v2.34 ALPK1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: ALPK1.
Tag Q2_25_ NHS_review was removed from gene: ALPK1.
Autoinflammatory disorders v2.34 TBK1 Achchuthan Shanmugasundram commented on gene: TBK1: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Autoinflammatory disorders v2.34 RIPK1 Achchuthan Shanmugasundram commented on gene: RIPK1: The rating of this gene has been updated to green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Autoinflammatory disorders v2.34 RELA Achchuthan Shanmugasundram reviewed gene: RELA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Autoinflammatory disorders v2.34 POMP Achchuthan Shanmugasundram reviewed gene: POMP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Autoinflammatory disorders v2.34 IKBKG Achchuthan Shanmugasundram reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Autoinflammatory disorders v2.34 ELF4 Achchuthan Shanmugasundram commented on gene: ELF4: The rating of this gene has been updated to green and the mode of inheritance set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) following NHS Genomic Medicine Service approval.
Autoinflammatory disorders v2.34 COPA Achchuthan Shanmugasundram reviewed gene: COPA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Autoinflammatory disorders v2.34 ALPK1 Achchuthan Shanmugasundram commented on gene: ALPK1: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Autoinflammatory disorders v2.33 TBK1 Achchuthan Shanmugasundram Source NHS GMS was added to TBK1.
Source Expert Review Green was added to TBK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 RIPK1 Achchuthan Shanmugasundram Source NHS GMS was added to RIPK1.
Source Expert Review Green was added to RIPK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 RELA Achchuthan Shanmugasundram Source NHS GMS was added to RELA.
Source Expert Review Green was added to RELA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 POMP Achchuthan Shanmugasundram Source NHS GMS was added to POMP.
Source Expert Review Green was added to POMP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 IKBKG Achchuthan Shanmugasundram Source NHS GMS was added to IKBKG.
Source Expert Review Green was added to IKBKG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 ELF4 Achchuthan Shanmugasundram Source NHS GMS was added to ELF4.
Source Expert Review Green was added to ELF4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 COPA Achchuthan Shanmugasundram Source NHS GMS was added to COPA.
Source Expert Review Green was added to COPA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 ALPK1 Achchuthan Shanmugasundram Source NHS GMS was added to ALPK1.
Source Expert Review Green was added to ALPK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.6 STX16 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: STX16.
Tag Q2_25_expert_review was removed from gene: STX16.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.6 STX16 Achchuthan Shanmugasundram edited their review of gene: STX16: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GMS reviewers commented as follows: Only STX16 deletions are clinically relevant and STX16 probes are included in the MS-MLPA kit which is an essential component of R293 testing as STX16 deletions act on methylation only. Adding this gene to Panelapp could be missleading as would suggest analysis of SNVs.; Changed rating: AMBER
Acute intermittent porphyria v1.5 HMBS Achchuthan Shanmugasundram Tag Q2_25_ MOI was removed from gene: HMBS.
Acute intermittent porphyria v1.5 HMBS Achchuthan Shanmugasundram commented on gene: HMBS
Acute intermittent porphyria v1.4 HMBS Achchuthan Shanmugasundram Mode of inheritance for gene HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Skeletal dysplasia v8.21 H2AFY Julie Evans gene: H2AFY was added
gene: H2AFY was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: H2AFY was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: H2AFY were set to PMID: 30711920, PMID: 23587911
Phenotypes for gene: H2AFY were set to Liebenberg syndrome
Penetrance for gene: H2AFY were set to Complete
Review for gene: H2AFY was set to GREEN
Added comment: H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome
Sources: Literature
Hypertrophic cardiomyopathy v5.17 TBX1 Riyaad Aungraheeta gene: TBX1 was added
gene: TBX1 was added to Hypertrophic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: TBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TBX1 were set to PMID: 41130538
Phenotypes for gene: TBX1 were set to Hypertrophic cardiomyopathy
Review for gene: TBX1 was set to AMBER
Added comment: Sources: Literature
Mosaic skin disorders - deep sequencing v3.22 TP63 Arina Puzriakova Tag watchlist was removed from gene: TP63.
Mosaic skin disorders - deep sequencing v3.22 GJA1 Arina Puzriakova Mode of inheritance for gene: GJA1 was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mosaic skin disorders - deep sequencing v3.21 GJA1 Arina Puzriakova Publications for gene: GJA1 were set to PMID:
Hereditary neuropathy or pain disorder v7.29 KIF21A Alexander Rossor gene: KIF21A was added
gene: KIF21A was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: KIF21A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF21A were set to 39643435; 41282472
Phenotypes for gene: KIF21A were set to CFEOM; agenesis of the corpus callosum; peripheral neuropathy
Penetrance for gene: KIF21A were set to Complete
Mode of pathogenicity for gene: KIF21A 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: KIF21A was set to AMBER
Added comment: Currently only two unrelated individuals reported with peripheral neuropathy
Sources: Expert list
Retinal disorders v8.74 EGFLAM Siying Lin gene: EGFLAM was added
gene: EGFLAM was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: EGFLAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EGFLAM were set to PMID: 41343198
Phenotypes for gene: EGFLAM were set to Congenital Stationary Night Blindness
Mode of pathogenicity for gene: EGFLAM was set to Other
Review for gene: EGFLAM was set to AMBER
Added comment: PMID 41343198 - 3 patients from 2 unrelated families with different homozygous LOF variants and CSNB phenotype
Sources: Literature
Mosaic skin disorders - deep sequencing v3.20 TSC2 Ida Ertmanska Phenotypes for gene: TSC2 were changed from to Tuberous sclerosis-2, OMIM: 613254; tuberous sclerosis 2, MONDO:0013199
Mosaic skin disorders - deep sequencing v3.19 TSC2 Ida Ertmanska Publications for gene: TSC2 were set to PMID: 37356622
Mosaic skin disorders - deep sequencing v3.18 TSC2 Ida Ertmanska Mode of inheritance for gene: TSC2 was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.17 TSC2 Ida Ertmanska Classified gene: TSC2 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v3.17 TSC2 Ida Ertmanska Gene: tsc2 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v3.16 TSC2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TSC2.
Tag Q4_25_NHS_review tag was added to gene: TSC2.
Mosaic skin disorders - deep sequencing v3.16 TSC2 Ida Ertmanska commented on gene: TSC2: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring heterozygous mosaic TSC2 variants. Variants are sometimes detected in skin biopsy samples only - not in blood or saliva. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (down to <1%). Based on the available evidence, TSC2 should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.16 TSC2 Ida Ertmanska reviewed gene: TSC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26540169, 31160751, 31114024, 32461669, 37141891, 37356622; Phenotypes: Tuberous sclerosis-2, OMIM: 613254; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring heterozygous mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants may be detected in skin biopsy samples but not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.; to: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring heterozygous mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants are sometimes detected in skin biopsy samples only - not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska changed review comment from: Tuberous sclerosis complex present with hamartomatous tumors affecting multiple organs, including the skin: facial angiofibroma, ungual fibroma, and shagreen patch (PMID: 37141891).

PMID: 37356622 Blasco-Perez et al., 2023
Cohort of Tuberous sclerosis complex (TSC) patients. Seq method: deep coverage NGS seq of TSC1 and TSC2 - average coverage >400x. 8/29 variants were detected in mosaicism, 4 at extremely low levels ( <16%).
Patients with TSC1 variants:
10 non-mosaic heterozygous cases;
Patient 6: mosaic variant TSC1:c.994del, p.Ser332Profs∗6; variant detected in saliva (36%) and affected skin (42%); blood sequencing not performed
Patient 12: mosaic variant TSC1:c.2101_2107del, p.Gln701Serfs∗21 - 4% in peripheral blood

PMID: 37141891 Klonowska et al., 2023
Cohort of 95 individuals with TSC and confirmed mosaicism. Method: Deep massively parallel sequencing (MPS) (median read depth ≥ 500×). 9/95 individuals had variants in TSC1, and 86/95 patients had variants detected in TCS2.
The cohort included patients previously reported in PMID: 26540169 Tyburczy et al., 2015, as well as PMID: 31160751 Giannikou et al., 2019; PMID: 31114024 Treichel et al., 2019; PMID: 32461669 Ogorek et al., 2020.

PMID: 26540169 Tyburczy et al., 2015
Cohort of 53 patients with TSC and no mutation identified in previous testing. Median read depth was ≥ 5,000x for long-range PCR, and ≥ 500x in hybrid capture method. All 53 TSC patients had skin involvement.
Reported 4 patients with non-mosaic heterozygous TSC1 variants (allele freq = 50%), as well as 4 mosaic cases (allele freq <50%):
P53: 22yo male; TSC1 c.1776delG - 30% mutant allele in saliva and blood
P2: 20yo male; c.2689C>T; p.Q897* in TSC1 - 15% mutant allele in blood
P6: 4yo male; TSC1 c.2111_2112delAT - 4.7% in blood and normal skin
P5f: 57yo female; TSC1 c.2374C>T; p.Q792* - 3.3% in blood

This gene is associated with AD Tuberous sclerosis-1, MIM:191100 in OMIM (accessed 3rd Dec 2025).; to: Tuberous sclerosis complex present with hamartomatous tumors affecting multiple organs, including the skin: facial angiofibroma, ungual fibroma, and shagreen patch (PMID: 37141891).

PMID: 37356622 Blasco-Perez et al., 2023
Cohort of Tuberous sclerosis complex (TSC) patients. Seq method: deep coverage NGS seq of TSC1 and TSC2 - average coverage >400x. 8/29 variants were detected in mosaicism, 4 at extremely low levels ( <16%). Variants are sometimes detected in skin biopsy samples only - not in blood or saliva.
Patients with TSC1 variants:
10 non-mosaic heterozygous cases;
Patient 6: mosaic variant TSC1:c.994del, p.Ser332Profs∗6; variant detected in saliva (36%) and affected skin (42%); blood sequencing not performed
Patient 12: mosaic variant TSC1:c.2101_2107del, p.Gln701Serfs∗21 - 4% in peripheral blood

PMID: 37141891 Klonowska et al., 2023
Cohort of 95 individuals with TSC and confirmed mosaicism. Method: Deep massively parallel sequencing (MPS) (median read depth ≥ 500×). 9/95 individuals had variants in TSC1, and 86/95 patients had variants detected in TCS2.
The cohort included patients previously reported in PMID: 26540169 Tyburczy et al., 2015, as well as PMID: 31160751 Giannikou et al., 2019; PMID: 31114024 Treichel et al., 2019; PMID: 32461669 Ogorek et al., 2020.

PMID: 26540169 Tyburczy et al., 2015
Cohort of 53 patients with TSC and no mutation identified in previous testing. Median read depth was ≥ 5,000x for long-range PCR, and ≥ 500x in hybrid capture method. All 53 TSC patients had skin involvement.
Reported 4 patients with non-mosaic heterozygous TSC1 variants (allele freq = 50%), as well as 4 mosaic cases (allele freq <50%):
P53: 22yo male; TSC1 c.1776delG - 30% mutant allele in saliva and blood
P2: 20yo male; c.2689C>T; p.Q897* in TSC1 - 15% mutant allele in blood
P6: 4yo male; TSC1 c.2111_2112delAT - 4.7% in blood and normal skin
P5f: 57yo female; TSC1 c.2374C>T; p.Q792* - 3.3% in blood

This gene is associated with AD Tuberous sclerosis-1, MIM:191100 in OMIM (accessed 3rd Dec 2025).
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska Deleted their comment
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants may be detected in skin biopsy samples but not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.; to: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring heterozygous mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants may be detected in skin biopsy samples but not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska Phenotypes for gene: TSC1 were changed from Cutaneous pigmentary abnormalities, and/or other aspects of germline TSC disease to Tuberous sclerosis-1, OMIM:191100; tuberous sclerosis 1, MONDO:0008612
Mosaic skin disorders - deep sequencing v3.15 TSC1 Ida Ertmanska Publications for gene: TSC1 were set to PMID: 37356622
Mosaic skin disorders - deep sequencing v3.14 TSC1 Ida Ertmanska Mode of inheritance for gene: TSC1 was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.13 TSC1 Ida Ertmanska Added comment: Comment on mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.13 TSC1 Ida Ertmanska Mode of inheritance for gene: TSC1 was changed from Other to Other
Mosaic skin disorders - deep sequencing v3.12 TSC1 Ida Ertmanska Classified gene: TSC1 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v3.12 TSC1 Ida Ertmanska Gene: tsc1 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v3.11 TSC1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TSC1.
Tag Q4_25_NHS_review tag was added to gene: TSC1.
Mosaic skin disorders - deep sequencing v3.11 TSC1 Ida Ertmanska commented on gene: TSC1: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants may be detected in skin biopsy samples but not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.11 TSC1 Ida Ertmanska changed review comment from: Tuberous sclerosis complex present with hamartomatous tumors affecting multiple organs, including the skin: facial angiofibroma, ungual fibroma, shagreen patch.

PMID: 37356622 Blasco-Perez et al., 2023
Cohort of Tuberous sclerosis complex (TSC) patients. Seq method: deep coverage NGS seq of TSC1 and TSC2 - average coverage >400x. 8/29 variants were detected in mosaicism, 4 at extremely low levels ( <16%).
Patients with TSC1 variants:
10 non-mosaic heterozygous cases;
Patient 6: mosaic variant TSC1:c.994del, p.Ser332Profs∗6; variant detected in saliva (36%) and affected skin (42%); blood sequencing not performed
Patient 12: mosaic variant TSC1:c.2101_2107del, p.Gln701Serfs∗21 - 4% in peripheral blood

PMID: 37141891 Klonowska et al., 2023
Cohort of 95 individuals with TSC and confirmed mosaicism. Method: Deep massively parallel sequencing (MPS) (median read depth ≥ 500×). 9/95 individuals had variants in TSC1, and 86/95 patients had variants detected in TCS2.
The cohort included patients previously reported in PMID: 26540169 Tyburczy et al., 2015, as well as PMID: 31160751 Giannikou et al., 2019; PMID: 31114024 Treichel et al., 2019; PMID: 32461669 Ogorek et al., 2020.

PMID: 26540169 Tyburczy et al., 2015
Cohort of patients with TSC and no mutation identified in previous testing. Median read depth was ≥ 5,000x for long-range PCR, and ≥ 500x in hybrid capture method.
Reported 4 patients with non-mosaic heterozygous TSC1 variants (allele freq = 50%), as well as 4 mosaic cases (allele freq <50%):
P53: 22yo male; TSC1 c.1776delG - 30% mutant allele in saliva and blood
P2: 20yo male; c.2689C>T; p.Q897* in TSC1 - 15% mutant allele in blood
P6: 4yo male; TSC1 c.2111_2112delAT - 4.7% in blood and normal skin
P5f: 57yo female; TSC1 c.2374C>T; p.Q792* - 3.3% in blood

This gene is associated with AD Tuberous sclerosis-1, MIM:191100 in OMIM (accessed 3rd Dec 2025).; to: Tuberous sclerosis complex present with hamartomatous tumors affecting multiple organs, including the skin: facial angiofibroma, ungual fibroma, and shagreen patch (PMID: 37141891).

PMID: 37356622 Blasco-Perez et al., 2023
Cohort of Tuberous sclerosis complex (TSC) patients. Seq method: deep coverage NGS seq of TSC1 and TSC2 - average coverage >400x. 8/29 variants were detected in mosaicism, 4 at extremely low levels ( <16%).
Patients with TSC1 variants:
10 non-mosaic heterozygous cases;
Patient 6: mosaic variant TSC1:c.994del, p.Ser332Profs∗6; variant detected in saliva (36%) and affected skin (42%); blood sequencing not performed
Patient 12: mosaic variant TSC1:c.2101_2107del, p.Gln701Serfs∗21 - 4% in peripheral blood

PMID: 37141891 Klonowska et al., 2023
Cohort of 95 individuals with TSC and confirmed mosaicism. Method: Deep massively parallel sequencing (MPS) (median read depth ≥ 500×). 9/95 individuals had variants in TSC1, and 86/95 patients had variants detected in TCS2.
The cohort included patients previously reported in PMID: 26540169 Tyburczy et al., 2015, as well as PMID: 31160751 Giannikou et al., 2019; PMID: 31114024 Treichel et al., 2019; PMID: 32461669 Ogorek et al., 2020.

PMID: 26540169 Tyburczy et al., 2015
Cohort of 53 patients with TSC and no mutation identified in previous testing. Median read depth was ≥ 5,000x for long-range PCR, and ≥ 500x in hybrid capture method. All 53 TSC patients had skin involvement.
Reported 4 patients with non-mosaic heterozygous TSC1 variants (allele freq = 50%), as well as 4 mosaic cases (allele freq <50%):
P53: 22yo male; TSC1 c.1776delG - 30% mutant allele in saliva and blood
P2: 20yo male; c.2689C>T; p.Q897* in TSC1 - 15% mutant allele in blood
P6: 4yo male; TSC1 c.2111_2112delAT - 4.7% in blood and normal skin
P5f: 57yo female; TSC1 c.2374C>T; p.Q792* - 3.3% in blood

This gene is associated with AD Tuberous sclerosis-1, MIM:191100 in OMIM (accessed 3rd Dec 2025).
Mosaic skin disorders - deep sequencing v3.11 TSC1 Ida Ertmanska reviewed gene: TSC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26540169, 31160751, 31114024, 32461669, 37141891, 37356622; Phenotypes: Tuberous sclerosis-1, OMIM:191100, tuberous sclerosis 1, MONDO:0008612; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tubulointerstitial kidney disease v3.10 APOA4 Nour Elkhateeb gene: APOA4 was added
gene: APOA4 was added to Tubulointerstitial kidney disease. Sources: Literature
Mode of inheritance for gene: APOA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOA4 were set to PMID 38096951
Phenotypes for gene: APOA4 were set to tubulointerstitial kidney disease; Chronic kidney disease
Penetrance for gene: APOA4 were set to unknown
Review for gene: APOA4 was set to GREEN
Added comment: Kmochova et al. (2024) (PMID: 38096951) reported 35 patients from 5 large unrelated families with onset of tubulointerstitial kidney disease in late adulthood associated with mutations in the APOA4 gene.
Sources: Literature
Mosaic skin disorders - deep sequencing v3.11 TP63 Ida Ertmanska Phenotypes for gene: TP63 were changed from Split hand foot malformation with whorl-like pigmentary pattern to Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292
Mosaic skin disorders - deep sequencing v3.10 TP63 Ida Ertmanska Publications for gene: TP63 were set to 18792980
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TP63.
Tag Q4_25_NHS_review tag was added to gene: TP63.
Tag Q4_25_expert_review tag was added to gene: TP63.
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska commented on gene: TP63: Comment on list classification: There is only one reported case of a confirmed mosaic TP63 variant in a parent, which has been passed on to offspring in an autosomal dominant manner (PMID:18792980). PMID: 34703865 reports another individual described as mosaic, but variant details are not specified. Both patients presented with linear hypopigmented patches following Blaschkoid lines - usually indicative of cutaneous mosaicism. In addition, 3 unrelated sets of siblings, harbouring the same rare 'de novo' TP63 mutations, have been described - suggestive of undetected mosaicism in parents (PMIDs: 22740388; 27351625; 28977327). Based on available evidence, this gene will be tagged for promotion to Green on Mosaic skin disorders - deep sequencing. Expert Review will be requested regarding the evidence for mosaicism in four cases (suspected but not confirmed through sequencing).
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska changed review comment from: PMID: 34703865 Chen, Issa and Schmidt, 2021
Report of a 31 yo African American man harbouring a 'TP63 gene copy number variant' (not specified) with a mosaic distribution (ratio not given). Putative diagnosis: ectodermal dysplasia (ED). Phenotype: patterned skin hypopigmentation (including linear hypopigmented patches following Blaschkoid lines), alopecia, and dental anomaly (one hypoplastic, conical tooth). Variant identified through an ED-associated gene panel.

PMID: 28977327 Rosa et al., 2017
3 siblings with Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, parents unaffected. Germline mosaicism hypothesised, but no DNA sequencing described.

PMID: 27351625 Enriquez et al., 2016
Report of two sibling fetuses with urogenital abnormalities, split hand and foot malformation, and bilateral cleft lip and palate. Both het for c.1051G > A; p.D351N in TP63. Both parents were unaffected. 'Parental lymphocyte DNA showed no evidence of the TP63 mutation but germline mosaicism in a parent is assumed' - only TP63 sequenced, parents are WT. Mosaicism presumed due to recurrence in the two siblings. The same missense mutation was reported de novo in other families (PMID: 21434540 Ergin et al., 2010 and PMID: 16691622 Rinne et al., 2006).

PMID: 22740388 Barbaro et al., 2012
Two sisters with Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Both sisters were heterozygous for TP63 c.1568T>C p.L523P (NM_003722.5: c.1574T>C, p.Leu525Pro) - not in gnomAD v4.1.0. Parental DNA analysis (blood, father's seminal fluid and mother's buccal, vaginal, and cervical cells) did not reveal the mutation. Authors pose that the apparently de novo variant was actually inherited through very low grade somatic mosaicism or maternal gonadal mosaicism.

PMID: 18792980 Kosaki et al., 2008


TP63 is associated with several AD conditions in OMIM, including Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 MIM:604292 (accessed 3rd Dec 2025).; to: PMID: 34703865 Chen, Issa and Schmidt, 2021
Report of a 31 yo African American man harbouring a 'TP63 gene copy number variant' (not specified) with a mosaic distribution (ratio not given). Putative diagnosis: ectodermal dysplasia (ED). Phenotype: patterned skin hypopigmentation (including linear hypopigmented patches following Blaschkoid lines), alopecia, and dental anomaly (one hypoplastic, conical tooth). Variant identified through an ED-associated gene panel.

PMID: 28977327 Rosa et al., 2017
3 siblings with Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, parents unaffected. Germline mosaicism hypothesised, but no DNA sequencing described.

PMID: 27351625 Enriquez et al., 2016
Report of two sibling fetuses with urogenital abnormalities, split hand and foot malformation, and bilateral cleft lip and palate. Both het for c.1051G > A; p.D351N in TP63. Both parents were unaffected. 'Parental lymphocyte DNA showed no evidence of the TP63 mutation but germline mosaicism in a parent is assumed' - only TP63 sequenced, parents are WT. Mosaicism presumed due to recurrence in the two siblings. The same missense mutation was reported de novo in other families (PMID: 21434540 Ergin et al., 2010 and PMID: 16691622 Rinne et al., 2006).

PMID: 22740388 Barbaro et al., 2012
Two sisters with Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Both sisters were heterozygous for TP63 c.1568T>C p.L523P (NM_003722.5: c.1574T>C, p.Leu525Pro) - not in gnomAD v4.1.0. Parental DNA analysis (blood, father's seminal fluid and mother's buccal, vaginal, and cervical cells) did not reveal the mutation. Authors pose that the apparently de novo variant was actually inherited through very low grade somatic mosaicism or maternal gonadal mosaicism.

PMID: 18792980 Kosaki et al., 2008
Newborn with split hand/foot malformation with whorl-like pigmentary pattern following Blaschko lines, heterozygous for c.727C>T, p.R204W (NM_003722.5: c.727C>T, p.Arg243Trp) - germline, variant not present in gnomAD v4.1.0. Mosaicism confirmed in the father (sequencing of peripheral blood and hair). Father presented with ectrodactyly of the hands a whorl-like pigmentary pattern following Blaschko lines.

TP63 is associated with several AD conditions in OMIM, including Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 MIM:604292 (accessed 3rd Dec 2025).
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska edited their review of gene: TP63: Changed rating: GREEN; Changed publications to: 18792980, 22740388, 27351625, 28977327, 34703865; Changed phenotypes to: Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska reviewed gene: TP63: Rating: ; Mode of pathogenicity: None; Publications: 18792980, 22740388, 27351625, 34703865; Phenotypes: ; Mode of inheritance: None
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska Tag Q4_25_NHS_review tag was added to gene: PMVK.
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska commented on gene: PMVK: Comment on list classification: There are at least 13 unrelated individuals reported in literature with germline heterozygous variants in PMVK, diagnosed with a type of porokeratosis. Porokeratosis is characterised by keratotic lesions with an atrophic center rimmed by an elevated border. Disease onset is mostly in childhood or adolescence. Based on the available evidence, PMVK should be promoted to Green for Pigmentary skin disorders.
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated cases (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated cases (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES. Age of onset: mostly between 5-10 yo.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man, presented with persistent non-pruritic skin lesions since childhood: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated cases (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska changed review comment from: PMID: 38360177 Polubothu et al., 2024
Patient with Inflammatory linear verrucous epidermal nevus (ILVEN) reported to carry a de novo PMVK variant c.126delG, p.R42fs (NM_006556.4: c.124del, p.Arg42Glyfs*16) - not in gnomAD v4.1.0; method: 250x WES; mosaic in blood and skin, no second variant detected in the same gene in skin.

PMID: 30942823 Atzmony et al., 2019 / PMID: 35853659 Atzmony et al., 2022
Report of 2 patients with Linear Porokeratosis. Inheritance pattern unknown.
Patient 1: 20 yo man with a germline-heterozygous PMVK c.329G>A, p.R110Q mutation in blood & affected skin. Skin showed a higher mutant allele fraction (Ref:Non-Ref read ratio was 21:15 in blood and 16:61 in tissue). Suggested somatic loss-of-heterozygosity.
Patient 2: 5 yo girl with a germline mutation PMVK c.79G>T, p.Glu27* & a somatic mutation PMVK c.379C>T, p.Gln127* (Ref:Non-Ref = 113:0 in blood, and 119:34 in tissue). Variant p.Glu27* has MAF = 0.0005930 in gnomAD v4.1.0 (Admixed American pop), no homozygotes.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87). PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).; to: PMID: 38360177 Polubothu et al., 2024
Patient with Inflammatory linear verrucous epidermal nevus (ILVEN) reported to carry a de novo PMVK variant c.126delG, p.R42fs (NM_006556.4: c.124del, p.Arg42Glyfs*16) - not in gnomAD v4.1.0; method: 250x WES; mosaic in blood and skin, no second variant detected in the same gene in skin.

PMID: 30942823 Atzmony et al., 2019 / PMID: 35853659 Atzmony et al., 2022
Report of 2 patients with Linear Porokeratosis - plaques distributed along the lines of Blaschko, suggesting cutaneous mosaicism. Inheritance pattern unknown.
Patient 1: 20 yo man with a germline-heterozygous PMVK c.329G>A, p.R110Q mutation in blood & affected skin. Skin showed a higher mutant allele fraction (Ref:Non-Ref read ratio was 21:15 in blood and 16:61 in tissue). Suggested somatic loss-of-heterozygosity.
Patient 2: 5 yo girl with a germline mutation PMVK c.79G>T, p.Glu27* & a somatic mutation PMVK c.379C>T, p.Gln127* (Ref:Non-Ref = 113:0 in blood, and 119:34 in tissue). Variant p.Glu27* has MAF = 0.0005930 in gnomAD v4.1.0 (Admixed American pop), no homozygotes.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87). PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska Phenotypes for gene: PMVK were changed from Porokeratosis 1, multiple types, OMIM:175800 to Porokeratosis 1, multiple types, OMIM:175800; porokeratosis, MONDO:0006602
Pigmentary skin disorders v4.7 PMVK Ida Ertmanska Publications for gene: PMVK were set to 26202976; 27052676
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska commented on gene: PMVK: Comment on list classification: There are 3 unrelated individuals diagnosed with linear porokeratosis / ILVEN with mosaic PMVK variants. 1 individual harboured a mosaic PMVK variant only (vPMID: 38360177), while two patients carried a germline PMVK mutation together with either a somatic PMVK variant, or evidence of loss of heterozygosity (PMID: 30942823). Based on the available evidence, this gene should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: PMVK.
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska Phenotypes for gene: PMVK were changed from Linear porokeratosis to inflammatory linear verrucous epidermal nevus, MONDO:0019318; Porokeratosis 1, multiple types OMIM:175800
Mosaic skin disorders - deep sequencing v3.8 PMVK Ida Ertmanska Publications for gene: PMVK were set to 30942823
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of DSP in 2 five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*;c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of DSP in 2 five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of DSP in 2 five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska edited their review of gene: PMVK: Changed phenotypes to: Porokeratosis 1, multiple types, OMIM:175800, porokeratosis, MONDO:0006602
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska edited their review of gene: PMVK: Changed publications to: 26202976, 27052676, 37315547, 41296516
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska Classified gene: PMVK as Amber List (moderate evidence)
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska Gene: pmvk has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v4.5 PMVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: PMVK.
Pigmentary skin disorders v4.5 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 cases (including related individuals) reported in Table 1. 2 variants (from a family and an individual) recorded in OMIM. These cases do NOT include DSAP/DSP cases though and instead include other subtypes of porokeratosis.

PMID: 27052676 Wang et al 2016
investigated the genetic basis of DSP in two five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.
Sources: Literature; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*;c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of DSP in 2 five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.
Pigmentary skin disorders v4.5 PMVK Ida Ertmanska gene: PMVK was added
gene: PMVK was added to Pigmentary skin disorders. Sources: Literature
Mode of inheritance for gene: PMVK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMVK were set to 26202976; 27052676
Phenotypes for gene: PMVK were set to Porokeratosis 1, multiple types, OMIM:175800
Review for gene: PMVK was set to GREEN
Added comment: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 cases (including related individuals) reported in Table 1. 2 variants (from a family and an individual) recorded in OMIM. These cases do NOT include DSAP/DSP cases though and instead include other subtypes of porokeratosis.

PMID: 27052676 Wang et al 2016
investigated the genetic basis of DSP in two five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.
Sources: Literature
Mosaic skin disorders - deep sequencing v3.7 PMVK Ida Ertmanska reviewed gene: PMVK: Rating: GREEN; Mode of pathogenicity: None; Publications: 30942823, 35853659, 38360177; Phenotypes: inflammatory linear verrucous epidermal nevus, MONDO:0019318, Porokeratosis 1, multiple types OMIM:175800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 TK2 William Macken gene: TK2 was added
gene: TK2 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: NHS GMS
Mode of inheritance for gene: TK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TK2 were set to 22345218 23303857 24198295 31092255 25948719
Phenotypes for gene: TK2 were set to mitochondrial disease; limb girdle muscular dystrophy; congenital muscular dystrophy
Penetrance for gene: TK2 were set to Complete
Review for gene: TK2 was set to GREEN
Added comment: This is already green in mitochondrial disease. It causes limb girdle muscular dystrophy and should be on this panel and the wider related panel other rare neuromuscular
Sources: NHS GMS
Congenital muscular dystrophy v6.1 TK2 William Macken changed review comment from: Sources: NHS GMS; to: Sources: NHS GMS, TK2 is on a mitochondrial panel however, it causes a muscle predominant phenotype and should be present on congenital muscular dystrophy, LGMD and as a consequence other rare neuromuscular disorders and hypotonic infant
Congenital muscular dystrophy v6.1 TK2 William Macken gene: TK2 was added
gene: TK2 was added to Congenital muscular dystrophy. Sources: NHS GMS
Mode of inheritance for gene: TK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TK2 were set to 11687801 18021809 19736010 16831967 36146520
Phenotypes for gene: TK2 were set to Congenital muscular dystrophy; mitochondrial disease; limb girdle muscular dystrophy
Penetrance for gene: TK2 were set to Complete
Mode of pathogenicity for gene: TK2 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: TK2 was set to GREEN
gene: TK2 was marked as current diagnostic
Added comment: Sources: NHS GMS
Mitochondrial disorders v9.36 MT-ATP8 Zornitza Stark reviewed gene: MT-ATP8: Rating: AMBER; Mode of pathogenicity: None; Publications: 24153443, 20207608, 32858252, 33340416, 32858252, 19759059, 22919063; Phenotypes: Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency; Mode of inheritance: MITOCHONDRIAL
Mosaic skin disorders - deep sequencing v3.7 GJA1 Ida Ertmanska changed review comment from: PMID: 27890787 Umegaki-Arao et al., 2017
14-year-old girl with inflammatory linear verrucous epidermal nevus (ILVEN); onset at 1yo, worsening over time. At age 14, she developed widespread erythematous plaques and verrucous plaques along Blaschko’s lines on the extremities and buttocks, as well as palmoplantar hyperkeratosis. Hair, teeth, and nails were not affected.
8 candidate variants detected; GJA1 c.131C>T (p.A44V) was the only candidate mutation detected in affected epidermis but not in white blood cells; detected in 22 of 72 reads (30.5%).
The same variant but germline was reported as causative in erythrokeratodermia variabilis et progressiva (EKVP) in PMID: 25398053 Boyden et al., 2015).; to: PMID: 27890787 Umegaki-Arao et al., 2017
14-year-old girl with inflammatory linear verrucous epidermal nevus (ILVEN); onset at 1yo, worsening over time. At age 14, she developed widespread erythematous plaques and verrucous plaques along Blaschko’s lines on the extremities and buttocks, as well as palmoplantar hyperkeratosis. Hair, teeth, and nails were not affected.
8 candidate variants detected; GJA1 c.131C>T (p.A44V) was the only candidate mutation detected in affected epidermis but not in white blood cells; detected in 22 of 72 reads (30%).
The same variant but germline was reported as causative in erythrokeratodermia variabilis et progressiva (EKVP) in PMID: 25398053 Boyden et al., 2015).
Mosaic skin disorders - deep sequencing v3.7 GJA1 Ida Ertmanska Phenotypes for gene: GJA1 were changed from Inflammatory Linear Verrucous Epidermal Naevi (ILVEN) to inflammatory linear verrucous epidermal nevus, MONDO:0019318
Mosaic skin disorders - deep sequencing v3.6 GJA1 Ida Ertmanska Publications for gene: GJA1 were set to PMID: 27890787
Mosaic skin disorders - deep sequencing v3.5 GJA1 Ida Ertmanska Classified gene: GJA1 as Red List (low evidence)
Mosaic skin disorders - deep sequencing v3.5 GJA1 Ida Ertmanska Added comment: Comment on list classification: As there is only one individual reported in literature with a skin disorder and a mosaic GJA1 variant, this gene should remain Red for Mosaic skin disorders - deep sequencing, until more evidence emerges.
Mosaic skin disorders - deep sequencing v3.5 GJA1 Ida Ertmanska Gene: gja1 has been classified as Red List (Low Evidence).
Mosaic skin disorders - deep sequencing v3.4 GJA1 Ida Ertmanska changed review comment from: PMID: 27890787 Umegaki-Arao et al., 2017
14-year-old girl with inflammatory linear verrucous epidermal nevus (ILVEN); onset at 1yo, worsening over time. At age 14, she developed widespread erythematous plaques and verrucous plaques along Blaschko’s lines on the extremities and buttocks, as well as palmoplantar hyperkeratosis. Hair, teeth, and nails were not affected.
8 candidate variants detected; GJA1 c.131C>T (p.A44V) was the only candidate mutation detected in affected epidermis but not in white blood cells; detected in 22 of 72 reads (30.5%).; to: PMID: 27890787 Umegaki-Arao et al., 2017
14-year-old girl with inflammatory linear verrucous epidermal nevus (ILVEN); onset at 1yo, worsening over time. At age 14, she developed widespread erythematous plaques and verrucous plaques along Blaschko’s lines on the extremities and buttocks, as well as palmoplantar hyperkeratosis. Hair, teeth, and nails were not affected.
8 candidate variants detected; GJA1 c.131C>T (p.A44V) was the only candidate mutation detected in affected epidermis but not in white blood cells; detected in 22 of 72 reads (30.5%).
The same variant but germline was reported as causative in erythrokeratodermia variabilis et progressiva (EKVP) in PMID: 25398053 Boyden et al., 2015).
Mosaic skin disorders - deep sequencing v3.4 GJA1 Ida Ertmanska edited their review of gene: GJA1: Changed rating: RED
Mosaic skin disorders - deep sequencing v3.4 GJA1 Ida Ertmanska reviewed gene: GJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27890787; Phenotypes: inflammatory linear verrucous epidermal nevus, MONDO:0019318; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.191 CYP27A1 Ida Ertmanska Mode of inheritance for gene: CYP27A1 was changed from Other - please specify in evaluation comments to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.640 CPOX Ida Ertmanska Mode of inheritance for gene: CPOX was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.190 SOX3 Sahana Chatakondu reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: Other; Publications: 25402377; Phenotypes: Dyspraxia, Growth Hormone Deficiency, Intellectual Disability, Short stature,; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Vascular skin disorders v2.4 FECH Arina Puzriakova Publications for gene: FECH were set to 7857832; 9649563
Non-acute porphyrias v1.32 FECH Arina Puzriakova Publications for gene: FECH were set to 857832; 16911284; 39969427; 32873934; 38940544; 11753383; 16385445
Mosaic skin disorders - deep sequencing v3.4 CARD14 Arina Puzriakova Publications for gene: CARD14 were set to
Mosaic skin disorders - deep sequencing v3.3 CARD14 Ida Ertmanska Phenotypes for gene: CARD14 were changed from ILVEN (submitted 2 cases) to inflammatory linear verrucous epidermal nevus, MONDO:0019318
Mosaic skin disorders - deep sequencing v3.2 CARD14 Ida Ertmanska Classified gene: CARD14 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v3.2 CARD14 Ida Ertmanska Gene: card14 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: CARD14.
Tag Q4_25_NHS_review tag was added to gene: CARD14.
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated individuals reported with inflammatory linear verrucous epidermal nevus and mosaic variants in CARD14. 2 more cases have been reported without clinical or variant details.; to: Comment on list classification: There are 2 unrelated individuals reported with inflammatory linear verrucous epidermal nevus and mosaic variants in CARD14. 2 more mosaic cases have been reported without clinical or variant details. There is some functional evidence in cell cultures supporting the role of CARD14 in keratinocyte proliferation. Based on available evidence, this gene should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska changed review comment from: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.
Functional evidence - patient 2 keratinocyte culture: WST-1 proliferation assay showed a significant a proliferation rate increase; ELISA showed a significant increase in NF-κB p65 subunit activity.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).; to: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.
Functional evidence: WST-1 proliferation assay showed a significant a proliferation rate increase in SVK14 cells transfected with the mutant CARD14 construct; ELISA showed a significant increase in NF-κB p65 subunit activity in patient 2 keratinocyte culture.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska changed review comment from: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).; to: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.
Functional evidence - patient 2 keratinocyte culture: WST-1 proliferation assay showed a significant a proliferation rate increase; ELISA showed a significant increase in NF-κB p65 subunit activity.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska edited their review of gene: CARD14: Added comment: Comment on list classification: There are 2 unrelated individuals reported with inflammatory linear verrucous epidermal nevus and mosaic variants in CARD14. 2 more cases have been reported without clinical or variant details.; Changed rating: GREEN; Changed publications to: 34116062, 35853659, 38360177
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska changed review comment from: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.
This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?; to: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska reviewed gene: CARD14: Rating: AMBER; Mode of pathogenicity: None; Publications: 34116062, 35853659; Phenotypes: inflammatory linear verrucous epidermal nevus, MONDO:0019318; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Vascular skin disorders v2.3 FECH Ida Ertmanska reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 10954661, 9649563; Phenotypes: Protoporphyria, erythropoietic,1 OMIM:177000, protoporphyria, erythropoietic, 1 MONDO:0008319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Iron metabolism disorders - NOT common HFE mutations v3.1 FECH Ida Ertmanska changed review comment from: FECH product, ferrochelatase, is an enzyme in the heme biosynthesis pathway that catalyses insertion of an iron atom into protoporphyrin IX. According to Barman-Aksoezen et al., 2017 (PMID: 28185024) Erythropoietic protoporphyria (EPP) patients 'frequently exhibit low serum iron and a microcytic hypochromic anemia'. However, as reviewed by Sharon Whatley, the iron deficiency is often mild.

PMID: 21659066 Morais et al., 2011
Portuguese male proband with compound het mutations c.1052delA, p.Glu351Glyfs*6 and IVS3-48T>C in FECH - diagnosed with EPP, presented with acute episodes of photosensitivity, microcytic anemia and mild hepatic dysfunction.

PMID: 20412370 Wahlin et al., 2011
Swedish cohort of 51 EPP patients - 44% had low ferritin levels.

PMID: 28614581 Balwani et al., 2017
US report of 226 patients, 37.4% of EPP patients were anemic.; to: FECH product, ferrochelatase, is an enzyme in the heme biosynthesis pathway that catalyses insertion of an iron atom into protoporphyrin IX. According to Barman-Aksoezen et al., 2017 (PMID: 28185024) Erythropoietic protoporphyria (EPP) patients 'frequently exhibit low serum iron and a microcytic hypochromic anemia'. However, as reviewed by Sharon Whatley, the iron deficiency is often mild (low to low-normal serum iron).

PMID: 21659066 Morais et al., 2011
Portuguese male proband with compound het mutations c.1052delA, p.Glu351Glyfs*6 and IVS3-48T>C in FECH - diagnosed with EPP, presented with acute episodes of photosensitivity, microcytic anemia and mild hepatic dysfunction.

PMID: 20412370 Wahlin et al., 2011
Swedish cohort of 51 EPP patients - 44% had low ferritin levels.

PMID: 28614581 Balwani et al., 2017
US report of 226 patients, 37.4% of EPP patients were anemic.

FECH is associated with Protoporphyria, erythropoietic,1 OMIM:177000 (OMIM accessed 26th Nov 2025).
Optic neuropathy v5.26 NDUFAF8 Neringa Jurkute gene: NDUFAF8 was added
gene: NDUFAF8 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF8 were set to PMID: 41234160
Phenotypes for gene: NDUFAF8 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFAF8 was set to Other
Review for gene: NDUFAF8 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
3 unrelated families were carrying NDUFS7 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFAF4 Neringa Jurkute gene: NDUFAF4 was added
gene: NDUFAF4 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFAF4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF4 were set to PMID: 41234160
Phenotypes for gene: NDUFAF4 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFAF4 was set to Other
Review for gene: NDUFAF4 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
2 unrelated families were carrying NDUFS7 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFAF3 Neringa Jurkute gene: NDUFAF3 was added
gene: NDUFAF3 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFAF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF3 were set to PMID: 41234160
Phenotypes for gene: NDUFAF3 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFAF3 was set to Other
Review for gene: NDUFAF3 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
1 family were carrying NDUFAF3 pathogenic variants and affected individual was diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFAF2 Neringa Jurkute gene: NDUFAF2 was added
gene: NDUFAF2 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFAF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF2 were set to PMID: 41234160
Phenotypes for gene: NDUFAF2 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFAF2 was set to Other
Review for gene: NDUFAF2 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
2 unrelated families were carrying NDUFAF2 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFB11 Neringa Jurkute gene: NDUFB11 was added
gene: NDUFB11 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFB11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NDUFB11 were set to PMID: 41234160
Phenotypes for gene: NDUFB11 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFB11 was set to Other
Review for gene: NDUFB11 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
1 family were carrying NDUFB11 pathogenic variant and affected individual was diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFA10 Neringa Jurkute gene: NDUFA10 was added
gene: NDUFA10 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFA10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA10 were set to PMID: 41234160
Phenotypes for gene: NDUFA10 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFA10 was set to Other
Review for gene: NDUFA10 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
3 unrelated families were carrying NDUFA10 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFA1 Neringa Jurkute gene: NDUFA1 was added
gene: NDUFA1 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NDUFA1 were set to PMID: 41234160
Phenotypes for gene: NDUFA1 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFA1 was set to Other
Review for gene: NDUFA1 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
3 unrelated families were carrying NDUFA1 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFV2 Neringa Jurkute gene: NDUFV2 was added
gene: NDUFV2 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFV2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFV2 were set to PMID: 41234160
Phenotypes for gene: NDUFV2 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFV2 was set to Other
Review for gene: NDUFV2 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
1 family was carrying NDUFV2 pathogenic variant and affected individual was diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFV1 Neringa Jurkute gene: NDUFV1 was added
gene: NDUFV1 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFV1 were set to PMID: 41234160
Phenotypes for gene: NDUFV1 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFV1 was set to Other
Review for gene: NDUFV1 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
1 family was carrying NDUFV1 pathogenic variant and affected individual was diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFS7 Neringa Jurkute gene: NDUFS7 was added
gene: NDUFS7 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFS7 were set to PMID: 41234160
Phenotypes for gene: NDUFS7 were set to Optic neuropathy; optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFS7 was set to Other
Review for gene: NDUFS7 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
5 unrelated families were carrying NDUFS7 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NSUN3 Neringa Jurkute gene: NSUN3 was added
gene: NSUN3 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NSUN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSUN3 were set to PMID: 38790159; PMID: 40465263
Phenotypes for gene: NSUN3 were set to optic neuropathy; optic atrophy; LHON; LHON-like
Mode of pathogenicity for gene: NSUN3 was set to Other
Review for gene: NSUN3 was set to GREEN
Added comment: PMID: 40465263
Biallelic NSUN3 variants were reported to be associated with an early onset severe mitochondrial disorder characterized by combined mitochondrial respiratory chain complex deficiency.
2 individuals from the paper presented with LHON-like phenotype;
5 with attenuated
2 syndromic
Optic atrophy was unifying feature.

PMID: 38790159
Mutations in NSUN3, a Mitochondrial Methyl Transferase Gene, Cause Inherited Optic Neuropathy
Reports early onset optic neuropathy

A follow up par
Sources: Literature, Research
Severe microcephaly v8.21 KBTBD2 Arina Puzriakova Classified gene: KBTBD2 as Amber List (moderate evidence)
Severe microcephaly v8.21 KBTBD2 Arina Puzriakova Added comment: Comment on list classification: Adding to this panel as Amber as despite there being 3 unrelated cases, a specific description of the phenotype is not provided in one case (GDX6) making it challenging to make genotype-phenotype correlations. Microcephaly is reported in the other two individuals, however the severity is not specified. Based on the current evidence additional support is needed before this gene can be added to a diagnostic panel.
Severe microcephaly v8.21 KBTBD2 Arina Puzriakova Gene: kbtbd2 has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.7 KBTBD2 Arina Puzriakova Classified gene: KBTBD2 as Amber List (moderate evidence)
Monogenic diabetes v3.7 KBTBD2 Arina Puzriakova Added comment: Comment on list classification: Adding to this panel as Amber as despite there being 3 unrelated cases, a specific description of the phenotype is not provided in one case (GDX6) making it challenging to make genotype-phenotype correlations.

There is only one reported case with diabetes, although it is possible that the other individuals may develop diabetes later in life. It is worth noting that this association is supported by the mouse model where insulin resistance and severe diabetes is observed. However, based on the current evidence additional support is needed before this gene can be added to a diagnostic panel.
Monogenic diabetes v3.7 KBTBD2 Arina Puzriakova Gene: kbtbd2 has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.6 KBTBD2 Arina Puzriakova gene: KBTBD2 was added
gene: KBTBD2 was added to Monogenic diabetes. Sources: Literature
Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KBTBD2 were set to 39313616
Phenotypes for gene: KBTBD2 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: KBTBD2 was set to AMBER
Added comment: PMID: 39313616 (2024) - 3 unrelated cases with biallelic variants in this gene. Variants were LOF/missense compound het in 2 cases and homozygous LOF in the other case. Phenotypes include growth retardation (3/3), hyperglycemia and diabetes in an adolescent individual (1/3 - others thought to be too young to have developed diabetes), microcephaly (2/2), motor developmental delay. One individual had cardiomyopathy but also harboured an additional variant in MYH7 which could be contributing this phenotype.

Knock down in mice resulted in elevated expression of p85α and a phenotype involving lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes and growth retardation, which recapitulates some of the features observed in human cases.
Sources: Literature
Severe microcephaly v8.20 KBTBD2 Arina Puzriakova gene: KBTBD2 was added
gene: KBTBD2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KBTBD2 were set to 39313616
Phenotypes for gene: KBTBD2 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: KBTBD2 was set to AMBER
Added comment: PMID: 39313616 (2024) - 3 unrelated cases with biallelic variants in this gene. Variants were LOF/missense compound het in 2 cases and homozygous LOF in the other case. Phenotypes include growth retardation (3/3), hyperglycemia and diabetes in an adolescent individual (1/3 - others thought to be too young to have developed diabetes), microcephaly (2/2), motor developmental delay. One individual had cardiomyopathy but also harboured an additional variant in MYH7 which could be contributing this phenotype.

Knock down in mice resulted in elevated expression of p85α and a phenotype involving lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes and growth retardation, which recapitulates some of the features observed in human cases.
Sources: Literature
Iron metabolism disorders - NOT common HFE mutations v3.1 FECH Ida Ertmanska reviewed gene: FECH: Rating: AMBER; Mode of pathogenicity: None; Publications: 20412370, 21659066, 28185024, 28614581; Phenotypes: Protoporphyria, erythropoietic,1 OMIM:177000, protoporphyria, erythropoietic, 1 MONDO:0008319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Vascular skin disorders v2.3 FECH Ida Ertmanska Publications for gene: FECH were set to 9649563
Vascular skin disorders v2.2 FECH Ida Ertmanska Phenotypes for gene: FECH were changed from Protoporphyria, erythropoietic, 1, OMIM:177000 to Protoporphyria, erythropoietic, 1, OMIM:177000; protoporphyria, erythropoietic, 1, MONDO:0008319
Rare genetic inflammatory skin disorders v4.7 FECH Ida Ertmanska Tag curated_removed tag was added to gene: FECH.
Rare genetic inflammatory skin disorders v4.7 FECH Ida Ertmanska commented on gene: FECH
Non-acute porphyrias v1.31 FECH Ida Ertmanska Publications for gene: FECH were set to
Non-acute porphyrias v1.30 FECH Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 26th Nov 2025.
Non-acute porphyrias v1.30 FECH Ida Ertmanska Phenotypes for gene: FECH were changed from Protoporphyria, erythropoietic,1 OMIM:177000; protoporphyria, erythropoietic, 1 MONDO:0008319 to Protoporphyria, erythropoietic,1 OMIM:177000; protoporphyria, erythropoietic, 1 MONDO:0008319
Cutaneous photosensitivity with a likely genetic cause v3.15 FECH Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 26th Nov 2025.
Cutaneous photosensitivity with a likely genetic cause v3.15 FECH Ida Ertmanska Phenotypes for gene: FECH were changed from Erythropoietic Protoporphyria; Protoporphyria, erythropoietic, autosomal recessive, 177000 to Protoporphyria, erythropoietic, 1, OMIM:177000; protoporphyria, erythropoietic, 1, MONDO:0008319
Cutaneous photosensitivity with a likely genetic cause v3.14 FECH Ida Ertmanska Publications for gene: FECH were set to
Fetal anomalies v6.117 ITGAV Eleanor Williams Phenotypes for gene: ITGAV were changed from Syndromic disease, MONDO:0002254 to syndromic disease, MONDO:0002254
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Eleanor Williams Tag watchlist tag was added to gene: SVIL.
Arthrogryposis v9.14 SVIL Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 26th Nov 2025
Arthrogryposis v9.14 SVIL Eleanor Williams Phenotypes for gene: SVIL were changed from Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620 to Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620
Congenital myopathy v6.40 SVIL Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 26th Nov 2025
Congenital myopathy v6.40 SVIL Eleanor Williams Phenotypes for gene: SVIL were changed from Myofibrillar myopathy 10, OMIM:619040 to Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620
Arthrogryposis v9.13 SVIL Eleanor Williams Tag watchlist tag was added to gene: SVIL.
Arthrogryposis v9.13 SVIL Eleanor Williams Phenotypes for gene: SVIL were changed from Myofibrillar myopathy 10, OMIM:619040 to Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620
Hypertrophic cardiomyopathy v5.17 SVIL Eleanor Williams Publications for gene: SVIL were set to 39966646
Hypertrophic cardiomyopathy v5.16 SVIL Eleanor Williams Added comment: Comment on publications: PMID:36778260 is a preprint of PMID:39966646
Hypertrophic cardiomyopathy v5.16 SVIL Eleanor Williams Publications for gene: SVIL were set to 39966646
Hypertrophic cardiomyopathy v5.15 SVIL Eleanor Williams Publications for gene: SVIL were set to PMID: 36778260
Retinal disorders v8.74 RNU6-9 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU6-9.
Tag Q3_25_promote_green tag was added to gene: RNU6-9.
Retinal disorders v8.74 RNU6-8 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU6-8.
Tag Q3_25_promote_green tag was added to gene: RNU6-8.
Retinal disorders v8.74 RNU4-2 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU4-2.
Tag Q3_25_promote_green tag was added to gene: RNU4-2.
Retinal disorders v8.74 RNU6-2 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU6-2.
Tag Q3_25_promote_green tag was added to gene: RNU6-2.
Rare genetic inflammatory skin disorders v4.7 FECH Ida Ertmanska Phenotypes for gene: FECH were changed from 177000 to Protoporphyria, erythropoietic, 1, OMIM:177000
Retinal disorders v8.74 RNU6-1 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU6-1.
Tag Q3_25_promote_green tag was added to gene: RNU6-1.
Monogenic hearing loss v5.47 TBX2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TBX2.
Monogenic hearing loss v5.47 TBX2 Ida Ertmanska edited their review of gene: TBX2: Added comment: Comment on list classification: As the article by Hua et al. has now been published (PMID: 40962492, Sep 2025), there is enough evidence to promote this gene to Green for Monogenic hearing loss (2 unrelated probands with nonsense variants in TBX2 & a supportive mouse model).; Changed rating: GREEN; Changed publications to: 15459098, 20206336, 21271665, 22052739, 35508658, 40962492
Monogenic hearing loss v5.47 TBX2 Ida Ertmanska changed review comment from: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple.

A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS.

Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern.

Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood.

Functional data:
Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs*42) knock-in mice did not show any signs of hearing loss.

TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss.
Sources: Literature; to: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple.

A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS.

Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern.

Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood.

Functional data:
Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs*42) knock-in mice did not show any signs of hearing loss.

TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss.
Sources: Literature
Severe microcephaly v8.19 GPKOW Eleanor Williams changed review comment from: To date, three GPKOW variants have been associated with male-lethal microcephaly with intrauterine growth restriction (PMID: 28612833; 40221893).

Carroll et al 2017 (PMID: 28612833) report a splicing variant (NM_015698.4: c.331+5G>A) in a multigenerational family, with four female carriers, all of those who could be measured have short stature and microcephaly. Male-lethal microcephaly with intrauterine growth restriction was seen in three males within the family and two further male fetuses were terminated after ultrasound diagnosis of intrauterine growth restriction (IUGR). Analysis of patient IV-1 (terminated fetus), showed the presence of a hemizygous NM_015698.4: c.331+5G>A, which had been inherited from his carrier mother.

Two further GPKOW variants were identified by Mok, et al 2025 (PMID: 40221893), in three individuals from two families. These frameshift variants were in the last exon of GPKOW (NM_015698.5: c.1329dupG, p.(Arg441SerfsTer30) and c.1323_1324del, p.(Ser444GlufsTer28)). The male carriers of NM_015698.5: c.1329dupG had IUGR, and other features, but not microcephaly nor lethality. The male carrier of c.1323_1324del had IUGR and microcephaly and was terminated at (33/40). The mothers of these cases had short stature, microcephaly (in one case) and other phenotypic features.

Extensive support from functional studies were also presented in PMID: 28612833; 40221893.; to: To date, three GPKOW variants have been associated with male-lethal microcephaly with intrauterine growth restriction (PMID: 28612833; 40221893).

Carroll et al 2017 (PMID: 28612833) report a splicing variant (NM_015698.4: c.331+5G>A) in a multigenerational family, with four female carriers, all of those who could be measured have short stature and microcephaly. Male-lethal microcephaly with intrauterine growth restriction was seen in three males within the family and two further male fetuses were terminated after ultrasound diagnosis of intrauterine growth restriction (IUGR). Analysis of patient IV-1 (terminated fetus), showed the presence of a hemizygous NM_015698.4: c.331+5G>A, which had been inherited from his carrier mother.

Two further GPKOW variants were identified by Mok, et al 2025 (PMID: 40221893), in three individuals from two families. These frameshift variants were in the last exon of GPKOW (NM_015698.5: c.1329dupG, p.(Arg441SerfsTer30) and c.1323_1324del, p.(Ser444GlufsTer28)). The male carriers of NM_015698.5: c.1329dupG had IUGR, and other features, but not microcephaly nor lethality. The male carrier of c.1323_1324del had IUGR and microcephaly and was terminated at (33/40). The mothers of these cases had short stature, microcephaly (in one case) and other phenotypic features.

Extensive support from functional studies were also presented in PMID: 28612833; 40221893.
Fetal anomalies v6.116 GPKOW Eleanor Williams edited their review of gene: GPKOW: Changed rating: GREEN
Fetal anomalies v6.116 GPKOW Eleanor Williams edited their review of gene: GPKOW: Changed rating: AMBER
Hypertrophic cardiomyopathy v5.14 SVIL Ida Ertmanska Phenotypes for gene: SVIL were changed from HCM to hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy v5.13 SVIL Ida Ertmanska Classified gene: SVIL as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v5.13 SVIL Ida Ertmanska Gene: svil has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska changed review comment from: Comment on list classification: The main piece of evidence for this gene-disease association is a GWAS study, with very limited co-segregation evidence (PMID: 39966646). There are no other cases reported with Hypertrophic cardiomyopathy and heterozygous variants in SVIL. Individuals homozygous for nonsense variants in SVIL have been reported, but the myopathy presentation includes very mild to no cardiac involvement (PMID: 32779703). Based on available evidence, this gene should be rated Amber for Hypertrophic cardiomyopathy, until more evidence emerges.; to: Comment on list classification: The main piece of evidence for this gene-disease association is a GWAS study, with no clinical details and limited co-segregation evidence (PMID: 39966646). There are no other cases reported with Hypertrophic cardiomyopathy and heterozygous variants in SVIL. Individuals homozygous for nonsense variants in SVIL have been reported, but the myopathy presentation includes very mild to no cardiac involvement (PMID: 32779703). Based on available evidence, this gene should be rated Amber for Hypertrophic cardiomyopathy, until more evidence emerges.
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska edited their review of gene: SVIL: Added comment: Comment on list classification: The main piece of evidence for this gene-disease association is a GWAS study, with very limited co-segregation evidence (PMID: 39966646). There are no other cases reported with Hypertrophic cardiomyopathy and heterozygous variants in SVIL. Individuals homozygous for nonsense variants in SVIL have been reported, but the myopathy presentation includes very mild to no cardiac involvement (PMID: 32779703). Based on available evidence, this gene should be rated Amber for Hypertrophic cardiomyopathy, until more evidence emerges.; Changed rating: AMBER
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska changed review comment from: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myopathy with myofibrillar disorganization, homozygous for truncating variants in SVIL. Very mild cardiac involvement: Slightly hypertrophic left ventricular wall 2/4, slight tricuspid regurgitation 2/4; Increased basal wall thickness (30mm) in Individual 1 - noted on cardiac MRI at age 27.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).; to: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL. Numerous other rare nonsense variants in SVIL were also reported in the non-HCM control cohort (see supplementary table 19).
Limited evidence of segregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myopathy with myofibrillar disorganization, homozygous for truncating variants in SVIL. Very mild cardiac involvement: Slightly hypertrophic left ventricular wall 2/4, slight tricuspid regurgitation 2/4; Increased basal wall thickness (30mm) in Individual 1 - noted on cardiac MRI at age 27.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska changed review comment from: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).; to: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myopathy with myofibrillar disorganization, homozygous for truncating variants in SVIL. Very mild cardiac involvement: Slightly hypertrophic left ventricular wall 2/4, slight tricuspid regurgitation 2/4; Increased basal wall thickness (30mm) in Individual 1 - noted on cardiac MRI at age 27.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Ida Ertmanska changed review comment from: PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myofibrillar myopathy. Muscle biopsy showed Structural myopathy with prominent lobulated type 1 fibres, myofibrillar disintegration and signs of altered proteostasis/impaired autophagy in all 4 affected individuals. All patients showed increased creatine kinase levels, but no or minor muscle weakness. Variable presentation, including muscle pain, slowly progressive stiffness, exercise intolerance, as well as distinct anomalies of neck and shoulder girdle; 3/4 patients presented with contractures. Very mild heart involvement.
Seq method: WES/ targeted exome with Sanger confirmation.
Family 1: Lebanese, 2 sibs affected, both homozygous for c.4812C>A, p.(Tyr1604*) - variant not in gnomAD v4.1.0. Symptom onset: childhood/adolescence.
Family 2: Turkish, 2 sibs affected, both homozygous for c.3578_3579del, p.(Val1193Glufs*46) - variant not in gnomAD v4.1.0; symptoms onset at birth/ in infancy.

SVIL is associated with AR Myofibrillar myopathy 10, MIM: 619040 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myopathy with myofibrillar disorganization. Muscle biopsy showed Structural myopathy with prominent lobulated type 1 fibres, myofibrillar disintegration and signs of altered proteostasis/impaired autophagy in all 4 affected individuals. All patients showed increased creatine kinase levels, but no or minor muscle weakness. Variable presentation, including muscle pain, slowly progressive stiffness, exercise intolerance, as well as distinct anomalies of neck and shoulder girdle; 3/4 patients presented with contractures. Very mild heart involvement.
Seq method: WES/ targeted exome with Sanger confirmation.
Family 1: Lebanese, 2 sibs affected, both homozygous for c.4812C>A, p.(Tyr1604*) - variant not in gnomAD v4.1.0. Symptom onset: childhood/adolescence.
Family 2: Turkish, 2 sibs affected, both homozygous for c.3578_3579del, p.(Val1193Glufs*46) - variant not in gnomAD v4.1.0; symptoms onset at birth/ in infancy.

SVIL is associated with AR Myofibrillar myopathy 10, MIM: 619040 (OMIM accessed 24th Nov 2025).
Sources: Literature
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska changed review comment from: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).; to: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska reviewed gene: SVIL: Rating: RED; Mode of pathogenicity: None; Publications: 36778260, 39966646; Phenotypes: hypertrophic cardiomyopathy, MONDO:0005045; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Ida Ertmanska changed review comment from: Comment on list classification: There are 4 individuals from 2 unrelated families reported in literature with homozygous nonsense variants in SVIL, diagnosed with myofibrillar myopathy. This gene should be rated Amber on Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies until more evidence emerges.; to: Comment on list classification: There are 4 individuals from 2 unrelated families reported in literature with homozygous nonsense variants in SVIL, diagnosed with myopathy with myofibrillar disorganization. This gene should be rated Amber on Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies until more evidence emerges.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Ida Ertmanska edited their review of gene: SVIL: Changed phenotypes to: Myofibrillar myopathy 10, OMIM:619040, myofibrillar myopathy 10, MONDO:0033620
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Ida Ertmanska Phenotypes for gene: SVIL were changed from Myofibrillar myopathy 10, OMIM:619040 to Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.21 SVIL Ida Ertmanska Classified gene: SVIL as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.21 SVIL Ida Ertmanska Added comment: Comment on list classification: There are 4 individuals from 2 unrelated families reported in literature with homozygous nonsense variants in SVIL, diagnosed with myofibrillar myopathy. This gene should be rated Amber on Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies until more evidence emerges.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.21 SVIL Ida Ertmanska Gene: svil has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.20 SVIL Ida Ertmanska edited their review of gene: SVIL: Changed rating: AMBER; Changed publications to: 32779703
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.20 SVIL Ida Ertmanska changed review comment from: Sources: Literature; to: PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myofibrillar myopathy. Muscle biopsy showed Structural myopathy with prominent lobulated type 1 fibres, myofibrillar disintegration and signs of altered proteostasis/impaired autophagy in all 4 affected individuals. All patients showed increased creatine kinase levels, but no or minor muscle weakness. Variable presentation, including muscle pain, slowly progressive stiffness, exercise intolerance, as well as distinct anomalies of neck and shoulder girdle; 3/4 patients presented with contractures. Very mild heart involvement.
Seq method: WES/ targeted exome with Sanger confirmation.
Family 1: Lebanese, 2 sibs affected, both homozygous for c.4812C>A, p.(Tyr1604*) - variant not in gnomAD v4.1.0. Symptom onset: childhood/adolescence.
Family 2: Turkish, 2 sibs affected, both homozygous for c.3578_3579del, p.(Val1193Glufs*46) - variant not in gnomAD v4.1.0; symptoms onset at birth/ in infancy.

SVIL is associated with AR Myofibrillar myopathy 10, MIM: 619040 (OMIM accessed 24th Nov 2025).
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.20 SVIL Ida Ertmanska gene: SVIL was added
gene: SVIL was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature
Mode of inheritance for gene: SVIL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SVIL were set to Myofibrillar myopathy 10, OMIM:619040
Review for gene: SVIL was set to GREEN
Added comment: Sources: Literature
DDG2P v6.8 CCNK Ida Ertmanska commented on gene: CCNK
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- knockdown mouse model showed deficient neural progenitor cell proliferation and enhanced apoptotic cell death.

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects. Variant not reported in gnomAD v4.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms. Variant not reported in gnomAD v4.
Functional evidence: Ccnk +/- knockdown mouse model showed deficient neural progenitor cell proliferation and enhanced apoptotic cell death.

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate features of human disease. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.; to: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are also several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate features of human disease. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.190 CCNK Ida Ertmanska commented on gene: CCNK: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate features of human disease. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.190 CCNK Ida Ertmanska Deleted their comment
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- mouse model

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- knockdown mouse model showed deficient neural progenitor cell proliferation and enhanced apoptotic cell death.

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska commented on gene: CCNK: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate the human disease phenotype. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- mouse model

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska edited their review of gene: CCNK: Changed phenotypes to: ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147, intellectual developmental disorder with hypertelorism and distinctive facies, MONDO:0029143
Intellectual disability v9.190 CCNK Ida Ertmanska Phenotypes for gene: CCNK were changed from ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147 to ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147; intellectual developmental disorder with hypertelorism and distinctive facies, MONDO:0029143
Intellectual disability v9.189 CCNK Ida Ertmanska Classified gene: CCNK as Amber List (moderate evidence)
Intellectual disability v9.189 CCNK Ida Ertmanska Gene: ccnk has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.188 CCNK Ida Ertmanska gene: CCNK was added
gene: CCNK was added to Intellectual disability. Sources: Literature
Q4_25_promote_green tags were added to gene: CCNK.
Mode of inheritance for gene: CCNK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CCNK were set to 30122539; 35063350; 37597256; 41101726
Phenotypes for gene: CCNK were set to ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147
Review for gene: CCNK was set to GREEN
Added comment: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.
Sources: Literature
Vici Syndrome and other autophagy disorders v1.3 Eleanor Williams List of related panels changed from to
Thoracic dystrophies v1.22 Eleanor Williams List of related panels changed from to
Structural basal ganglia disorders v1.40 Eleanor Williams List of related panels changed from to
Skeletal Muscle Channelopathies v1.48 Eleanor Williams List of related panels changed from to
Severe multi-system atopic disease with high IgE v1.9 Eleanor Williams List of related panels changed from to
Radial dysplasia v1.25 Eleanor Williams List of related panels changed from to
Pityriasis rubra pilaris v1.3 Eleanor Williams List of related panels changed from to
Peeling skin syndrome v1.5 Eleanor Williams List of related panels changed from to
Palmoplantar keratoderma and erythrokeratodermas v1.35 Eleanor Williams List of related panels changed from to
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Ocular coloboma v1.51 Eleanor Williams List of related panels changed from to
Ocular and oculo-cutaneous albinism v1.24 Eleanor Williams List of related panels changed from to
Non-syndromic hypotrichosis v1.15 Eleanor Williams List of related panels changed from to
Non-CF bronchiectasis v1.32 Eleanor Williams List of related panels changed from to
Neurotransmitter disorders v1.11 Eleanor Williams List of related panels changed from to
Neurofibromatosis Type 1 v1.33 Eleanor Williams List of related panels changed from to
Multiple lipomas v1.2 Eleanor Williams List of related panels changed from to
Multiple Epiphyseal Dysplasia v1.7 Eleanor Williams List of related panels changed from to
Multi-organ autoimmune diabetes v1.12 Eleanor Williams List of related panels changed from to
Mucopolysaccharideosis, Gaucher, Fabry v1.5 Eleanor Williams List of related panels changed from to
Left Ventricular Noncompaction Cardiomyopathy v1.5 Eleanor Williams List of related panels changed from to
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Kabuki syndrome v1.6 Eleanor Williams List of related panels changed from to
IUGR and IGF abnormalities v1.70 Eleanor Williams List of related panels changed from to
Inherited non-medullary thyroid cancer v1.8 Eleanor Williams List of related panels changed from to
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Hydroa vacciniforme v1.3 Eleanor Williams List of related panels changed from to
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Ectodermal dysplasia without a known gene mutation v1.30 Eleanor Williams List of related panels changed from to
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Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.84 Eleanor Williams List of related panels changed from to
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.68 Eleanor Williams List of related panels changed from to
Early onset or syndromic epilepsy v8.76 RANBP2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.; to: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy with seizures, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.
Early onset or syndromic epilepsy v8.76 RANBP2 Ida Ertmanska Phenotypes for gene: RANBP2 were changed from {Encephalopathy, acute, infection-induced, 3, susceptibility to} 608033 to {Encephalopathy, acute, infection-induced, 3, susceptibility to}, OMIM:608033
Early onset or syndromic epilepsy v8.75 RANBP2 Ida Ertmanska Publications for gene: RANBP2 were set to
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska edited their review of gene: RANBP2: Changed publications to: 34377735, 36621064, 38050538, 40538544
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion on this panel.; to: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska commented on gene: RANBP2: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion on this panel.
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska changed review comment from: RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025).

PMID: 40538544 Varghese et al., 2025
Case 1 - previously healthy 23-month-old female presented with lethargy and acute-onset encephalopathy, following a 2-day fever. Brain MRI consistent with Acute necrotizing encephalopathy (ANE). She presented with another episode of acute-onset encephalopathy at 4yrs 10 mo; she remains non-verbal and non-ambulatory. Family history: 2 maternal uncles, deceased at 16 & 22 months old - both with working diagnoses of Leigh-like disease. Patient was heterozygous for c.1754C>G, p.Thr585Met (maternally inherited) - rare in gnomAD v4.1.0 (2 heterozygotes), Revel score = 0.18 Benign Moderate. Seq method: rapid Trio WES.

Case 2 - A 24-month-old male, previously described in PMID: 36632547 Olubiyi et al., 2022. Patient presented with acute encephalopathy, seizures, and emesis. Positive for respiratory SARS-CoV-2; brain MRI concerning for ANE; discharged from hospital on day 7. Presented again at 30 months with acute-onset encephalopathy, delirium, and seizures. At 4.5yrs, patient is much improved - he was forming sentences and ambulated independently with a mildly ataxic gait, WPPSI-IV IQ 65 (mild ID). Heterozygous for RANBP2 c.1966A>G (p.Ile656Val) - maternally inherited; variant rare in gnomAD v4.1.0 (1 heterozygote), Revel score = 0.31 Uncertain.

PMID: 38050538 Li et al., 2023
Report of 1‐year‐old girl - presented with influenza‐associated encephalopathy after which she made a full recovery; followed by severe acute respiratory syndrome coronavirus 2 infection - the patient presented with seizures and deteriorating mental status. Brain MRI revealed necrotic lesions. WES revealed heterozygous c.1754C>T, p.Thr585Met and c.6952G>A, p.Asp2318Asn variants in RANBP2 (presumed in cis?). Variant c.6952G>A, p.Asp2318Asn is not in gnomAD v4, Revel score = 0.34 Benign Supporting.
The penetrance of RANBP2 missense variants is estimated at around 40%.

PMID: 36621064 Forest et al., 2023
Report of a 10-year-old girl with acute onset of decreased level of consciousness and fever. Brain and spinal cord MRI confirmed extensive areas of cytotoxic edema; MRI suggestive for necrosis. Diagnosed with ANE associated with Sars-CoV-2 infection. First episode noted to be at 2yo - trigerred by Influenza A. WES revealed a de novo c.1754C>T p.(Thr585Met) mutation in RANBP2.

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Patient recovered after 42 days. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.; to: PMID: 40538544 Varghese et al., 2025
Case 1 - previously healthy 23-month-old female presented with lethargy and acute-onset encephalopathy, following a 2-day fever. Brain MRI consistent with Acute necrotizing encephalopathy (ANE). She presented with another episode of acute-onset encephalopathy at 4yrs 10 mo; she remains non-verbal and non-ambulatory. Family history: 2 maternal uncles, deceased at 16 & 22 months old - both with working diagnoses of Leigh-like disease. Patient was heterozygous for c.1754C>G, p.Thr585Met (maternally inherited) - rare in gnomAD v4.1.0 (2 heterozygotes), Revel score = 0.18 Benign Moderate. Seq method: rapid Trio WES.

Case 2 - A 24-month-old male, previously described in PMID: 36632547 Olubiyi et al., 2022. Patient presented with acute encephalopathy, seizures, and emesis. Positive for respiratory SARS-CoV-2; brain MRI concerning for ANE; discharged from hospital on day 7. Presented again at 30 months with acute-onset encephalopathy, delirium, and seizures. At 4.5yrs, patient is much improved - he was forming sentences and ambulated independently with a mildly ataxic gait, WPPSI-IV IQ 65 (mild ID). Heterozygous for RANBP2 c.1966A>G (p.Ile656Val) - maternally inherited; variant rare in gnomAD v4.1.0 (1 heterozygote), Revel score = 0.31 Uncertain.

PMID: 38050538 Li et al., 2023
Report of 1‐year‐old girl - presented with influenza‐associated encephalopathy after which she made a full recovery; followed by severe acute respiratory syndrome coronavirus 2 infection - the patient presented with seizures and deteriorating mental status. Brain MRI revealed necrotic lesions. WES revealed heterozygous c.1754C>T, p.Thr585Met and c.6952G>A, p.Asp2318Asn variants in RANBP2 (presumed in cis?). Variant c.6952G>A, p.Asp2318Asn is not in gnomAD v4, Revel score = 0.34 Benign Supporting.
The penetrance of RANBP2 missense variants is estimated at around 40%.

PMID: 36621064 Forest et al., 2023
Report of a 10-year-old girl with acute onset of decreased level of consciousness and fever. Brain and spinal cord MRI confirmed extensive areas of cytotoxic edema; MRI suggestive for necrosis. Diagnosed with ANE associated with Sars-CoV-2 infection. First episode noted to be at 2yo - trigerred by Influenza A. WES revealed a de novo c.1754C>T p.(Thr585Met) mutation in RANBP2.

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Patient recovered after 42 days. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.

RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025). RANBP2 association with familial acute necrotizing encephalopathy has been classified as Moderate in ClinGen by the Epilepsy Expert panel (April 2024) and Limited for Leigh Syndrome (Mitochondrial Diseases Expert Panel, June 2021).
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska changed review comment from: RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025).

PMID: 40538544 Varghese et al., 2025
Case 1 - previously healthy 23-month-old female presented with lethargy and acute-onset encephalopathy, following a 2-day fever. Brain MRI consistent with Acute necrotizing encephalopathy (ANE). She presented with another episode of acute-onset encephalopathy at 4yrs 10 mo; she remains non-verbal and non-ambulatory. Family history: 2 maternal uncles, deceased at 16 & 22 months old - both with working diagnoses of Leigh-like disease. Patient was heterozygous for c.1754C>G, p.Thr585Met (maternally inherited) - rare in gnomAD v4.1.0 (2 heterozygotes), Revel score = 0.18 Benign Moderate. Seq method: rapid Trio WES.

Case 2 - A 24-month-old male, previously described in PMID: 36632547 Olubiyi et al., 2022. Patient presented with acute encephalopathy, seizures, and emesis. Positive for respiratory SARS-CoV-2; brain MRI concerning for ANE; discharged from hospital on day 7. Presented again at 30 months with acute-onset encephalopathy, delirium, and seizures. At 4.5yrs, patient is much improved - he was forming sentences and ambulated independently with a mildly ataxic gait, WPPSI-IV IQ 65 (mild ID). Heterozygous for RANBP2 c.1966A>G (p.Ile656Val) - maternally inherited; variant rare in gnomAD v4.1.0 (1 heterozygote), Revel score = 0.31 Uncertain.

PMID: 38050538 Li et al., 2023
Report of 1‐year‐old girl - presented with influenza‐associated encephalopathy after which she made a full recovery; followed by severe acute respiratory syndrome coronavirus 2 infection - the patient presented with seizures and deteriorating mental status. Brain MRI revealed necrotic lesions. WES revealed heterozygous c.1754C>T, p.Thr585Met and c.6952G>A, p.Asp2318Asn variants in RANBP2 (presumed in cis?). Variant c.6952G>A, p.Asp2318Asn is not in gnomAD v4, Revel score = 0.34 Benign Supporting.
The penetrance of RANBP2 missense variants is estimated at around 40%.

PMID: 36621064 Forest et al., 2023
Report of a 10-year-old girl with acute onset of decreased level of consciousness and fever. Brain and spinal cord MRI confirmed extensive areas of cytotoxic edema; MRI suggestive for necrosis. Diagnosed with ANE associated with Sars-CoV-2 infection. First episode noted to be at 2yo - trigerred by Influenza A. WES revealed a de novo c.1754C>T p.(Thr585Met) mutation in RANBP2.

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.

PMID: 32426208 Levine et al., 2020; to: RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025).

PMID: 40538544 Varghese et al., 2025
Case 1 - previously healthy 23-month-old female presented with lethargy and acute-onset encephalopathy, following a 2-day fever. Brain MRI consistent with Acute necrotizing encephalopathy (ANE). She presented with another episode of acute-onset encephalopathy at 4yrs 10 mo; she remains non-verbal and non-ambulatory. Family history: 2 maternal uncles, deceased at 16 & 22 months old - both with working diagnoses of Leigh-like disease. Patient was heterozygous for c.1754C>G, p.Thr585Met (maternally inherited) - rare in gnomAD v4.1.0 (2 heterozygotes), Revel score = 0.18 Benign Moderate. Seq method: rapid Trio WES.

Case 2 - A 24-month-old male, previously described in PMID: 36632547 Olubiyi et al., 2022. Patient presented with acute encephalopathy, seizures, and emesis. Positive for respiratory SARS-CoV-2; brain MRI concerning for ANE; discharged from hospital on day 7. Presented again at 30 months with acute-onset encephalopathy, delirium, and seizures. At 4.5yrs, patient is much improved - he was forming sentences and ambulated independently with a mildly ataxic gait, WPPSI-IV IQ 65 (mild ID). Heterozygous for RANBP2 c.1966A>G (p.Ile656Val) - maternally inherited; variant rare in gnomAD v4.1.0 (1 heterozygote), Revel score = 0.31 Uncertain.

PMID: 38050538 Li et al., 2023
Report of 1‐year‐old girl - presented with influenza‐associated encephalopathy after which she made a full recovery; followed by severe acute respiratory syndrome coronavirus 2 infection - the patient presented with seizures and deteriorating mental status. Brain MRI revealed necrotic lesions. WES revealed heterozygous c.1754C>T, p.Thr585Met and c.6952G>A, p.Asp2318Asn variants in RANBP2 (presumed in cis?). Variant c.6952G>A, p.Asp2318Asn is not in gnomAD v4, Revel score = 0.34 Benign Supporting.
The penetrance of RANBP2 missense variants is estimated at around 40%.

PMID: 36621064 Forest et al., 2023
Report of a 10-year-old girl with acute onset of decreased level of consciousness and fever. Brain and spinal cord MRI confirmed extensive areas of cytotoxic edema; MRI suggestive for necrosis. Diagnosed with ANE associated with Sars-CoV-2 infection. First episode noted to be at 2yo - trigerred by Influenza A. WES revealed a de novo c.1754C>T p.(Thr585Met) mutation in RANBP2.

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Patient recovered after 42 days. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska edited their review of gene: RANBP2: Changed rating: AMBER; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska reviewed gene: RANBP2: Rating: ; Mode of pathogenicity: None; Publications: 38050538, 40538544; Phenotypes: {Encephalopathy, acute, infection-induced, 3, susceptibility to}, OMIM:608033; Mode of inheritance: None
Retinal disorders v8.74 RNU6-9 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6-9.
Retinal disorders v8.74 RNU6-8 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6-8.
Retinal disorders v8.74 RNU6-2 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6-2.
Retinal disorders v8.74 RNU6-1 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6-1.
Retinal disorders v8.74 RNU4-2 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU4-2.
Retinal disorders v8.74 RNU6-1 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-1 specific data: n.55_56insG insertion in RNU6-1 reported in patients from 4 diverse RP families - 2 cases suspected to be de novo; n.56_57insG detected in 2 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.74 RNU6-1 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: Recurrent RNU6-1 variants (n.55_56insG & n.56_57insG) were detected in patients from 6 unrelated families with retinitis pigmentosa - 2 cases suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-1 should be promoted to Green for Retinal disorders at the next GMS update.; to: Comment on list classification: Recurrent RNU6-1 variants (n.55_56insG & n.56_57insG) were detected in patients from 6 unrelated families with retinitis pigmentosa - 2 cases suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-1 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.74 RNU6-1 Ida Ertmanska Classified gene: RNU6-1 as Amber List (moderate evidence)
Retinal disorders v8.74 RNU6-1 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: Recurrent RNU6-1 variants (n.55_56insG & n.56_57insG) were detected in patients from 6 unrelated families with retinitis pigmentosa - 2 cases suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-1 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.74 RNU6-1 Ida Ertmanska Gene: rnu6-1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.73 RNU6-1 Ida Ertmanska gene: RNU6-1 was added
gene: RNU6-1 was added to Retinal disorders. Sources: Literature
Q4_25_promote_green tags were added to gene: RNU6-1.
Mode of inheritance for gene: RNU6-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU6-1 were set to 39830270
Phenotypes for gene: RNU6-1 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU6-1 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.72 RNU6-9 Ida Ertmanska changed review comment from: Comment on list classification: RNU6-9 variants (n.55_56insG & n.56_57insG) were detected in patients from 17 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 6 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-9 should be promoted to Green for Retinal disorders at the next GMS update.; to: Comment on list classification: Recurrent RNU6-9 variants (n.55_56insG & n.56_57insG) were detected in patients from 17 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 6 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-9 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.72 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms. Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families - 1 case de novo; incomplete penetrance was observed for nine obligate carriers, without visual symptoms. Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature
Retinal disorders v8.72 RNU6-9 Ida Ertmanska Classified gene: RNU6-9 as Amber List (moderate evidence)
Retinal disorders v8.72 RNU6-9 Ida Ertmanska Gene: rnu6-9 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.71 RNU6-9 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.71 RNU6-9 Ida Ertmanska commented on gene: RNU6-9: Comment on list classification: RNU6-9 variants (n.55_56insG & n.56_57insG) were detected in patients from 17 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 6 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-9 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.71 RNU6-9 Ida Ertmanska gene: RNU6-9 was added
gene: RNU6-9 was added to Retinal disorders. Sources: Literature
Q4_25_promote_green tags were added to gene: RNU6-9.
Mode of inheritance for gene: RNU6-9 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU6-9 were set to 39830270
Phenotypes for gene: RNU6-9 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU6-9 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Sources: Literature
Retinal disorders v8.70 RNU6-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families - 3 cases confirmed de novo, 3 suspected to be de novo; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.70 RNU6-8 Ida Ertmanska Classified gene: RNU6-8 as Amber List (moderate evidence)
Retinal disorders v8.70 RNU6-8 Ida Ertmanska Added comment: Comment on list classification: Recurrent RNU6-8 variant n.55_56insG was detected in patients from 12 unrelated diverse families with retinitis pigmentosa - 1 case confirmed de novo, 1 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-8 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.70 RNU6-8 Ida Ertmanska Gene: rnu6-8 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.69 RNU6-2 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: RNU6-2 variants (n.55_56insG & n.56_57insG) were detected in patients from 14 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 3 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-2 should be promoted to Green for Retinal disorders at the next GMS update.; to: Comment on list classification: RNU6-2 variants (n.55_56insG & n.56_57insG) were detected in patients from 14 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 3 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-2 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.69 RNU6-8 Ida Ertmanska gene: RNU6-8 was added
gene: RNU6-8 was added to Retinal disorders. Sources: Literature
Q4_25_promote_green tags were added to gene: RNU6-8.
Mode of inheritance for gene: RNU6-8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU6-8 were set to 39830270
Phenotypes for gene: RNU6-8 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU6-8 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-8 specific data: n.55_56insG insertion in RNU6-8 reported in numerous patients from 12 diverse RP families - 1 case confirmed and 1 suspected to be de novo; n.56_57insG not detected in RNU6-8 (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.68 RNU6-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7.
Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total). Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.68 RNU6-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7.
Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total). Insertion n.56_57insG was detected in RNU6 paralogs in 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7.
Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total). Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.68 RNU6-2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: RNU6-2.
Retinal disorders v8.68 RNU6-2 Ida Ertmanska Classified gene: RNU6-2 as Amber List (moderate evidence)
Retinal disorders v8.68 RNU6-2 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: RNU6-2 variants (n.55_56insG & n.56_57insG) were detected in patients from 14 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 3 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-2 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.68 RNU6-2 Ida Ertmanska Gene: rnu6-2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.67 RNU6-2 Ida Ertmanska gene: RNU6-2 was added
gene: RNU6-2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: RNU6-2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU6-2 were set to 39830270
Phenotypes for gene: RNU6-2 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU6-2 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7.
Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total). Insertion n.56_57insG was detected in RNU6 paralogs in 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.66 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).
Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms. Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature
Retinal disorders v8.66 RNU4-2 Ida Ertmanska commented on gene: RNU4-2: Comment on list classification: Recurrent RNU4-2 variants (n.56T>C & n.18_19insA) were detected in 41 patients from 15 unrelated families with retinitis pigmentosa - 1 case de novo. 78% of the individuals presented with first symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU4-2 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.66 RNU4-2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: RNU4-2.
Retinal disorders v8.66 RNU4-2 Ida Ertmanska Classified gene: RNU4-2 as Amber List (moderate evidence)
Retinal disorders v8.66 RNU4-2 Ida Ertmanska Gene: rnu4-2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.65 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), cataract/lens opacity (24%), vitreoretinal complications (31%).
Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).
Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature
Retinal disorders v8.65 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), cataract/lens opacity (24%), vitreoretinal complications (31%).
Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature
Retinal disorders v8.65 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Intellectual disability v9.187 SPAST Arina Puzriakova Publications for gene: SPAST were set to 39731306
Intellectual disability v9.186 SPAST Arina Puzriakova reviewed gene: SPAST: Rating: ; Mode of pathogenicity: None; Publications: 39457434; Phenotypes: ; Mode of inheritance: None
Retinal disorders v8.65 RNU4-2 Ida Ertmanska gene: RNU4-2 was added
gene: RNU4-2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: RNU4-2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU4-2 were set to 39830270
Phenotypes for gene: RNU4-2 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU4-2 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Hereditary ataxia with onset in adulthood v8.12 PNPT1 Lucy Jackson gene: PNPT1 was added
gene: PNPT1 was added to Hereditary ataxia with onset in adulthood. Sources: NHS GMS
Mode of inheritance for gene: PNPT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: PNPT1 was set to GREEN
Added comment: Already green on childhood ataxia panel, see https://panelapp.genomicsengland.co.uk/panels/477/gene/PNPT1/
The ataxia phenotype can manifest in adulthood, therefore suggest adding to this panel also.
Sources: NHS GMS
Intellectual disability v9.186 ANKS1B Nour Elkhateeb gene: ANKS1B was added
gene: ANKS1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ANKS1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKS1B were set to 31388001; 38129387
Phenotypes for gene: ANKS1B were set to Developmental delay; Intellectual disability; Autism; Speech and language delay
Review for gene: ANKS1B was set to GREEN
Added comment: Monoallelic ANKS1B microdeletion resulting in Haploinsufficiency have been reported to be associated with variable developmental delays, intellectual disability, behavioural difficulties, as well as other features such as Craniofacial dysmorphism, and MRI brain abnormalities in 4 families (PMID 31388001, 38129387).
Sources: Literature
Intellectual disability v9.186 AFF3_GGC Eleanor Williams commented on STR: AFF3_GGC: To align with other STRs within PanelApp, the STR name AFF3_GCC was changed to AFF3_GGC and the repeat sequence has been changed from GCC to GGC in March 2025.
Amelogenesis imperfecta v4.24 LTBP3 Claire Smith reviewed gene: LTBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29625025; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Currarino triad v1.2 Eleanor Williams List of related panels changed from to
Classical tuberous sclerosis v1.3 Eleanor Williams List of related panels changed from to
Chondrodysplasia punctata v1.6 Eleanor Williams List of related panels changed from to
Choanal atresia v1.17 Eleanor Williams List of related panels changed from to
Cerebral folate deficiency v1.4 Eleanor Williams List of related panels changed from to
Autosomal recessive congenital ichthyosis v1.15 Eleanor Williams List of related panels changed from to
Intellectual disability v9.186 BSN Ida Ertmanska Classified gene: BSN as Amber List (moderate evidence)
Intellectual disability v9.186 BSN Ida Ertmanska Gene: bsn has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.185 BSN Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: BSN.
Intellectual disability v9.185 BSN Ida Ertmanska changed review comment from: Literature review by Helen Lord (Oxford Medical Genetics Laboratories) copied from the Epilepsy panel:

There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Sources: Other; to: Literature review by Helen Lord (Oxford Medical Genetics Laboratories) copied from the Epilepsy panel:

There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Intellectual disability v9.185 BSN Ida Ertmanska commented on gene: BSN: Comment on list classification: As reviewed by Helen Lord, there are numerous individuals reported in literature with a neurodevelopmental disorder with monoallelic variants in BSN. The disorder includes a range of variably penetrant features, with DD/ID and epilepsy being the most common (PMID: 40393460 Guzman et al., 2025). There are 4 individuals reported with compound heterozygous variants in BSN with early onset epilepsy. However, only 1/4 of the biallelic cases presented with developmental delay (PMID: 36600631, Ye et al., 2023). Based on the available evidence this gene should be rated Green for Intellectual disability, with MOI set to BIALLELIC, autosomal or pseudoautosomal.

BSN is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Intellectual disability v9.185 BSN Ida Ertmanska gene: BSN was added
gene: BSN was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: BSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BSN were set to 36600631; 39616287; 40393460
Phenotypes for gene: BSN were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: BSN was set to GREEN
Added comment: Literature review by Helen Lord (Oxford Medical Genetics Laboratories) copied from the Epilepsy panel:

There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Sources: Other
Early onset or syndromic epilepsy v8.74 BSN Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: BSN.
Tag Q4_25_NHS_review tag was added to gene: BSN.
Early onset or syndromic epilepsy v8.74 BSN Ida Ertmanska Phenotypes for gene: BSN were changed from Seizures - different types to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v8.73 BSN Ida Ertmanska Publications for gene: BSN were set to PMID: 36600631; 39616287; 40393460
Early onset or syndromic epilepsy v8.72 BSN Ida Ertmanska Mode of inheritance for gene: BSN was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.71 BSN Ida Ertmanska Classified gene: BSN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.71 BSN Ida Ertmanska Gene: bsn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.70 BSN Ida Ertmanska reviewed gene: BSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 36600631, 39616287, 40393460; Phenotypes: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Malformations of cortical development v7.17 BAIAP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). As only 1 patient presented with lissencephaly, BAIAP2 should be rated Red for Malformations of cortical development, until more evidence emerges.; to: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). Baiap2 knockdown in mouse causes abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). As only 1 patient presented with lissencephaly, BAIAP2 should be rated Red for Malformations of cortical development, until more evidence emerges.
Malformations of cortical development v7.17 BAIAP2 Ida Ertmanska commented on gene: BAIAP2: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). As only 1 patient presented with lissencephaly, BAIAP2 should be rated Red for Malformations of cortical development, until more evidence emerges.
Malformations of cortical development v7.17 BAIAP2 Ida Ertmanska gene: BAIAP2 was added
gene: BAIAP2 was added to Malformations of cortical development. Sources: Other
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BAIAP2 were set to 30696821; 38149472; 41133935
Phenotypes for gene: BAIAP2 were set to developmental and epileptic encephalopathy, MONDO:0100620; classic lissencephaly, MONDO:0015146
Review for gene: BAIAP2 was set to RED
Added comment: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2.

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Sources: Other
Intellectual disability v9.184 BAIAP2 Ida Ertmanska Classified gene: BAIAP2 as Amber List (moderate evidence)
Intellectual disability v9.184 BAIAP2 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). All 7 individuals presented with global developmental delay, intellectual disability, poor motor milestone achievement, and poor / lack of speech development.
Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). Additional functional evidence from coimmunoprecipitation studies shows that missense variants around aa 340-366 in BAIAP2 are likely to disrupt binding of 14-3-3, necessary for BAIAP2 inhibition (PMID: 30696821). Based on the available evidence, BAIAP2 should be promoted to Green for Intellectual disability.
Intellectual disability v9.184 BAIAP2 Ida Ertmanska Gene: baiap2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.183 BAIAP2 Ida Ertmanska gene: BAIAP2 was added
gene: BAIAP2 was added to Intellectual disability. Sources: Other
Q4_25_promote_green tags were added to gene: BAIAP2.
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BAIAP2 were set to 30696821; 38149472; 41133935
Phenotypes for gene: BAIAP2 were set to developmental and epileptic encephalopathy, MONDO:0100620; classic lissencephaly, MONDO:0015146
Review for gene: BAIAP2 was set to GREEN
Added comment: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2.

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Sources: Other
Early onset or syndromic epilepsy v8.70 BAIAP2 Ida Ertmanska edited their review of gene: BAIAP2: Changed publications to: 30696821, 38149472, 41133935
Early onset or syndromic epilepsy v8.70 BAIAP2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: BAIAP2.
Tag Q4_25_NHS_review tag was added to gene: BAIAP2.
Early onset or syndromic epilepsy v8.70 BAIAP2 Ida Ertmanska Publications for gene: BAIAP2 were set to PMID: 41133935
Early onset or syndromic epilepsy v8.69 BAIAP2 Ida Ertmanska Phenotypes for gene: BAIAP2 were changed from DEE to developmental and epileptic encephalopathy, MONDO:0100620; classic lissencephaly, MONDO:0015146
Early onset or syndromic epilepsy v8.68 BAIAP2 Ida Ertmanska Mode of inheritance for gene: BAIAP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v8.67 BAIAP2 Ida Ertmanska Classified gene: BAIAP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.67 BAIAP2 Ida Ertmanska Gene: baiap2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472).; to: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). All individuals presented with early onset epilepsy. Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). Additional functional evidence from coimmunoprecipitation studies shows that missense variants around aa 340-366 in BAIAP2 are likely to disrupt binding of 14-3-3, necessary for BAIAP2 inhibition (PMID: 30696821). Based on the available evidence, BAIAP2 should be promoted to Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska changed review comment from: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2. 14-3-3

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).; to: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2.

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska changed review comment from: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2. 14-3-3

Functional evidence: Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).; to: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2. 14-3-3

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska edited their review of gene: BAIAP2: Added comment: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472).; Changed phenotypes to: developmental and epileptic encephalopathy, MONDO:0100620, classic lissencephaly, MONDO:0015146
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska reviewed gene: BAIAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38149472, 41133935; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100620; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes v5.9 TARS2 Ida Ertmanska edited their review of gene: TARS2: Changed phenotypes to: Combined oxidative phosphorylation deficiency 21, OMIM:615918, combined oxidative phosphorylation defect type 21, MONDO:0014398
Neonatal diabetes v5.9 TARS2 Ida Ertmanska Phenotypes for gene: TARS2 were changed from Neonatal diabetes; developmental delay; epilepsy to Combined oxidative phosphorylation deficiency 21, OMIM:615918; combined oxidative phosphorylation defect type 21, MONDO:0014398
Neonatal diabetes v5.8 TARS2 Ida Ertmanska Publications for gene: TARS2 were set to PMID: 39509107 and PMID: 37454282
Neonatal diabetes v5.7 TARS2 Ida Ertmanska Classified gene: TARS2 as Amber List (moderate evidence)
Neonatal diabetes v5.7 TARS2 Ida Ertmanska Gene: tars2 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.6 TARS2 Ida Ertmanska commented on gene: TARS2: Comment on list classification: Out of more than 30 individuals reported in literature with biallelic TARS2 variants and Combined oxidative phosphorylation deficiency 21, only 4 patients presented with the additional phenotype of neonatal diabetes. 4/4 of those patients were homozygous for the same missense variant p.(Arg327Gln) - 3 families had a shared haplotype (PMID:39509107, Donis et al., 2025). An additional patient with TARS2-related COXPD-21 and diabetes was reported in PMID: 37454282 Accogli et al., 2023 - age of onset unknown. Based on the available evidence, this gene should be rated Amber for Neonatal diabetes until more evidence emerges.

Importantly, ID/DD and axial hypotonia are the main features reported in COXPD-21 patients (92% and 85% of individuals respectively - PMID: 39509107). TARS2 is already rated Green / tagged for promotion on other panels in PanelApp which cover the most common symptoms, including: Intellectual disability; Childhood onset dystonia, chorea or related movement disorder; Mitochondrial disorders .
Neonatal diabetes v5.6 TARS2 Ida Ertmanska reviewed gene: TARS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24827421, 34508595, 37454282, 39394138, 39509107; Phenotypes: Combined oxidative phosphorylation deficiency 21, OMIM:615918; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v6.18 PRKCI Ida Ertmanska edited their review of gene: PRKCI: Changed phenotypes to: van der Woude syndrome, MONDO:0019508, orofacial cleft, MONDO:0000358
Clefting v6.18 PRKCI Ida Ertmanska Phenotypes for gene: PRKCI were changed from van der Woude syndrome, MONDO:0019508 to van der Woude syndrome, MONDO:0019508; orofacial cleft, MONDO:0000358
Clefting v6.17 PRKCI Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort).
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); lower lip pits + hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Clefting v6.17 PRKCI Ida Ertmanska commented on gene: PRKCI: Comment on list classification: There are at least 21 individuals from unrelated families reported in literature with monoallelic variants in PRKCI. 18/21 individuals presented with orofacial clefts (as an isolated phenotype in 13 of them). Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance); 3 individuals had a syndromic presentation WITHOUT orofacial clefts. Ambiguous functional evidence and segregation studies indicate a complex genetic mechanism. There is not yet enough evidence to ascertain a disease mechanism. Based on a large number of cases reported, this gene should be promoted to Green on the Clefting panel.
Clefting v6.17 PRKCI Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort).
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01).

Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort).
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Clefting v6.17 PRKCI Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants).
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe
walking & muscle weakness (1/4), chronic
constipation (1/4).

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not LoF intolerant!

pLI score for this gene = 0.01 - not predicted to be loss-of-function intolerant.
This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort).
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01).

Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Clefting v6.17 PRKCI Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts and peridermopathies.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by trio WGS.

Vairant c.1148A>G (p.Asn383Ser) was found de novo in five unrelated individuals, indicating a hotspot mutation.

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF.


This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Sources: Other; to: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants).
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe
walking & muscle weakness (1/4), chronic
constipation (1/4).

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not LoF intolerant!

pLI score for this gene = 0.01 - not predicted to be loss-of-function intolerant.
This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Clefting v6.17 PRKCI Ida Ertmanska Classified gene: PRKCI as Amber List (moderate evidence)
Clefting v6.17 PRKCI Ida Ertmanska Gene: prkci has been classified as Amber List (Moderate Evidence).
Clefting v6.16 PRKCI Ida Ertmanska gene: PRKCI was added
gene: PRKCI was added to Clefting. Sources: Other
Q4_25_promote_green tags were added to gene: PRKCI.
Mode of inheritance for gene: PRKCI was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKCI were set to 40902599
Phenotypes for gene: PRKCI were set to van der Woude syndrome, MONDO:0019508
Review for gene: PRKCI was set to GREEN
Added comment: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts and peridermopathies.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by trio WGS.

Vairant c.1148A>G (p.Asn383Ser) was found de novo in five unrelated individuals, indicating a hotspot mutation.

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF.


This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Sources: Other
Intellectual disability v9.182 UROC1 Ida Ertmanska Phenotypes for gene: UROC1 were changed from UROCANASE DEFICIENCY (UROD) to ?Urocanase deficiency , OMIM:276880; urocanic aciduria, MONDO:0010167
Intellectual disability v9.181 UROC1 Ida Ertmanska Publications for gene: UROC1 were set to 19304569
Intellectual disability v9.180 UROC1 Ida Ertmanska Tag Q4_25_demote_red tag was added to gene: UROC1.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 - mild (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 - mild ID (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 - mild (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska commented on gene: UROC1: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025).; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025).; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025).
Intellectual disability v9.180 UROC1 Ida Ertmanska reviewed gene: UROC1: Rating: RED; Mode of pathogenicity: None; Publications: 19304569, 27391121, 30619714, 32439973; Phenotypes: ?Urocanase deficiency , OMIM:276880, urocanic aciduria, MONDO:0010167; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.180 SPRTN Ida Ertmanska Classified gene: SPRTN as Red List (low evidence)
Intellectual disability v9.180 SPRTN Ida Ertmanska Gene: sprtn has been classified as Red List (Low Evidence).
Intellectual disability v9.179 SPRTN Ida Ertmanska Classified gene: SPRTN as No list
Intellectual disability v9.179 SPRTN Ida Ertmanska Gene: sprtn has been removed from the panel.
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: SPRTN.
Tag Q4_25_NHS_review tag was added to gene: SPRTN.
Childhood solid tumours v5.8 SPRTN Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features (PMID: 25261934). Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be rated Amber for Childhood solid tumours, until more evidence emerges.; to: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma (died before 18yo), genomic instability, and progeroid features (PMID: 25261934). Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be rated Amber for Childhood solid tumours, until more evidence emerges.
Childhood solid tumours v5.8 SPRTN Ida Ertmanska Classified gene: SPRTN as Amber List (moderate evidence)
Childhood solid tumours v5.8 SPRTN Ida Ertmanska Added comment: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features (PMID: 25261934). Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be rated Amber for Childhood solid tumours, until more evidence emerges.
Childhood solid tumours v5.8 SPRTN Ida Ertmanska Gene: sprtn has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v5.7 SPRTN Ida Ertmanska gene: SPRTN was added
gene: SPRTN was added to Childhood solid tumours. Sources: Other
Mode of inheritance for gene: SPRTN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRTN were set to 12503110; 25261934; 25501849
Phenotypes for gene: SPRTN were set to Ruijs-Aalfs syndrome, OMIM:616200; progeroid features-hepatocellular carcinoma predisposition syndrome, MONDO:0014527
Review for gene: SPRTN was set to AMBER
Added comment: PMID: 25261934 Lessel et al., 2014
Reported biallelic germline mutations in SPRTN in three patients from two unrelated families, affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. Seq method: linkage analysis + WES.

Family A: NM_032018.7:c.723del, p.Lys241Asnfs*9 homozygous
Family A originally described in PMID: 12503110 Ruijs et al., 2003 - Report of a Moroccan boy from a consanguineous family with chromosomal breakage syndrome, who died at 17yo due to hepatocellular carcinoma. Presented with short stature, bilateral cataracts, premature hair graying.

Family B: NM_032018.7:c.350A>G, p.Tyr117Cys & c.717_718+2delAGGT compound heterozygous
Family B = nonconsanguineous Australian family of European ancestry. 2 affected male sibs B-II:1 and B-II:4 presented with low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age and mild joint restrictions. Both individuals developed early onset HCC at age 16 and 14.

FUNCTIONAL EVIDENCE: PMID: 25501849: Maskey et al., 2014: Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Complete Spartan knockout causes early embryonic lethality; hypomorphic mice are viable, but growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Mouse model recapitulated human phenotype, except for the carcinoma susceptibility (no tumours detected in 1 year old Spartan-deficient mice).

SPRTN is associated with AR Ruijs-Aalfs syndrome, OMIM:616200 (OMIM accessed 13th Nov 2025).
Sources: Other
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features. Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be promoted to Green on Paediatric disorders - additional genes at the next GMS update; to: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features (PMID: 25261934). Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be promoted to Green on Paediatric disorders - additional genes at the next GMS update
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska changed review comment from: PMID: 25261934 Lessel et al., 2014
Found biallelic germline mutations in SPRTN in three patients from two unrelated families, affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. Seq method: linkage analysis + WES.

Family A: NM_032018.7:c.723del, p.Lys241Asnfs*9 homozygous
Family A originally described in PMID: 12503110 Ruijs et al., 2003 - Report of a Moroccan boy from a consanguineous family with chromosomal breakage syndrome, who died at 17yo due to hepatocellular carcinoma. Presented with short stature, bilateral cataracts, premature hair graying.

Family B: NM_032018.7:c.350A>G, p.Tyr117Cys & c.717_718+2delAGGT compound heterozygous
Family B = nonconsanguineous Australian family of European ancestry. 2 affected male sibs B-II:1 and B-II:4 presented with low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age and mild joint restrictions. Both individuals developed early onset HCC at age 16 and 14.

FUNCTIONAL EVIDENCE: PMID: 25501849: Maskey et al., 2014: Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Complete Spartan knockout causes early embryonic lethality; hypomorphic mice are viable, but growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Mouse model recapitulated human phenotype, except for the carcinoma susceptibility (no tumours detected in 1 year old Spartan-deficient mice).

SPRTN is associated with AR Ruijs-Aalfs syndrome, OMIM:616200 (OMIM accessed 13th Nov 2025).; to: PMID: 25261934 Lessel et al., 2014
Reported biallelic germline mutations in SPRTN in three patients from two unrelated families, affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. Seq method: linkage analysis + WES.

Family A: NM_032018.7:c.723del, p.Lys241Asnfs*9 homozygous
Family A originally described in PMID: 12503110 Ruijs et al., 2003 - Report of a Moroccan boy from a consanguineous family with chromosomal breakage syndrome, who died at 17yo due to hepatocellular carcinoma. Presented with short stature, bilateral cataracts, premature hair graying.

Family B: NM_032018.7:c.350A>G, p.Tyr117Cys & c.717_718+2delAGGT compound heterozygous
Family B = nonconsanguineous Australian family of European ancestry. 2 affected male sibs B-II:1 and B-II:4 presented with low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age and mild joint restrictions. Both individuals developed early onset HCC at age 16 and 14.

FUNCTIONAL EVIDENCE: PMID: 25501849: Maskey et al., 2014: Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Complete Spartan knockout causes early embryonic lethality; hypomorphic mice are viable, but growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Mouse model recapitulated human phenotype, except for the carcinoma susceptibility (no tumours detected in 1 year old Spartan-deficient mice).

SPRTN is associated with AR Ruijs-Aalfs syndrome, OMIM:616200 (OMIM accessed 13th Nov 2025).
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska edited their review of gene: SPRTN: Changed phenotypes to: Ruijs-Aalfs syndrome, OMIM:616200, progeroid features-hepatocellular carcinoma predisposition syndrome, MONDO:0014527
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska Phenotypes for gene: SPRTN were changed from Ruijs-Aalfs syndrome, MIM# 616200 to Ruijs-Aalfs syndrome, OMIM:616200; progeroid features-hepatocellular carcinoma predisposition syndrome, MONDO:0014527
Paediatric disorders - additional genes v7.23 SPRTN Ida Ertmanska Publications for gene: SPRTN were set to 12503110; 25261934
Paediatric disorders - additional genes v7.22 SPRTN Ida Ertmanska Classified gene: SPRTN as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.22 SPRTN Ida Ertmanska Added comment: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features. Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be promoted to Green on Paediatric disorders - additional genes at the next GMS update
Paediatric disorders - additional genes v7.22 SPRTN Ida Ertmanska Gene: sprtn has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.21 SPRTN Ida Ertmanska reviewed gene: SPRTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 12503110, 25261934, 25501849; Phenotypes: Ruijs-Aalfs syndrome, OMIM:616200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset dystonia v1.151 ACTB Ida Ertmanska Mode of inheritance for gene: ACTB was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset dystonia v1.150 ARX Ida Ertmanska Mode of inheritance for gene: ARX was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Epidermolysis bullosa and congenital skin fragility v2.10 ATP2A2 Ida Ertmanska Publications for gene: ATP2A2 were set to
Epidermolysis bullosa and congenital skin fragility v2.9 ATP2A2 Ida Ertmanska Phenotypes for gene: ATP2A2 were changed from Darier-White disease, OMIM:124200 to Darier disease, OMIM:124200; Acrokeratosis verruciformis, OMIM:101900; Darier disease, MONDO:0007417; acrokeratosis verruciformis, MONDO:0007048
Epidermolysis bullosa and congenital skin fragility v2.8 ATP2A2 Ida Ertmanska Classified gene: ATP2A2 as Red List (low evidence)
Epidermolysis bullosa and congenital skin fragility v2.8 ATP2A2 Ida Ertmanska Gene: atp2a2 has been classified as Red List (Low Evidence).
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in childhood/adolescence. Due to the age of onset, this gene does not fit into the scope of this panel.; to: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in childhood/adolescence. Due to the age of onset, this gene does not fit into the scope of this panel and should be rated Red.
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Ida Ertmanska changed review comment from: PMID: 38536168 Atzmony et al., 2024
9 patients with Darier disease (DD) from (presumed) unrelated families with heterozygous pathogenic germline LoF variants in ATP2A2. 8/9 patients had family history of DD. 8/9 individuals had classic disease distribution with hyperkeratotic papules and plaques over seborrheic areas and v-shaped notching of the nails. One patient had comedonal DD, manifested over forehead, cheeks and trunk.
Variants detected in ATP2A2 - none of which are present in gnomAD v4.1.0.:
c.1000C>T, p.Arg334X
c.1582C>T, p.Arg528X
c.2256_2256Dup, p.(Tyr753Leufs*60)
c.1406_1415del, p.(Asn469Thrfs*7)
c.530A>C, p.Gln177Pro (recurring, 3/9 families)
c.395A>C, p.Gln132Pro; c.392G>T, p. Arg131Leu - detected in cis in patient DD5
c.1327 A>C, p.Thr443Pro
Patients with persistent lesions had additional somatic variants in ATP2A2, while individuals with a 'wax and wane' skin presentation did not.

Many other cases of ATP2A2-related Darier disease have been reported in literature:
PMID: 10080178 Sakuntabhai et al., 1999 - 8 unrelated British families and 5 sporadic cases with DD
PMID: 10441325 Jacobsen et al., 1999 - 19 unrelated DD patients with 17 mutations detected in ATP2A2 + link to neuropsychiatric phenotypes
PMID: 35283639 Hagino et al., 2022 - 34-year-old Japanese woman with familial DD, het for c.616A>C (p.Asn206His) in ATP2A2
PMID: 38791022 Frustaci et al., 2024 - 62-year-old female (DD onset at 9yo), developed cardiac symptoms at 60yo, heterozygous for ATP2A2 c.118G>A

This gene is associated with AD Darier disease, OMIM:124200 and Acrokeratosis verruciformis, OMIM:101900 (accessed 13th Nov 2025).; to: PMID: 38536168 Atzmony et al., 2024
9 patients with Darier disease (DD) from (presumed) unrelated families with heterozygous pathogenic germline LoF variants in ATP2A2. 8/9 patients had family history of DD. Age ranged from 40 to 69 years on enrollment. 8/9 individuals had classic disease distribution with hyperkeratotic papules and plaques over seborrheic areas and v-shaped notching of the nails. One patient had comedonal DD, manifested over forehead, cheeks and trunk.
Variants detected in ATP2A2 - none of which are present in gnomAD v4.1.0.:
c.1000C>T, p.Arg334X
c.1582C>T, p.Arg528X
c.2256_2256Dup, p.(Tyr753Leufs*60)
c.1406_1415del, p.(Asn469Thrfs*7)
c.530A>C, p.Gln177Pro (recurring, 3/9 families)
c.395A>C, p.Gln132Pro; c.392G>T, p. Arg131Leu - detected in cis in patient DD5
c.1327 A>C, p.Thr443Pro
Patients with persistent lesions had additional somatic variants in ATP2A2, while individuals with a 'wax and wane' skin presentation did not.

Many other cases of ATP2A2-related Darier disease have been reported in literature:
PMID: 10080178 Sakuntabhai et al., 1999 - 8 unrelated British families and 5 sporadic cases with DD
PMID: 10441325 Jacobsen et al., 1999 - 19 unrelated DD patients with 17 mutations detected in ATP2A2 + link to neuropsychiatric phenotypes
PMID: 35283639 Hagino et al., 2022 - 34-year-old Japanese woman with familial DD, het for c.616A>C (p.Asn206His) in ATP2A2
PMID: 38791022 Frustaci et al., 2024 - 62-year-old female (DD onset at 9yo), developed cardiac symptoms at 60yo, heterozygous for ATP2A2 c.118G>A

This gene is associated with AD Darier disease, OMIM:124200 and Acrokeratosis verruciformis, OMIM:101900 (accessed 13th Nov 2025).
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Ida Ertmanska edited their review of gene: ATP2A2: Added comment: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in childhood/adolescence. Due to the age of onset, this gene does not fit into the scope of this panel.; Changed rating: RED; Changed publications to: 10080178, 10441325, 35283639, 38791022, 38536168
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Ida Ertmanska reviewed gene: ATP2A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38536168; Phenotypes: Darier disease, OMIM:124200, Acrokeratosis verruciformis, OMIM:101900, Darier disease, MONDO:0007417, acrokeratosis verruciformis, MONDO:0007048; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Amelogenesis imperfecta v4.24 CLDN16 Achchuthan Shanmugasundram Publications for gene: CLDN16 were set to 26426912
Amelogenesis imperfecta v4.23 CLDN16 Achchuthan Shanmugasundram Phenotypes for gene: CLDN16 were changed from Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis (FHHNC) to familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis, MONDO:0017624; amelogenesis imperfecta, MONDO:0019507
Congenital myaesthenic syndrome v5.4 UNC13A Achchuthan Shanmugasundram Tag Q4_25_NHS_review tag was added to gene: UNC13A.
Familial non syndromic congenital heart disease v1.89 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as No list
Familial non syndromic congenital heart disease v1.89 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been removed from the panel.
Familial non syndromic congenital heart disease v1.88 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Familial non syndromic congenital heart disease v1.88 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore has been removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Familial non syndromic congenital heart disease v1.88 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Familial non syndromic congenital heart disease v1.87 ISCA-37433-Loss Arina Puzriakova Tag curated_removed tag was added to Region: ISCA-37433-Loss.
Intellectual disability v9.178 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Intellectual disability v9.178 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.178 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Clefting v6.15 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_promote_green was removed from Region: ISCA-37433-Loss.
Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Early onset or syndromic epilepsy v8.66 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Early onset or syndromic epilepsy v8.66 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Early onset or syndromic epilepsy v8.66 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Intellectual disability v9.177 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Early onset or syndromic epilepsy v8.65 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Clefting v6.15 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Clefting v6.15 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Clefting v6.15 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Clefting v6.14 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_promote_green tag was added to Region: ISCA-37433-Loss.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.75 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.75 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.75 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.74 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Intellectual disability v9.177 ISCA-37433-Gain Arina Puzriakova Classified Region: ISCA-37433-Gain as Green List (high evidence)
Intellectual disability v9.177 ISCA-37433-Gain Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Gain)

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.177 ISCA-37433-Gain Arina Puzriakova Region: isca-37433-gain has been classified as Green List (High Evidence).
Intellectual disability v9.176 ISCA-37433-Gain Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Gain.
Congenital hypothyroidism v3.2 ISCA-37404-Loss Arina Puzriakova Tag curated_removed tag was added to Region: ISCA-37404-Loss.
Congenital hypothyroidism v3.2 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as No list
Congenital hypothyroidism v3.2 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore has been removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Congenital hypothyroidism v3.2 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been removed from the panel.
Hereditary ataxia with onset in adulthood v8.12 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Hereditary ataxia with onset in adulthood v8.12 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Hereditary ataxia with onset in adulthood v8.12 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Hereditary ataxia with onset in adulthood v8.11 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Intellectual disability v9.176 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Intellectual disability v9.176 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.176 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.65 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Early onset or syndromic epilepsy v8.65 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Early onset or syndromic epilepsy v8.65 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Intellectual disability v9.175 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Early onset or syndromic epilepsy v8.64 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Paediatric motor neuronopathies v3.11 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Paediatric motor neuronopathies v3.11 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Paediatric motor neuronopathies v3.11 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Paediatric motor neuronopathies v3.10 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Ataxia and cerebellar anomalies - narrow panel v8.31 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Ataxia and cerebellar anomalies - narrow panel v8.31 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Ataxia and cerebellar anomalies - narrow panel v8.31 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.30 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova changed review comment from: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).; to: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.175 ISCA-37404-Gain Arina Puzriakova Classified Region: ISCA-37404-Gain as Green List (high evidence)
Intellectual disability v9.175 ISCA-37404-Gain Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Gain).

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.175 ISCA-37404-Gain Arina Puzriakova Region: isca-37404-gain has been classified as Green List (High Evidence).
Intellectual disability v9.174 ISCA-37404-Gain Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Gain.
Intellectual disability v9.174 ISCA-37498-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review (Last Evaluated:06/25/2025): Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Sources: ClinGen
Intellectual disability v9.174 ISCA-37448-Loss Arina Puzriakova Phenotypes for Region: ISCA-37448-Loss were changed from to Developmental delay/intellectual disability, epilepsy, autism spectrum disorder, schizophrenia, congenital heart disease, and variable dysmorphic features
Early onset or syndromic epilepsy v8.64 ISCA-37448-Loss Arina Puzriakova Phenotypes for Region: ISCA-37448-Loss were changed from to Developmental delay/intellectual disability, epilepsy, autism spectrum disorder, schizophrenia, congenital heart disease, and variable dysmorphic features
Intellectual disability v9.173 ISCA-37448-Loss Arina Puzriakova Classified Region: ISCA-37448-Loss as Amber List (moderate evidence)
Intellectual disability v9.173 ISCA-37448-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Early onset or syndromic epilepsy v8.63 ISCA-37448-Loss Arina Puzriakova Classified Region: ISCA-37448-Loss as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.63 ISCA-37448-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.173 ISCA-37448-Loss Arina Puzriakova Region: isca-37448-loss has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.63 ISCA-37448-Loss Arina Puzriakova Region: isca-37448-loss has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.62 ISCA-37448-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review (Last Evaluated:04/12/2021): Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Intellectual disability v9.172 ISCA-37448-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review (Last Evaluated:04/12/2021): Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Early onset or syndromic epilepsy v8.62 ISCA-37448-Loss Arina Puzriakova Region: ISCA-37448-Loss was added
Region: ISCA-37448-Loss was added to Early onset or syndromic epilepsy. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-37448-Loss.
Mode of inheritance for Region: ISCA-37448-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37448-Loss were set to 31451536; 24352232; 30767844; 31665216
Review for Region: ISCA-37448-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Intellectual disability v9.172 ISCA-37448-Loss Arina Puzriakova Region: ISCA-37448-Loss was added
Region: ISCA-37448-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-37448-Loss.
Mode of inheritance for Region: ISCA-37448-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37448-Loss were set to 31451536; 24352232; 30767844; 31665216
Review for Region: ISCA-37448-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Intellectual disability v9.171 ISCA-46296-Loss Arina Puzriakova Classified Region: ISCA-46296-Loss as Amber List (moderate evidence)
Intellectual disability v9.171 ISCA-46296-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.171 ISCA-46296-Loss Arina Puzriakova Region: isca-46296-loss has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.170 ISCA-46296-Loss Arina Puzriakova Region: ISCA-46296-Loss was added
Region: ISCA-46296-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46296-Loss.
Mode of inheritance for Region: ISCA-46296-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46296-Loss were set to 22180641; 19921647
Phenotypes for Region: ISCA-46296-Loss were set to Developmental delays, intellectual disability, brain anomalies, non-specific craniofacial abnormalities, hypotonia, ocular abnormalities, hearing loss, and other variable clinical features
Review for Region: ISCA-46296-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46296

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 LCR A-C recurrent region has been reported in at least 5 patients. The reported clinical findings include developmental delays (speech and motor), intellectual disability, brain anomalies, non-specific craniofacial abnormalities, hypotonia, ocular abnormalities, hearing loss, and other variable clinical features. In all cases where parental studies have been performed, deletions were found to be de novo. Case-control comparison studies have provided evidence for enrichment of this deletion in the clinical population, although overall numbers are somewhat limited.
Sources: ClinGen
Intellectual disability v9.169 ISCA-46300-Loss Arina Puzriakova Classified Region: ISCA-46300-Loss as Amber List (moderate evidence)
Intellectual disability v9.169 ISCA-46300-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.169 ISCA-46300-Loss Arina Puzriakova Region: isca-46300-loss has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.16 ISCA-46300-Loss Arina Puzriakova Classified Region: ISCA-46300-Loss as Amber List (moderate evidence)
Malformations of cortical development v7.16 ISCA-46300-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Malformations of cortical development v7.16 ISCA-46300-Loss Arina Puzriakova Region: isca-46300-loss has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.19 ISCA-46300-Loss Arina Puzriakova Classified Region: ISCA-46300-Loss as Amber List (moderate evidence)
Severe microcephaly v8.19 ISCA-46300-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen, however, microcephaly reported in patients is often now within the severity range relevant to this panel (OFC reported in 27399968; 22180641: 10-15th, 0.6-2nd, 3rd, 10th percentile) so will include as Amber based on this evidence.
Severe microcephaly v8.19 ISCA-46300-Loss Arina Puzriakova Region: isca-46300-loss has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.18 ISCA-46300-Loss Arina Puzriakova Tag Q3_25_promote_green was removed from Region: ISCA-46300-Loss.
Severe microcephaly v8.18 ISCA-46300-Loss Arina Puzriakova edited their review of Region: ISCA-46300-Loss: Changed rating: AMBER
Severe microcephaly v8.18 ISCA-46300-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Malformations of cortical development v7.15 ISCA-46300-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Intellectual disability v9.168 ISCA-46300-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Malformations of cortical development v7.15 ISCA-46300-Loss Arina Puzriakova Region: ISCA-46300-Loss was added
Region: ISCA-46300-Loss was added to Malformations of cortical development. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46300-Loss.
Mode of inheritance for Region: ISCA-46300-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46300-Loss were set to 27399968; 22180641
Phenotypes for Region: ISCA-46300-Loss were set to Developmental delays/intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features
Review for Region: ISCA-46300-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Severe microcephaly v8.18 ISCA-46300-Loss Arina Puzriakova Region: ISCA-46300-Loss was added
Region: ISCA-46300-Loss was added to Severe microcephaly. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46300-Loss.
Mode of inheritance for Region: ISCA-46300-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46300-Loss were set to 27399968; 22180641
Phenotypes for Region: ISCA-46300-Loss were set to Developmental delays/intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features
Review for Region: ISCA-46300-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Intellectual disability v9.168 ISCA-46300-Loss Arina Puzriakova Region: ISCA-46300-Loss was added
Region: ISCA-46300-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46300-Loss.
Mode of inheritance for Region: ISCA-46300-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46300-Loss were set to 27399968; 22180641
Phenotypes for Region: ISCA-46300-Loss were set to Developmental delays/intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features
Review for Region: ISCA-46300-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Sources: ClinGen
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova Classified Region: ISCA-37498-Loss as Amber List (moderate evidence)
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova Region: isca-37498-loss has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.166 ISCA-37498-Loss Arina Puzriakova Region: ISCA-37498-Loss was added
Region: ISCA-37498-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-37498-Loss.
Mode of inheritance for Region: ISCA-37498-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37498-Loss were set to 28211979; 21373257; 37152320
Phenotypes for Region: ISCA-37498-Loss were set to Developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features
Review for Region: ISCA-37498-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Sources: ClinGen
Bilateral congenital or childhood onset cataracts v7.5 PTBP1 Ida Ertmanska commented on gene: PTBP1: Comment on list classification: While there are several individuals reported with monoallelic PTBP1 variants with an ocular phenotype as part of a syndromic presentation, only 1/27 reported patients presented with cataracts. Hence, PTBP1 should be rated Red for Bilateral congenital or childhood onset cataracts.
Bilateral congenital or childhood onset cataracts v7.5 PTBP1 Ida Ertmanska gene: PTBP1 was added
gene: PTBP1 was added to Bilateral congenital or childhood onset cataracts. Sources: Other
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PTBP1 were set to 40965981
Review for gene: PTBP1 was set to RED
Added comment: PMID: 40965981 Masson et al., 2025
27 individuals with heterozygous variants in PTBP1 diagnosed with syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. 12/27 individuals noted to have a variable 'ophthalmological' phenotype: microphthalmos (1), myopia (6), strabismus (1), glaucoma (4), papilledema (1), astigmatism (4), cataract (1), septo-optic dysplasia (1), nystagmus (1), amblyopia (1).

This gene is not yet associated with a phenotype in OMIM (accessed 12th Nov 2025).
Sources: Other
Hereditary ataxia v1.343 ISCA-37404-Loss Arina Puzriakova Tag curated_removed tag was added to Region: ISCA-37404-Loss.
Hereditary ataxia v1.343 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as No list
Hereditary ataxia v1.343 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: Removing this region as it has been deprecated by ClinGen and has been subsumed into ISCA-37478 which is green on multiple GMS panels (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)
Hereditary ataxia v1.343 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been removed from the panel.
Retinal disorders v8.64 PTBP1 Ida Ertmanska changed review comment from: PMID: 40965981 Masson et al., 2025
27 individuals with heterozygous variants in PTBP1 diagnosed with syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. 12/27 individuals noted to have a variable 'ophthalmological' phenotype: microphthalmos (1), myopia (6), strabismus (1), glaucoma (4), papilledema (1), astigmatism (4), cataract (1), septo-optic dysplasia (1), nystagmus (1), amblyopia (1).
Sources: Other; to: PMID: 40965981 Masson et al., 2025
27 individuals with heterozygous variants in PTBP1 diagnosed with syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. 12/27 individuals noted to have a variable 'ophthalmological' phenotype: microphthalmos (1), myopia (6), strabismus (1), glaucoma (4), papilledema (1), astigmatism (4), cataract (1), septo-optic dysplasia (1), nystagmus (1), amblyopia (1).

This gene is not yet associated with a phenotype in OMIM (accessed 12th Nov 2025).
Retinal disorders v8.64 PTBP1 Ida Ertmanska commented on gene: PTBP1: Comment on list classification: While there are several individuals reported with monoallelic PTBP1 variants with an ocular phenotype as part of a syndromic presentation, the symptoms do not fit into the scope of the Retinal disorders panel. Hence, PTBP1 should be rated Red for Retinal disorders.
Retinal disorders v8.64 PTBP1 Ida Ertmanska gene: PTBP1 was added
gene: PTBP1 was added to Retinal disorders. Sources: Other
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PTBP1 were set to 40965981
Review for gene: PTBP1 was set to RED
Added comment: PMID: 40965981 Masson et al., 2025
27 individuals with heterozygous variants in PTBP1 diagnosed with syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. 12/27 individuals noted to have a variable 'ophthalmological' phenotype: microphthalmos (1), myopia (6), strabismus (1), glaucoma (4), papilledema (1), astigmatism (4), cataract (1), septo-optic dysplasia (1), nystagmus (1), amblyopia (1).
Sources: Other
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova changed review comment from: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).; to: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova changed review comment from: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss) which is green on multiple GMS panels.; to: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss) which is green on multiple GMS panels.
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova Tag Q4_25_demote_red tag was added to Region: ISCA-37404-Loss.
Congenital myaesthenic syndrome v5.4 UNC13A Ida Ertmanska Phenotypes for gene: UNC13A were changed from to congenital myasthenic syndrome, MONDO:0018940
Congenital myaesthenic syndrome v5.3 UNC13A Ida Ertmanska Publications for gene: UNC13A were set to 27648472
Congenital myaesthenic syndrome v5.2 UNC13A Ida Ertmanska Classified gene: UNC13A as Amber List (moderate evidence)
Congenital myaesthenic syndrome v5.2 UNC13A Ida Ertmanska Gene: unc13a has been classified as Amber List (Moderate Evidence).
Congenital myaesthenic syndrome v5.1 UNC13A Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: UNC13A.
Congenital myaesthenic syndrome v5.1 UNC13A Ida Ertmanska commented on gene: UNC13A: Comment on list classification: There are 2 unrelated individuals with biallelic putative LoF variants in UNC13A who presented with congenital hypotonia and sever muscle weakness. Additionally, knockout mouse models show that Unc13A deficiency interferes with the synaptic maturation process. In contrast, 4 unrelated individuals with heterozygous missense variants in UNC13A presented with intellectual disability and seizures. Hence, there are two distinct disease entities, with different MOIs, associated with this gene. Based on the available evidence, UNC13A should be promoted to Green for Congenital myaesthenic syndrome at the next GMS update.
Congenital myaesthenic syndrome v5.1 UNC13A Ida Ertmanska changed review comment from: BIALLELIC CASES:
PMID: 27648472 Engel et al., 2016
Report of a native American girl, born prematurely at 32 weeks - hypotonic at birth, needed ventilatory support, developed aspiration pneumonia; died at age 50 months due to respiratory failure; EMG studies revealed abnormally low-amplitude CMAPs at rest; histochemical studies of the anconeus muscle revealed marked type 2 fiber atrophy and type 1 fiber hypertrophy; homozygous for NM_001080421.2; c.304C>T, p.(Gln102*) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

PMID: 36447687 Mullins et al., 2022
Case report of a female infant with congenital encephalopathy and a severe neuromuscular phenotype - delivered at 40 weeks due to abnormal heart rate and reduced fetal movement; she had mildly dysmorphic features, alternating hypertonia and hypotonia, extreme generalized muscle weakness, severe kyphoscoliosis and hernias. She died at 8 months due to bronchopneumonia. Homozygous for c.1188delC p.(Asp397Thrfs*107) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

MONOALLELIC: 4 heterozygous cases harbouring missense variants in UNC13A have been detailed previously by Tom Hodgkinson (see below) - individuals presented with seizures and intellectual disability, NOT myaesthenic syndrome.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Nov 2025).; to: BIALLELIC CASES:
PMID: 27648472 Engel et al., 2016
Report of a native American girl, born prematurely at 32 weeks - hypotonic at birth, needed ventilatory support, developed aspiration pneumonia; died at age 50 months due to respiratory failure; EMG studies revealed abnormally low-amplitude CMAPs at rest; histochemical studies of the anconeus muscle revealed marked type 2 fiber atrophy and type 1 fiber hypertrophy; homozygous for NM_001080421.2; c.304C>T, p.(Gln102*) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

PMID: 36447687 Mullins et al., 2022
Case report of a female infant with congenital encephalopathy and a severe neuromuscular phenotype - delivered at 40 weeks due to abnormal heart rate and reduced fetal movement; she had mildly dysmorphic features, alternating hypertonia and hypotonia, extreme generalized muscle weakness, severe kyphoscoliosis and hernias. She died at 8 months due to bronchopneumonia. Homozygous for c.1188delC p.(Asp397Thrfs*107) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

MONOALLELIC: 4 heterozygous cases harbouring missense variants in UNC13A have been detailed previously by Tom Hodgkinson (see below) - individuals presented with seizures and intellectual disability, NOT myaesthenic syndrome.

FUNCTIONAL EVIDENCE:
PMID: 10440375 Augustin et al., 1999: In glutamatergic hippocampal neurons from Unc13A -/- mice the synaptic-vesicle cycle is arrested at the maturation step, stopping transmitter release from the synapses.
PMID: 15988013 Frédérique Varoqueaux et al., 2005: Triple knockout of Unc13A/B/C in the mouse results in paralysis and death; double knockout Unc13B/C mice were viable and fertile - thus, Unc13A was highlighted as crucial for CNS development and function.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Nov 2025).
Congenital myaesthenic syndrome v5.1 UNC13A Ida Ertmanska reviewed gene: UNC13A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27648472, 28192369, 39634123; Phenotypes: congenital myasthenic syndrome, MONDO:0018940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v6.39 CASQ1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 12th Nov 2025.
Congenital myopathy v6.39 CASQ1 Ida Ertmanska Phenotypes for gene: CASQ1 were changed from Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231 to Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231; myopathy due to calsequestrin and SERCA1 protein overload, MONDO:0014546
Congenital myopathy v6.38 CASQ1 Ida Ertmanska reviewed gene: CASQ1: Rating: RED; Mode of pathogenicity: None; Publications: 30258016; Phenotypes: Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ophthalmological ciliopathies v5.9 LRRC45 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 unrelated families with biallelic variants in LRRC45. 2/5 individuals were noted to have an ophthalmological phenotype: isolated cone-rod dystrophy, and nystagmus as part of a syndromic presentation (PMIDs: 34716235; 39638757). Another individual was diagnosed with Bardet-Biedl syndrome-like multi-systemic ciliopathy - often associated with ocular findings, though not specified in the report (PMID: 34716235).; to: Comment on list classification: There are 5 individuals from 4 unrelated families with biallelic variants in LRRC45. 2/5 individuals were noted to have an ophthalmological phenotype: isolated cone-rod dystrophy, and nystagmus as part of a syndromic presentation (PMIDs: 34716235; 39638757). Another individual was diagnosed with Bardet-Biedl syndrome-like multi-systemic ciliopathy - often associated with ocular findings, though not specified in the report (PMID: 34716235). Based on the available evidence, this gene should be rated Amber for Ophthalmological ciliopathies until more evidence emerges.
Ophthalmological ciliopathies v5.9 LRRC45 Ida Ertmanska commented on gene: LRRC45: Comment on list classification: There are 5 individuals from 4 unrelated families with biallelic variants in LRRC45. 2/5 individuals were noted to have an ophthalmological phenotype: isolated cone-rod dystrophy, and nystagmus as part of a syndromic presentation (PMIDs: 34716235; 39638757). Another individual was diagnosed with Bardet-Biedl syndrome-like multi-systemic ciliopathy - often associated with ocular findings, though not specified in the report (PMID: 34716235).
Ophthalmological ciliopathies v5.9 LRRC45 Ida Ertmanska Classified gene: LRRC45 as Amber List (moderate evidence)
Ophthalmological ciliopathies v5.9 LRRC45 Ida Ertmanska Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v5.8 LRRC45 Ida Ertmanska gene: LRRC45 was added
gene: LRRC45 was added to Ophthalmological ciliopathies. Sources: Literature
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 30131441; 34716235; 39638757
Phenotypes for gene: LRRC45 were set to ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443; neurodevelopmental disorder, MONDO:0700092
Review for gene: LRRC45 was set to AMBER
Added comment: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal; patient died at 3 months old. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature
Intellectual disability v9.165 LRRC45 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: LRRC45.
Intellectual disability v9.165 LRRC45 Ida Ertmanska edited their review of gene: LRRC45: Added comment: Comment on list classification: There are 5 individuals form 4 unrelated families reported in literature with biallelic variants in LRRC45. 2/5 patients did not live beyond 3 months of age. In remaining 3 cases, 3/3 presented with severe developmental delay, delayed milestone attainment, and intellectual disability (severity not stated). Based on available evidence, this gene should be promoted to Green for Intellectual disability at the next GMS update.; Changed rating: GREEN
Intellectual disability v9.165 LRRC45 Ida Ertmanska Classified gene: LRRC45 as Amber List (moderate evidence)
Intellectual disability v9.165 LRRC45 Ida Ertmanska Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.164 LRRC45 Ida Ertmanska gene: LRRC45 was added
gene: LRRC45 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 30131441; 34716235; 39638757
Phenotypes for gene: LRRC45 were set to ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443; neurodevelopmental disorder, MONDO:0700092
Review for gene: LRRC45 was set to AMBER
Added comment: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal; patient died at 3 months old. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Other
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska edited their review of gene: LRRC45: Changed publications to: 30131441, 34716235, 39638757
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska changed review comment from: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature; to: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal; patient died at 3 months old. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska changed review comment from: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature; to: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: LRRC45.
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska commented on gene: LRRC45: Comment on list classification: There are 5 individuals from 4 unrelated families reported in literature with biallelic variants in LRRC45. The individuals presented with a range of symptoms from the ciliopathy spectrum: severe neurodevelopmental delay, seizures, cone-rod dystrophy, respiratory insufficiency, muscular hypotonia. The c.1402-2A>G variant was shown to result in a significant reduction of primary cilia frequency and length in patient fibroblasts. In addition, LRRC45 is known to have a role in ciliogenesis. Based on the available evidence, LRRC45 should be promoted to Green for Neurological ciliopathies at the next GMS update.
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska Phenotypes for gene: LRRC45 were changed from ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443 to ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443; neurodevelopmental disorder, MONDO:0700092
Neurological ciliopathies v6.10 LRRC45 Ida Ertmanska edited their review of gene: LRRC45: Changed phenotypes to: ciliopathy, MONDO:0005308, Abnormal brain morphology, HP:0012443, neurodevelopmental disorder, MONDO:0700092
Neurological ciliopathies v6.10 LRRC45 Ida Ertmanska edited their review of gene: LRRC45: Changed phenotypes to: ciliopathy, MONDO:0005308, Abnormal brain morphology, HP:0012443
Neurological ciliopathies v6.10 LRRC45 Ida Ertmanska Phenotypes for gene: LRRC45 were changed from ciliopathy, MONDO:0005308 to ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443
Neurological ciliopathies v6.9 LRRC45 Ida Ertmanska Classified gene: LRRC45 as Amber List (moderate evidence)
Neurological ciliopathies v6.9 LRRC45 Ida Ertmanska Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.8 LRRC45 Ida Ertmanska gene: LRRC45 was added
gene: LRRC45 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 34716235; 39638757
Phenotypes for gene: LRRC45 were set to ciliopathy, MONDO:0005308
Review for gene: LRRC45 was set to GREEN
Added comment: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature
Optic neuropathy v5.26 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, no homozygotes 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.
Amelogenesis imperfecta v4.22 SMARCD2 Ida Ertmanska Phenotypes for gene: SMARCD2 were changed from Specific granule deficiency 2, 617475 to Specific granule deficiency 2, OMIM:617475
Amelogenesis imperfecta v4.21 SMARCD2 Ida Ertmanska Publications for gene: SMARCD2 were set to 28369036
Amelogenesis imperfecta v4.20 SMARCD2 Ida Ertmanska Classified gene: SMARCD2 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.20 SMARCD2 Ida Ertmanska Gene: smarcd2 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.19 SMARCD2 Ida Ertmanska reviewed gene: SMARCD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 28369036, 33025377, 33279574, 36135322; Phenotypes: Specific granule deficiency 2, OMIM:617475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v4.17 TUFT1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TUFT1.
Ectodermal dysplasia v4.17 TUFT1 Ida Ertmanska Phenotypes for gene: TUFT1 were changed from ectodermal dysplasia syndrome, MONDO:0019287 to Woolly hair-skin fragility syndrome, OMIM:620415
Ectodermal dysplasia v4.16 TUFT1 Ida Ertmanska Publications for gene: TUFT1 were set to 36689522
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska changed review comment from: Comment on list classification: As there are now 11 individuals from 4 unrelated families reported in literature (including 2 families with the same founder variant), there is enough evidence to promote TUFT1 to Green for Ectodermal dysplasia at the next GMS update. This association is supported by a knockout mouse model that recapitulates the human phenotype.; to: Comment on list classification: As there are now 11 individuals from 4 unrelated families reported in literature (including 2 families with the same founder variant), there is enough evidence to promote TUFT1 to Green for Ectodermal dysplasia at the next GMS update. This association is supported by a knockout mouse model that recapitulates the human phenotype (PMID: 37716648).
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska commented on gene: TUFT1: Comment on list classification: As there are now 11 individuals from 4 unrelated families reported in literature (including 2 families with the same founder variant), there is enough evidence to promote TUFT1 to Green for Ectodermal dysplasia at the next GMS update. This association is supported by a knockout mouse model that recapitulates the human phenotype.
Amelogenesis imperfecta v4.19 TUFT1 Ida Ertmanska changed review comment from: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).; to: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted. WES identified a homozygous splice acceptor site variant in intron 8, c.724-2A>G in TUFT1.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska changed review comment from: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).; to: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted. WES identified a homozygous splice acceptor site variant in intron 8, c.724-2A>G in TUFT1.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).
Amelogenesis imperfecta v4.19 TUFT1 Ida Ertmanska Phenotypes for gene: TUFT1 were changed from amelogenesis imperfecta to Woolly hair-skin fragility syndrome, OMIM:620415
Amelogenesis imperfecta v4.18 TUFT1 Ida Ertmanska Publications for gene: TUFT1 were set to 7919663
Amelogenesis imperfecta v4.17 TUFT1 Ida Ertmanska Mode of inheritance for gene: TUFT1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska edited their review of gene: TUFT1: Changed rating: GREEN; Changed publications to: 36689522, 37716648; Changed phenotypes to: Woolly hair-skin fragility syndrome, OMIM:620415; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska commented on gene: TUFT1
Amelogenesis imperfecta v4.16 TUFT1 Ida Ertmanska edited their review of gene: TUFT1: Added comment: Comment on list classification: As reviewed by Claire Smith, variants in TUFT1 are not associates with dental abnormalities. Instead, 11 individuals from 4 families with biallelic variants in TUFT1 presented with woolly hair and skin fragility. Based on the available evidence, TUFT1 should remain Red for Amelogenesis imperfecta.; Changed phenotypes to: Woolly hair-skin fragility syndrome, OMIM:620415
Amelogenesis imperfecta v4.16 TUFT1 Ida Ertmanska changed review comment from: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. A Tuft1-knockout mouse model mimicked the patients' phenotypes. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).; to: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).
Amelogenesis imperfecta v4.16 TUFT1 Ida Ertmanska reviewed gene: TUFT1: Rating: ; Mode of pathogenicity: None; Publications: 25531160, 36689522, 37716648; Phenotypes: ; Mode of inheritance: None
Amelogenesis imperfecta v4.16 TP63 Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.; to: Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). The association is supported by a knockout mouse model, showing absence of hair follicles, teeth and mammary glands (PMID: 10227293). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.
Amelogenesis imperfecta v4.16 TP63 Ida Ertmanska Phenotypes for gene: TP63 were changed from Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 to Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, MONDO:0011428
Amelogenesis imperfecta v4.15 TP63 Ida Ertmanska Phenotypes for gene: TP63 were changed from Split hand-split foot-ectodermal dysplasia and amelogenesis imperfecta to Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292
Amelogenesis imperfecta v4.14 TP63 Ida Ertmanska Publications for gene: TP63 were set to
Amelogenesis imperfecta v4.13 TP63 Ida Ertmanska Classified gene: TP63 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.13 TP63 Ida Ertmanska Gene: tp63 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TP63.
Tag Q4_25_expert_review tag was added to gene: TP63.
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska edited their review of gene: TP63: Added comment: Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.; Changed rating: GREEN
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska changed review comment from: PMID: 22065540 Kantaputra et al., 2012
Mother and son affected with split hand-split foot (formerly described as ectrodactyly), ectodermal dysplasia, hyperpigmentation of skin, and dystrophic nails. Heterozygous c.588-2A > C variant detected in TP63 in both mother and son. Only the son was affected with Amelogenesis Imperfecta (hypocalcification, hypoplasia, and hypomaturation), in the primary and permanent dentition. Mother had no dental abnormalities - incomplete penetrance?

PMID: 33126320 Otsuki et al., 2020
Case report: 13-year-old Japanese boy with ectrodactyly in the right hand and left foot and syndactyly in the left and right foot; skin abnormalities including dry skin and café au lait spots; teeth with peg-shaped appearance. Het for a maternally transmitted c.956G>A, p.(R319H) variant in TP63 - however, the mother was healthy.

PMID: 31050217 Zheng et al., 2021
Proband 1 - 6yo Chinese girl - Phenotype: nail dysplasia of the second toe; her hair was yellow when she was a baby; cutaneous syndactyly; missing distal phalanx of the second toe of the left foot; congenital lack of deciduous and permanent teeth, and taurodontia; remaining deciduous teeth in the mouth could be seen with enamel hypoplasia and caries. WES and Sanger results revealed a heterozygous TP63 mutation c.728G>A (p.R243Q). Father of the proband was similarly affected, and carried the same TP63 variant.
Proband 2 - 18‐year‐old Chinese boy - phenotype: sparse and curly hair, missing teeth; ectrodactyly on both hands and feet with dysplastic nails; heterozygous for a de novo c.955C>T (p.R319C) variant in TP63.
Proband 3 - 12‐year‐old Chinese boy - severe ectodermal phenotypes: lack of hair, sparse eyebrows, no eyelashes, underactive sweat glands, nail dysplasia, and missing teeth; short stature noted; Oral examination showed multiple congenitally missing permanent teeth. The remaining teeth displayed enamel hypoplasia and dentin exposure. Proband was heterozygous for c.1769C>T (p.P590L) in TP63 - de novo.

Functional evidence: complete deletion of mouse TP63 results in epidermal defects and epithelial abnormalities - including absence of hair follicles, teeth and mammary glands (PMID: 10227293 Mills et al., 1999).

This gene is associated with multiple autosomal dominant conditions in OMIM, including AD Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 (accessed 7th Nov 2025).; to: PMID: 22065540 Kantaputra et al., 2012
Mother and son affected with split hand-split foot (formerly described as ectrodactyly), ectodermal dysplasia, hyperpigmentation of skin, and dystrophic nails. Heterozygous c.588-2A > C variant detected in TP63 in both mother and son. Only the son was affected with Amelogenesis Imperfecta (hypocalcification, hypoplasia, and hypomaturation), in the primary and permanent dentition. Mother had no dental abnormalities - incomplete penetrance?

PMID: 33126320 Otsuki et al., 2020
Case report: 13-year-old Japanese boy with ectrodactyly in the right hand and left foot and syndactyly in the left and right foot; skin abnormalities including dry skin and café au lait spots; teeth with peg-shaped appearance. Het for a maternally transmitted c.956G>A, p.(R319H) variant in TP63 - however, the mother was healthy.

PMID: 31050217 Zheng et al., 2021
Seq method: WES in probands and Sanger in family members.
Proband 1 - 6yo Chinese girl - Phenotype: nail dysplasia of the second toe; her hair was yellow when she was a baby; cutaneous syndactyly; missing distal phalanx of the second toe of the left foot; congenital lack of deciduous and permanent teeth, and taurodontia; remaining deciduous teeth in the mouth could be seen with enamel hypoplasia and caries. WES and Sanger results revealed a heterozygous TP63 mutation c.728G>A (p.R243Q). Father of the proband was similarly affected, and carried the same TP63 variant.
Proband 2 - 18‐year‐old Chinese boy - phenotype: sparse and curly hair, missing teeth; ectrodactyly on both hands and feet with dysplastic nails; heterozygous for a de novo c.955C>T (p.R319C) variant in TP63.
Proband 3 - 12‐year‐old Chinese boy - severe ectodermal phenotypes: lack of hair, sparse eyebrows, no eyelashes, underactive sweat glands, nail dysplasia, and missing teeth; short stature noted; Oral examination showed multiple congenitally missing permanent teeth. The remaining teeth displayed enamel hypoplasia and dentin exposure. Proband was heterozygous for c.1769C>T (p.P590L) in TP63 - de novo.

Functional evidence: complete deletion of mouse TP63 results in epidermal defects and epithelial abnormalities - including absence of hair follicles, teeth and mammary glands (PMID: 10227293 Mills et al., 1999).

This gene is associated with multiple autosomal dominant conditions in OMIM, including AD Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 (accessed 7th Nov 2025).
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska reviewed gene: TP63: Rating: AMBER; Mode of pathogenicity: None; Publications: 10227293, 22065540, 31050217, 33126320; Phenotypes: Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Amelogenesis imperfecta v4.12 NECTIN4 Ida Ertmanska changed review comment from: Comment on list classification: there are at least 6 unrelated individuals with biallelic NECTIN4 variants and Ectodermal dysplasia-syndactyly syndrome 1. All affected individuals presented with dental abnormalities, including enamel hypoplasia, tooth agenesis, and peg-shaped, widely-spaced teeth. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.; to: Comment on list classification: There are at least 6 unrelated individuals with biallelic NECTIN4 variants and Ectodermal dysplasia-syndactyly syndrome 1. All affected individuals presented with dental abnormalities, including enamel hypoplasia, tooth agenesis, and peg-shaped, widely-spaced teeth. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Ectodermal dysplasia v4.15 NECTIN4 Ida Ertmanska Phenotypes for gene: NECTIN4 were changed from Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573 to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573; ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565
Ectodermal dysplasia v4.14 NECTIN4 Ida Ertmanska Publications for gene: NECTIN4 were set to
Ectodermal dysplasia v4.13 NECTIN4 Ida Ertmanska reviewed gene: NECTIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 20691405, 21346770, 34067522, 37183149, 37829154; Phenotypes: Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573, ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v4.8 NECTIN4 Ida Ertmanska commented on gene: NECTIN4: Comment on list classification: Ectodermal dysplasia-syndactyly syndrome 1 has a variable presentation, mostly commonly including hair and dental abnormalities, as well as cutaneous syndactyly. There are at least 26 individuals from 3 unrelated families described in literature with biallelic NECTIN4 variants and palmoplantar keratoderma (PMIDs: 21346770, 34067522, 37183149). Based on the available evidence, NECTIN4 should be rated Green for Palmoplantar keratodermas.
Palmoplantar keratodermas v4.8 NECTIN4 Ida Ertmanska Classified gene: NECTIN4 as Amber List (moderate evidence)
Palmoplantar keratodermas v4.8 NECTIN4 Ida Ertmanska Gene: nectin4 has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v4.7 NECTIN4 Ida Ertmanska gene: NECTIN4 was added
gene: NECTIN4 was added to Palmoplantar keratodermas. Sources: Other
Q4_25_promote_green tags were added to gene: NECTIN4.
Mode of inheritance for gene: NECTIN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NECTIN4 were set to 20691405; 21346770; 34067522; 37183149; 37829154
Phenotypes for gene: NECTIN4 were set to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573; ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565
Review for gene: NECTIN4 was set to GREEN
Added comment: PMID: 20691405 Brancati et al. 2010
Family A - 4 affected siblings, Algerian origins, first-cousin parents; c.851G>A (p.Arg284Gln), homozygous; phenotype: progressive alopecia, pili torti, widely-spaced peg-shaped teeth, syndactyly fingers 2-3/3-4, toes 2-3/4-5. Study shows that the variants results in exon 4 skipping, leading to a p.(Phe244CysfsX22) change (premature stop codon).
Family B - 2 sibs born to nonconsanguineous Italian parents; phenotype: alopecia, pili torti, abnormal teeth, cutaneous syndactyly. Compound heterozygous c.554C>T (p.Thr185Met) + c.906delT (p.Pro304HisfsX2). 50% reduced mRNA expression in cultured epidermal keratinocytes of patient II:1 (family B).

PMID: 21346770, Jelani et al. 2011
10 affected individuals across a consanguineous Pakistani pedigree. Used microsatellite markers to assign disease locus. Affected individuals homozygous for c.635C>G; p.Pro212Arg - LOD score 5.05. Phenotype: sparse hair, conical teeth with enamel hypoplasia, nail dystrophy, palmoplantar keratoderma, bilateral syndactyly fingers 3-4 and toes 2-3.

PMID: 34067522 Rotunno et al., 2021
Reports 5yo female patient; c.1150delC (p.Gln384ArgfsTer7), homozygous; phenotype: Brittle hair, sparse eyebrows/eyelashes, toenail dystrophy, mild palmoplantar keratoderma. Her teeth were widely spaced and conical, with small crowns and enamel hypoplasia + agenesis of 4 wisdom teeth.

PMID: 37829154 Ali et al., 2023
Consanguineous Kashmiri Family. All 4 affected individuals harboured a homozygous nonsense variant NM 030916: c.181C > T, p.(Gln61Ter). Method: WES. Hypotrichosis, syndactyly fingers 3-4 and toes 2-3, discolored nails, upper lip cleft; conical teeth, with enamel ridges, and pits, widely spaced.

PMID: 37183149 Hajra et al., 2023
Large consanguineous Pakistani family. Only NECTIN4 coding region sequenced. All 15 affected individuals were homozygous for c.163C>T; p.(Arg55*). Phenotype: sparse hair; hypoplastic nails with thick flat discoloured nail plates; peg-shaped, conical, and widely spaced teeth with enamel hypoplasia; proximal cutaneous syndactyly of fingers and toes; skin was dry and scaly with hyperkeratosis and palmoplantar keratoderma.

NECTIN4, previously known as PVRL4, is linked to Ectodermal dysplasia-syndactyly syndrome 1, 613573 (OMIM, accessed 7th Nov 2025).
Sources: Other
Amelogenesis imperfecta v4.12 NECTIN4 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: NECTIN4.
Amelogenesis imperfecta v4.12 NECTIN4 Ida Ertmanska Publications for gene: NECTIN4 were set to PMID: 34067522; 37183149
Amelogenesis imperfecta v4.11 NECTIN4 Ida Ertmanska edited their review of gene: NECTIN4: Changed publications to: 20691405, 21346770, 34067522, 37183149, 37829154
Amelogenesis imperfecta v4.11 NECTIN4 Ida Ertmanska Phenotypes for gene: NECTIN4 were changed from syndactyly of the toes and fingers; hair abnormalities; variable dental genesis; enamel hypoplasia (amelogenesis imperfecta?); variable nail dystrophy; variable palmoplantar keratoderma, hyperkeratosis, reduced sweating to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573; ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565; amelogenesis imperfecta, MONDO:0019507
Amelogenesis imperfecta v4.10 NECTIN4 Ida Ertmanska Classified gene: NECTIN4 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.10 NECTIN4 Ida Ertmanska Gene: nectin4 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.9 NECTIN4 Ida Ertmanska commented on gene: NECTIN4: Comment on list classification: there are at least 6 unrelated individuals with biallelic NECTIN4 variants and Ectodermal dysplasia-syndactyly syndrome 1. All affected individuals presented with dental abnormalities, including enamel hypoplasia, tooth agenesis, and peg-shaped, widely-spaced teeth. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 NECTIN4 Ida Ertmanska changed review comment from: PMID: 20691405 Brancati et al. 2010
Family A - 4 affected siblings, Algerian origins, first-cousin parents; c.851G>A (p.Arg284Gln), homozygous; phenotype: progressive alopecia, pili torti, widely-spaced peg-shaped teeth, syndactyly fingers 2-3/3-4, toes 2-3/4-5. Study shows that the variants results in exon 4 skipping, leading to a p.(Phe244CysfsX22) change (premature stop codon).
Family B - 2 sibs born to nonconsanguineous Italian parents; phenotype: alopecia, pili torti, abnormal teeth, cutaneous syndactyly. Compound heterozygous c.554C>T (p.Thr185Met) + c.906delT (p.Pro304HisfsX2). 50% reduced mRNA expression in cultured epidermal keratinocytes of patient II:1 (family B).

PMID: 21346770, Jelani et al. 2011
10 affected individuals across a consanguineous Pakistani pedigree. Used microsatellite markers to assign disease locus. Affected individuals homozygous for c.635C>G; p.Pro212Arg - LOD score 5.05. Phenotype: sparse hair, conical teeth with enamel hypoplasia, nail dystrophy, palmoplantar keratoderma, bilateral syndactyly fingers 3-4 and toes 2-3.

PMID: 34067522 Rotunno et al., 2021
Reports 5yo female patient; c.1150delC (p.Gln384ArgfsTer7), homozygous; phenotype: Brittle hair, sparse eyebrows/eyelashes, toenail dystrophy, mild palmoplantar keratoderma. Her teeth were widely spaced and conical, with small crowns and enamel hypoplasia + agenesis of 4 wisdom teeth.

PMID: 37829154 Ali et al., 2023
Consanguineous Kashmiri Family. All 4 affected individuals harboured a homozygous nonsense variant NM 030916: c.181C > T, p.(Gln61Ter). Method: WES. Hypotrichosis, syndactyly fingers 3-4 and toes 2-3, discolored nails, upper lip cleft; conical teeth, with enamel ridges, and pits, widely spaced.

PMID: 37183149 Hajra et al., 2023
Large consanguineous Pakistani family. Only NECTIN4 coding region sequenced. All 15 affected individuals were homozygous for c.163C>T; p.(Arg55*). Phenotype: sparse hair; hypoplastic nails with thick flat discoloured nail plates; peg-shaped, conical, and widely spaced teeth with enamel hypoplasia; proximal cutaneous syndactyly of fingers and toes; skin was dry and scaly with hyperkeratosis and palmoplantar keratoderma.
;
PMID: 40586252 Abu Assab et al. 2025; to: PMID: 20691405 Brancati et al. 2010
Family A - 4 affected siblings, Algerian origins, first-cousin parents; c.851G>A (p.Arg284Gln), homozygous; phenotype: progressive alopecia, pili torti, widely-spaced peg-shaped teeth, syndactyly fingers 2-3/3-4, toes 2-3/4-5. Study shows that the variants results in exon 4 skipping, leading to a p.(Phe244CysfsX22) change (premature stop codon).
Family B - 2 sibs born to nonconsanguineous Italian parents; phenotype: alopecia, pili torti, abnormal teeth, cutaneous syndactyly. Compound heterozygous c.554C>T (p.Thr185Met) + c.906delT (p.Pro304HisfsX2). 50% reduced mRNA expression in cultured epidermal keratinocytes of patient II:1 (family B).

PMID: 21346770, Jelani et al. 2011
10 affected individuals across a consanguineous Pakistani pedigree. Used microsatellite markers to assign disease locus. Affected individuals homozygous for c.635C>G; p.Pro212Arg - LOD score 5.05. Phenotype: sparse hair, conical teeth with enamel hypoplasia, nail dystrophy, palmoplantar keratoderma, bilateral syndactyly fingers 3-4 and toes 2-3.

PMID: 34067522 Rotunno et al., 2021
Reports 5yo female patient; c.1150delC (p.Gln384ArgfsTer7), homozygous; phenotype: Brittle hair, sparse eyebrows/eyelashes, toenail dystrophy, mild palmoplantar keratoderma. Her teeth were widely spaced and conical, with small crowns and enamel hypoplasia + agenesis of 4 wisdom teeth.

PMID: 37829154 Ali et al., 2023
Consanguineous Kashmiri Family. All 4 affected individuals harboured a homozygous nonsense variant NM 030916: c.181C > T, p.(Gln61Ter). Method: WES. Hypotrichosis, syndactyly fingers 3-4 and toes 2-3, discolored nails, upper lip cleft; conical teeth, with enamel ridges, and pits, widely spaced.

PMID: 37183149 Hajra et al., 2023
Large consanguineous Pakistani family. Only NECTIN4 coding region sequenced. All 15 affected individuals were homozygous for c.163C>T; p.(Arg55*). Phenotype: sparse hair; hypoplastic nails with thick flat discoloured nail plates; peg-shaped, conical, and widely spaced teeth with enamel hypoplasia; proximal cutaneous syndactyly of fingers and toes; skin was dry and scaly with hyperkeratosis and palmoplantar keratoderma.

NECTIN4, previously known as PVRL4, is linked to Ectodermal dysplasia-syndactyly syndrome 1, 613573 (OMIM, accessed 7th Nov 2025).
Amelogenesis imperfecta v4.9 NECTIN4 Ida Ertmanska reviewed gene: NECTIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 34067522, 37183149; Phenotypes: Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573, ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565, amelogenesis imperfecta, MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia without a known gene mutation v1.29 NECTIN4 Ida Ertmanska Phenotypes for gene: NECTIN4 were changed from Ectodermal dysplasia-syndactyly syndrome 1 613573 to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573
Ectodermal dysplasia v4.13 NECTIN4 Ida Ertmanska Phenotypes for gene: NECTIN4 were changed from Ectodermal dysplasia-syndactyly syndrome 1 613573 to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: CLDN16.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska changed review comment from: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.; to: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The dental defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska changed review comment from: Comment on list classification: There are at 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.; to: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska commented on gene: CLDN16: Comment on list classification: There are at 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Likely inborn error of metabolism v8.83 CLDN16 Ida Ertmanska Phenotypes for gene: CLDN16 were changed from Hypomagnesemia 3, renal 248250 to Hypomagnesemia 3, renal, OMIM:248250
Undiagnosed metabolic disorders v1.638 CLDN16 Ida Ertmanska Phenotypes for gene: CLDN16 were changed from Hypomagnesemia 3, renal 248250 to Hypomagnesemia 3, renal, OMIM:248250
Nephrocalcinosis or nephrolithiasis v5.2 CLDN16 Ida Ertmanska Phenotypes for gene: CLDN16 were changed from Hypomagnesemia 3, renal to Hypomagnesemia 3, renal, OMIM:248250
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 26426912, 32710267; Phenotypes: familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis, MONDO:0017624, amelogenesis imperfecta, MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.61 BAIAP2 Alexander Symon-Allen gene: BAIAP2 was added
gene: BAIAP2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAIAP2 were set to PMID: 41133935
Phenotypes for gene: BAIAP2 were set to DEE
Penetrance for gene: BAIAP2 were set to unknown
Mode of pathogenicity for gene: BAIAP2 was set to Other
Review for gene: BAIAP2 was set to AMBER
Added comment: De novo missense variants detected in 6 unrelated individuals with DEE. One of which has also been seen on DECIPHER and deposited as a research variant (also de novo).
Seizure type is highly variable.
ID ranges from mild to profound.
Animal models (zebrafish) provide some evidence of pathogenicity through abnormal neurite growth (lack or absence of filopodia) and increased neuronal excitability (reduced rheobase & increased AP firing patterns in whole cell recordings). Ion channels within membrane remain unaffected - no significant difference between WT and mutants in specific AP characteristics such as amplitude, voltage threshold, afterhyperpolarisation, and half-width values.
The above evidence led the authors hypothesis that GoF is the mechanism of disease for the variants in this study, however, they propose that LoF variants may also be pathogenic (no evidence to confirm this).
Further studies needed to verify findings and confirm this proposed biphasic disease mechanism model (LoF & GoF variants cause disease).
Currently only evidence for GoF in for a very specific repertoire of residues that are clustered within the phosphorylation site region that is critical to 14-3-3 binding for autoinhibited conformation: T340, Pro342, Arg363 and one variant within the I-BAR domain which is crucial for maintaining the overall positive charge of the dimer: Glu189Val.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.74 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome, type I, with or without reversible metaphyseal dysplasia, 240300; Chronic mucocutaneous candidiasis (CMC); Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED); Autoimmune hypoparathyroidism chronic candidiasis Addison disease syndrome; Hypoparathyroidism Addison disease mucocutaneous candidiasis syndrome; Multiple endocrine deficiency Addison disease candidiasis syndrome; Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia; Diseases of Immune Dysregulation to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Intellectual disability v9.163 AIRE Ida Ertmanska Publications for gene: AIRE were set to
Intellectual disability v9.162 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without,reversible metaphyseal dysplasia, 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.; to: Comment on mode of inheritance: Both mono and bi allelic variants have been reported to cause Autoimmune polyendocrinopathy syndrome, type I (APS-1) - primarily characterised by hypoparathyroidism, enamel hypoplasia, adrenal insufficiency, and recurrent candidiasis. There are at least 3 indiviuals reported with monoallelic AIRE variants, and numerous cases with biallelic variants. Monoallelic variants in AIRE result in an incompletely penetrant, milder phenotype. Based on the available evidence, the MOI should remain as BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska edited their review of gene: AIRE: 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 v8.73 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients).

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

BIALLELIC:
PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 (age range: 19 months–44 years).
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. No immunodeficiency noted.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia & Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients).

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Retinal disorders v8.63 AIRE Ida Ertmanska changed review comment from: MONOALLELIC:
PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance suggested. No ocular phenotype reported in the cohort.

BIALLELIC:
PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years). All
patients showed fundus changes ranging from isolated patchy atrophy of the RPE to an RP-like fundus and attenuated vasculature.
P1: female, P539L/P539L - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Alopecia, Growth retardation.
P2: male, R257X/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Acne
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections
P4: male, R256X/c.967_c.979del13 - systemic findings: Oesophageal candidiasis/stricture, Hypoparathyroidism, Hypogonadism, Nails dystrophy, Alopecia
P5: female, c.463G>A/p.G155S/p.G155S - systemic findings: Autoimmune hepatitis, Mucocutaneous candidiasis, Hypoparathyroidism, Addison disease

PMID: 34122451 Sakaguchi et al. 2021
2-year-old Japanese girl homozygous for c.415C>T, (p.Arg139Ter), with bilateral autoimmune retinopathy, anti-recoverin antibodies, and steroid-responsive acute liver failure.

PMID: 37711606 Wang et al., 2023
3-year-old Chinese boy - F1-II2 - homozygous for c.769C>T, (p.Arg257Ter) - widespread tapetoretinal degeneration without bone-spicule pigmentation. rod and cone responses were non-recordable on ERG recordings. No other systemic symptoms.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC:
PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance suggested. No ocular phenotype reported in the cohort.

BIALLELIC:
PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years). All patients showed fundus changes ranging from isolated patchy atrophy of the RPE to an RP-like fundus and attenuated vasculature.
P1: female, P539L/P539L - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Alopecia, Growth retardation.
P2: male, R257X/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Acne
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections
P4: male, R256X/c.967_c.979del13 - systemic findings: Oesophageal candidiasis/stricture, Hypoparathyroidism, Hypogonadism, Nails dystrophy, Alopecia
P5: female, c.463G>A/p.G155S/p.G155S - systemic findings: Autoimmune hepatitis, Mucocutaneous candidiasis, Hypoparathyroidism, Addison disease

PMID: 34122451 Sakaguchi et al. 2021
2-year-old Japanese girl homozygous for c.415C>T, (p.Arg139Ter), with bilateral autoimmune retinopathy, anti-recoverin antibodies, and steroid-responsive acute liver failure.

PMID: 37711606 Wang et al., 2023
3-year-old Chinese boy - F1-II2 - homozygous for c.769C>T, (p.Arg257Ter) - widespread tapetoretinal degeneration without bone-spicule pigmentation. rod and cone responses were non-recordable on ERG recordings. No other systemic symptoms.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: Comment on list classification: Autoimmune polyendocrinopathy syndrome type I (APS-1) is characterised primarily by the presence of hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis, as well as enamel hypoplasia. Out of more than 90 families reported in literature, only 2 individuals harbouring monoallelic variants in AIRE were diagnosed with immunodeficiency. Based on the available evidence, AIRE should be downgraded to Amber for the Primary immunodeficiency or monogenic inflammatory bowel disease panel.; to: Comment on list classification: Autoimmune polyendocrinopathy syndrome type I (APS-1) is characterised primarily by the presence of hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis, as well as enamel hypoplasia. Out of more than 90 families reported in literature, only 2 individuals harbouring monoallelic variants in AIRE were diagnosed with immunodeficiency. Based on the available evidence, AIRE should be downgraded to Amber for the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska commented on gene: AIRE: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed rating: GREEN; Changed publications to: 11600535, 19393987, 27253668, 29129473, 31905445, 35521792, 37993717, 37235056
Retinal disorders v8.63 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Retinal disorders v8.62 AIRE Ida Ertmanska Publications for gene: AIRE were set to
Retinal disorders v8.61 AIRE Ida Ertmanska Tag Q4_25_MOI tag was added to gene: AIRE.
Retinal disorders v8.61 AIRE Ida Ertmanska changed review comment from: Comment on list mode of inheritance: There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as part of the APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list mode of inheritance: Autoimmune polyendocrinopathy syndrome type I (APS-1) is characterised primarily by the presence of hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis, and enamel hypoplasia. There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as an additional APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.
Retinal disorders v8.61 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed publications to: 25926518, 34122451, 37711606, 37235056
Retinal disorders v8.61 AIRE Ida Ertmanska changed review comment from: PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years). All
patients showed fundus changes ranging from isolated patchy atrophy of the RPE to an RP-like fundus and attenuated vasculature.
P1: female, P539L/P539L - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Alopecia, Growth retardation.
P2: male, R257X/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Acne
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections
P4: male, R256X/c.967_c.979del13 - systemic findings: Oesophageal candidiasis/stricture, Hypoparathyroidism, Hypogonadism, Nails dystrophy, Alopecia
P5: female, c.463G>A/p.G155S/p.G155S - systemic findings: Autoimmune hepatitis, Mucocutaneous candidiasis, Hypoparathyroidism, Addison disease

PMID: 34122451 Sakaguchi et al. 2021
2-year-old Japanese girl homozygous for c.415C>T, (p.Arg139Ter), with bilateral autoimmune retinopathy, anti-recoverin antibodies, and steroid-responsive acute liver failure.

PMID: 37711606 Wang et al., 2023
3-year-old Chinese boy - F1-II2 - homozygous for c.769C>T, (p.Arg257Ter) - widespread tapetoretinal degeneration without bone-spicule pigmentation. rod and cone responses were non-recordable on ERG recordings. No other systemic symptoms.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC:
PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance suggested. No ocular phenotype reported in the cohort.

BIALLELIC:
PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years). All
patients showed fundus changes ranging from isolated patchy atrophy of the RPE to an RP-like fundus and attenuated vasculature.
P1: female, P539L/P539L - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Alopecia, Growth retardation.
P2: male, R257X/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Acne
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections
P4: male, R256X/c.967_c.979del13 - systemic findings: Oesophageal candidiasis/stricture, Hypoparathyroidism, Hypogonadism, Nails dystrophy, Alopecia
P5: female, c.463G>A/p.G155S/p.G155S - systemic findings: Autoimmune hepatitis, Mucocutaneous candidiasis, Hypoparathyroidism, Addison disease

PMID: 34122451 Sakaguchi et al. 2021
2-year-old Japanese girl homozygous for c.415C>T, (p.Arg139Ter), with bilateral autoimmune retinopathy, anti-recoverin antibodies, and steroid-responsive acute liver failure.

PMID: 37711606 Wang et al., 2023
3-year-old Chinese boy - F1-II2 - homozygous for c.769C>T, (p.Arg257Ter) - widespread tapetoretinal degeneration without bone-spicule pigmentation. rod and cone responses were non-recordable on ERG recordings. No other systemic symptoms.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Retinal disorders v8.61 AIRE Ida Ertmanska changed review comment from: Comment on list mode of inheritance: There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as part of the APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list mode of inheritance: There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as part of the APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.
Retinal disorders v8.61 AIRE Ida Ertmanska edited their review of gene: AIRE: Added comment: Comment on list mode of inheritance: There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as part of the APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.61 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 25926518, 34122451, 37711606; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411; Mode of inheritance: None
Autoimmune Polyendocrine Syndrome v1.3 AIRE Ida Ertmanska Tag Q4_25_MOI tag was added to gene: AIRE.
Autoimmune Polyendocrine Syndrome v1.3 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Autoimmune Polyendocrine Syndrome v1.2 AIRE Ida Ertmanska Publications for gene: AIRE were set to
Autoimmune Polyendocrine Syndrome v1.1 AIRE Ida Ertmanska commented on gene: AIRE: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are only 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism; the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Autoimmune Polyendocrine Syndrome v1.1 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no adrenal insufficiency noted. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and hypoparathyroidism at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no adrenal insufficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance suggested.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and hypoparathyroidism at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Autoimmune Polyendocrine Syndrome v1.1 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 11600535, 19393987, 27253668, 29129473, 31905445, 35521792, 37993717, 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska commented on gene: AIRE: Comment on list classification: Autoimmune polyendocrinopathy syndrome type I (APS-1) is characterised primarily by the presence of hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis, as well as enamel hypoplasia. Out of more than 90 families reported in literature, only 2 individuals harbouring monoallelic variants in AIRE were diagnosed with immunodeficiency. Based on the available evidence, AIRE should be downgraded to Amber for the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients).

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed rating: AMBER
Familial hypoparathyroidism v3.4 AIRE Ida Ertmanska Publications for gene: AIRE were set to 19393987; 27253668; 31905445; 35521792; 37993717; 37235056
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed publications to: 11600535, 19393987, 27253668, 29129473, 31905445, 35521792, 37993717, 37235056
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and hypoparathyroidism at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative.; to: PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with APS-1, they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska Publications for gene: AIRE were set to
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska Tag Q4_25_MOI tag was added to gene: AIRE.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska commented on gene: AIRE: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with APS-1, they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 19393987, 27253668, 31905445, 35521792, 37993717, 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v4.6 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Ectodermal dysplasia v4.12 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Ectodermal dysplasia v4.11 AIRE Ida Ertmanska Mode of inheritance for gene: AIRE was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Congenital adrenal hypoplasia v4.6 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Ideopathic Primary Adrenal Failure; Congenital Adrenal Hypoplasia to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only 1 APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: AIRE.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Addison disease; hypoparathyroidism; chronic mucocutaneous candidiasis to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411; amelogenesis imperfecta, MONDO:0019507
Amelogenesis imperfecta v4.8 AIRE Ida Ertmanska Publications for gene: AIRE were set to PMID: 37993717; 19393987; 27253668
Amelogenesis imperfecta v4.7 AIRE Ida Ertmanska Mode of inheritance for gene: AIRE was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.6 AIRE Ida Ertmanska Classified gene: AIRE as Amber List (moderate evidence)
Amelogenesis imperfecta v4.6 AIRE Ida Ertmanska Gene: aire has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska commented on gene: AIRE: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only 1 APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska changed review comment from: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: R257X/T16M. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.; to: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska changed review comment from: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: R257X/T16M. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.; to: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: R257X/T16M. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 19393987, 27253668, 31905445, 35521792, 37993717, 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411, amelogenesis imperfecta, MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.61 BSN Helen Lord gene: BSN was added
gene: BSN was added to Early onset or syndromic epilepsy. Sources: Other
Mode of inheritance for gene: BSN was set to Unknown
Publications for gene: BSN were set to PMID: 36600631; 39616287; 40393460
Phenotypes for gene: BSN were set to Seizures - different types
Penetrance for gene: BSN were set to unknown
Review for gene: BSN was set to AMBER
Added comment: There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Undiagnosed metabolic disorders v1.637 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Undiagnosed metabolic disorders v1.637 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.29 CPOX Ida Ertmanska Tag Q3_25_MOI tag was added to gene: CPOX.
Tag Q3_25_expert_review tag was added to gene: CPOX.
Hereditary neuropathy or pain disorder v7.29 CPOX Ida Ertmanska edited their review of gene: CPOX: Added comment: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.82 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Likely inborn error of metabolism v8.82 CPOX Ida Ertmanska Tag Q3_25_expert_review tag was added to gene: CPOX.
Rare anaemia v3.13 CPOX Ida Ertmanska Tag Q3_25_expert_review was removed from gene: CPOX.
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Non-acute porphyrias v1.29 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Non-acute porphyrias v1.29 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.82 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare anaemia v3.13 CPOX Ida Ertmanska Tag Q3_25_expert_review tag was added to gene: CPOX.
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Ida Ertmanska Tag Q3_25_expert_review tag was added to gene: CPOX.
Non-acute porphyrias v1.29 CPOX Ida Ertmanska Tag Q3_25_expert_review tag was added to gene: CPOX.
Non-acute porphyrias v1.29 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the appropriate MOI is 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'. However, due to low clinical penetrance of monoallelic variants (<1%), this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Non-acute porphyrias v1.29 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the appropriate MOI is 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'. However, due to low clinical penetrance of monoallelic variants (<1%), this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Retinal disorders v8.61 PAX6 Achchuthan Shanmugasundram Mode of inheritance for gene: PAX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.60 FRMD7 Achchuthan Shanmugasundram commented on gene: FRMD7: This gene is proposed for green rating based on sufficient evidence for the association of FRMD7 variants with foveal hypoplasia. However, expert review is sought from NHS Genomic Laboratory Hubs on the relevance of this phenotype to the scope of retinal disorders panel.
Retinal disorders v8.60 FRMD7 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: FRMD7.
Tag Q3_25_expert_review tag was added to gene: FRMD7.
Retinal disorders v8.60 FRMD7 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM accessed on 04 November 2025.
Retinal disorders v8.60 FRMD7 Achchuthan Shanmugasundram Phenotypes for gene: FRMD7 were changed from Nystagmus 1, congenital, X-linked, OMIM:310700; Nystagmus, infantile periodic alternating, X-linked, OMIM:310700; foveal hypoplasia, MONDO:0044203 to Nystagmus 1, congenital, X-linked, OMIM:310700; Nystagmus, infantile periodic alternating, X-linked, OMIM:310700; foveal hypoplasia, MONDO:0044203
Neonatal diabetes v5.6 TARS2 Anna-Marie Johnson gene: TARS2 was added
gene: TARS2 was added to Neonatal diabetes. Sources: Literature
Mode of inheritance for gene: TARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS2 were set to PMID: 39509107 and PMID: 37454282
Phenotypes for gene: TARS2 were set to Neonatal diabetes; developmental delay; epilepsy
Penetrance for gene: TARS2 were set to Complete
Mode of pathogenicity for gene: TARS2 was set to Other
Review for gene: TARS2 was set to GREEN
Added comment: Donis et al 2024 (PMID: 39509107) performed WGS on 27 neonatal diabetes patients who also had epilepsy and/or developmental delay. 3 individuals were found to be homozygous for a TARS2 missense variant, c.980G>A, p.(Arg327Gln). A replication cohort identified 1 additional individual who is also homozygous for this variant. An additional patient with diabetes (age of diagnosis not provided) and COXPD-21 related features has been reported with compound heterozygous TARS2 variants (Accogli et al 2023, PMID: 37454282). Biallelic TARS2 variants cause Combined Oxidative Phosphorylation Deficiency-21(COXPD-21, 21;OMIM: 615918) and neonatal diabetes is a reported feature of this disorder. Evidence shows that the p.(Arg327Gln) variant disrupts TARS2's regulation of the mTORC1 pathway which is essential for pancreatic beta-cells.
Sources: Literature
Retinal disorders v8.59 PAX6 Achchuthan Shanmugasundram Classified gene: PAX6 as Amber List (moderate evidence)
Retinal disorders v8.59 PAX6 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are multiple families reported with foveal hypoplasia and with monoallelic PAX6 variants. However, expert opinion is sought from the NHS Genomic Laboratory Hubs on whether the foveal hypoplasia phenotype fits within the scope of the retinal disorders panel.
Retinal disorders v8.59 PAX6 Achchuthan Shanmugasundram Gene: pax6 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.58 PAX6 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PAX6.
Tag Q3_25_expert_review tag was added to gene: PAX6.
Retinal disorders v8.58 PAX6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 04 November 2025.
Retinal disorders v8.58 PAX6 Achchuthan Shanmugasundram Phenotypes for gene: PAX6 were changed from Foveal hypoplasia 1, OMIM:136520; Microphthalmia/coloboma 12, OMIM:120200; ?Coloboma of optic nerve, OMIM:120430; Anterior segment dysgenesis 5, multiple subtypes, OMIM:604229 to Foveal hypoplasia 1, OMIM:136520; Microphthalmia/coloboma 12, OMIM:120200; ?Coloboma of optic nerve, OMIM:120430; ?Morning glory disc anomaly, OMIM:120430; Aniridia, OMIM:106210; Cataract with late-onset corneal dystrophy, OMIM:106210; Keratitis, OMIM:148190; Optic nerve hypoplasia, OMIM:165550; Anterior segment dysgenesis 5, multiple subtypes, OMIM:604229
Retinal disorders v8.57 PAX6 Achchuthan Shanmugasundram edited their review of gene: PAX6: Changed phenotypes to: Foveal hypoplasia 1, OMIM:136520, Microphthalmia/coloboma 12, OMIM:120200, ?Coloboma of optic nerve, OMIM:120430, ?Morning glory disc anomaly, OMIM:120430, Aniridia, OMIM:106210, Cataract with late-onset corneal dystrophy, OMIM:106210, Keratitis, OMIM:148190, Optic nerve hypoplasia, OMIM:165550, Anterior segment dysgenesis 5, multiple subtypes, OMIM:604229
Retinal disorders v8.57 PAX6 Achchuthan Shanmugasundram Phenotypes for gene: PAX6 were changed from Foveal Hypoplasia and Presenile Cataract Syndrome; Developmental macular and foveal dystrophy (foveal hypoplasia in the context of aniridia) to Foveal hypoplasia 1, OMIM:136520; Microphthalmia/coloboma 12, OMIM:120200; ?Coloboma of optic nerve, OMIM:120430; Anterior segment dysgenesis 5, multiple subtypes, OMIM:604229
Intellectual disability v9.161 KIF26A Ida Ertmanska Classified gene: KIF26A as Amber List (moderate evidence)
Intellectual disability v9.161 KIF26A Ida Ertmanska Added comment: Comment on list classification: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). 6/8 individuals assessed presented with developmental delay and/or intellectual disability: 3 cases with mild cognitive impairment, 2 with moderate ID, 1 with 'growth retardation and developmental delay' - severity not specified. As only 2 cases meet the panel criteria of moderate/severe impairment, this gene should be rated Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.161 KIF26A Ida Ertmanska Gene: kif26a has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.92 MT-ND5 Achchuthan Shanmugasundram changed review comment from: After consultation with the clinical team, this gene is tagged for expert review by the Genomic Laboratory Hubs on the inclusion of this gene with green rating to this panel.; to: After consultation with the clinical team, this gene is tagged for expert review by the Genomic Laboratory Hubs on the inclusion of this gene with green rating on this panel.
Paediatric or syndromic cardiomyopathy v7.92 MT-TL1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

Expert review is being sought from the Genomic Medicine Service on whether this gene can be promoted to the next major version.; to: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

Expert opinion is sought from the Genomic Medicine Service on the inclusion of this gene on this panel with green raring in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.92 MT-TV Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: MT-TV.
Paediatric or syndromic cardiomyopathy v7.92 MT-TV Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in at least three unrelated patients with variants in MT-TV gene. This gene can therefore be promoted to green rating on the next GMS update.; to: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in at least three unrelated patients with variants in MT-TV gene.

Expert opinion is sought from the Genomic Medicine Service on the inclusion of this gene on this panel with green raring in the next GMS update.
Intellectual disability v9.160 KIF26A Ida Ertmanska gene: KIF26A was added
gene: KIF26A was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to 36228617; 36564622; 39305096
Phenotypes for gene: KIF26A were set to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332
Review for gene: KIF26A was set to AMBER
Added comment: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.

Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Sources: Other
Hydrocephalus v5.3 KIF26A Ida Ertmanska changed review comment from: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.

Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Sources: Other; to: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.

Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Hydrocephalus v5.3 KIF26A Ida Ertmanska Classified gene: KIF26A as Amber List (moderate evidence)
Hydrocephalus v5.3 KIF26A Ida Ertmanska Added comment: Comment on list classification: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). 12/12 cases with brain MRI available showed congenital brain malformations - in particular ventriculomegaly/hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases.
KIF26A is associated with AR 'Cortical dysplasia, complex, with other brain malformations 11, 620156' in OMIM (accessed 31st Oct 2025). The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024). Based on the available evidence, this gene should be promoted to Green on the Hydrocephalus panel.
Hydrocephalus v5.3 KIF26A Ida Ertmanska Gene: kif26a has been classified as Amber List (Moderate Evidence).
Hydrocephalus v5.2 KIF26A Ida Ertmanska gene: KIF26A was added
gene: KIF26A was added to Hydrocephalus. Sources: Other
Q4_25_promote_green tags were added to gene: KIF26A.
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to 36228617; 36564622; 39305096
Phenotypes for gene: KIF26A were set to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332
Review for gene: KIF26A was set to GREEN
Added comment: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.

Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Sources: Other
Limb disorders v7.13 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Limb disorders v7.13 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome, 605039 to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Intellectual disability v9.159 ASXL1 Ida Ertmanska Publications for gene: ASXL1 were set to
Intellectual disability v9.158 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Intellectual disability v9.158 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome, 605039Myelodysplastic syndrome, somatic, 614286; BOHRING-OPITZ SYNDROME to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Paediatric or syndromic cardiomyopathy v7.92 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: MT-TL1.
Paediatric or syndromic cardiomyopathy v7.92 MT-TL1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

This gene can therefore be promoted to green rating on the next GMS update.; to: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

Expert review is being sought from the Genomic Medicine Service on whether this gene can be promoted to the next major version.
Clefting v6.14 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Clefting v6.14 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from BOHRING-OPITZ SYNDROME; BOPS to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.2 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.2 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome, 605039; Metopic synostosis frequently associated with Bohring-Opitz syndrome to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Fetal anomalies v6.116 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Fetal anomalies v6.116 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from BOHRING-OPITZ SYNDROME to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Skeletal dysplasia v8.21 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Skeletal dysplasia v8.21 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome 605039 to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Arthrogryposis v9.12 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes accessed on 3rd Nov 2025.
Arthrogryposis v9.12 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome 605039 to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from chronic viral infections; v Bohring-Opitz syndrome, OMIM:605039; Myelodysplastic syndrome, somatic, OMIM: 614286iral-associated malignancies; combined immune deficiency to combined immunodeficiency, MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Boaz Palterer, there is a single case reported in literature with biallelic variants in ASXL1 and features of primary immunodeficiency. This gene should be rated Red for Primary immunodeficiency or monogenic inflammatory bowel disease until more evidence emerges.; to: Comment on list classification: As reviewed by Boaz Palterer, there is a single case reported in literature with biallelic variants in ASXL1 and features of primary immunodeficiency. This gene should be rated Red for Primary immunodeficiency or monogenic inflammatory bowel disease until more evidence emerges.
ASXL1 is associated with AD Bohring-Opitz syndrome, OMIM:605039 and Myelodysplastic syndrome, somatic, OMIM: 614286 (OMIM accessed 3rd Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska changed review comment from: Comment on phenotypes: ASXL1 is associated with AD Bohring-Opitz syndrome, OMIM:605039 and Myelodysplastic syndrome, somatic, OMIM: 614286 (OMIM accessed 3rd Nov 2025).; to: Comment on phenotypes:
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska edited their review of gene: ASXL1: Changed phenotypes to: combined immunodeficiency MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: ASXL1 is associated with AD Bohring-Opitz syndrome, OMIM:605039 and Myelodysplastic syndrome, somatic, OMIM: 614286 (OMIM accessed 3rd Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from chronic viral infections; viral-associated malignancies; combined immune deficiency to chronic viral infections; v Bohring-Opitz syndrome, OMIM:605039; Myelodysplastic syndrome, somatic, OMIM: 614286iral-associated malignancies; combined immune deficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v8.71 ASXL1 Ida Ertmanska reviewed gene: ASXL1: Rating: RED; Mode of pathogenicity: None; Publications: 40742536; Phenotypes: Bohring-Opitz syndrome, OMIM:605039, Myelodysplastic syndrome, somatic, OMIM: 614286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v4.2 BTK Achchuthan Shanmugasundram Phenotypes for gene: BTK were changed from Isolated growth hormone deficiency, type III, with agammaglobulinemia (307200) to Isolated growth hormone deficiency, type III, with agammaglobulinemia, OMIM:307200
Mosaic skin disorders - deep sequencing v3.1 GJA1 Veronica Kinsler gene: GJA1 was added
gene: GJA1 was added to Mosaic skin disorders - deep sequencing. Sources: Expert Review
Mode of inheritance for gene: GJA1 was set to Other
Publications for gene: GJA1 were set to PMID: 27890787
Phenotypes for gene: GJA1 were set to Inflammatory Linear Verrucous Epidermal Naevi (ILVEN)
Review for gene: GJA1 was set to GREEN
Added comment: Mosaic, potential for germline transmission
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v8.71 TNFSF9 Ida Ertmanska reviewed gene: TNFSF9: Rating: RED; Mode of pathogenicity: None; Publications: 35657354; Phenotypes: EBV lymphoproliferation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.71 TNFSF9 Ida Ertmanska Classified gene: TNFSF9 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.71 TNFSF9 Ida Ertmanska Gene: tnfsf9 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.70 GCC2 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Boaz Palterer, there are 2 unrelated individuals reported in literature with biallelic variants in GCC2 and recurrent viral infections (PMID:39813120). Hence, this gene should be rated Amber for Primary immunodeficiency or monogenic inflammatory bowel disease, until more evidence emerges.
This gene is not yet associated with a phenotype in OMIM (accessed 31st Oct 2025).; to: Comment on list classification: As reviewed by Boaz Palterer, there are 2 unrelated individuals reported in literature with biallelic variants in GCC2 and recurrent viral infections, with demonstrated reduced natural killer cell function (PMID:39813120). Hence, this gene should be rated Amber for Primary immunodeficiency or monogenic inflammatory bowel disease, until more evidence emerges.
This gene is not yet associated with a phenotype in OMIM (accessed 31st Oct 2025).
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska Tag Q4_25_NHS_review tag was added to gene: KIF26A.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.70 GCC2 Ida Ertmanska Classified gene: GCC2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.70 GCC2 Ida Ertmanska Gene: gcc2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.69 GCC2 Ida Ertmanska reviewed gene: GCC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 39813120; Phenotypes: NK cell deficiency, recurrent viral infections, immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mosaic skin disorders - deep sequencing v3.1 TSC1 Veronica Kinsler edited their review of gene: TSC1: Changed rating: GREEN
Mosaic skin disorders - deep sequencing v3.1 TSC2 Veronica Kinsler edited their review of gene: TSC2: Changed phenotypes to: Cutaneous pigmentary abnormalities, and/or other aspects of germline TSC disease
Mosaic skin disorders - deep sequencing v3.1 TSC2 Veronica Kinsler gene: TSC2 was added
gene: TSC2 was added to Mosaic skin disorders - deep sequencing. Sources: Expert Review
Mode of inheritance for gene: TSC2 was set to Other
Publications for gene: TSC2 were set to PMID: 37356622
Review for gene: TSC2 was set to GREEN
Added comment: Mosaic, potential for transmission to offspring in germline
Sources: Expert Review
Mosaic skin disorders - deep sequencing v3.1 TSC1 Veronica Kinsler gene: TSC1 was added
gene: TSC1 was added to Mosaic skin disorders - deep sequencing. Sources: Expert Review
Mode of inheritance for gene: TSC1 was set to Other
Publications for gene: TSC1 were set to PMID: 37356622
Phenotypes for gene: TSC1 were set to Cutaneous pigmentary abnormalities, and/or other aspects of germline TSC disease
Added comment: Mosaic, potential for germline transmission to offspring
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v8.69 ASXL1 Ida Ertmanska Classified gene: ASXL1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.69 ASXL1 Ida Ertmanska Gene: asxl1 has been classified as Red List (Low Evidence).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Veronica Kinsler reviewed gene: CARD14: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34116062, PMID: 38360177, PMID: 35853659; Phenotypes: Inflammatory Linear Verrucous Epidermal Naevi (ILVEN); Mode of inheritance: Other
Mosaic skin disorders - deep sequencing v3.1 TP63 Veronica Kinsler reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34703865, PMID: 27351625, PMID: 22740388; Phenotypes: Blaschkolinear hypopigmentation, with or without features of germline TP63 diseases; Mode of inheritance: None
Mosaic skin disorders - deep sequencing v3.1 PMVK Veronica Kinsler reviewed gene: PMVK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38360177, PMID: 35853659; Phenotypes: Inflammatory Linear Verrucous Epidermal Naevi (ILVEN); Mode of inheritance: Other
Mosaic skin disorders - deep sequencing v3.1 KITLG Veronica Kinsler reviewed gene: KITLG: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28257793; Phenotypes: Blaschkolinear hyperpigmentation; Mode of inheritance: Other
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Veronica Kinsler reviewed gene: ATP2A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 10080178; Phenotypes: Darier disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska changed review comment from: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.; to: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations - reported in all individuals. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska changed review comment from: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.; to: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska changed review comment from: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. These symptoms are likely caused by congenital cortical malformations. As reviewedpreviously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.; to: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska commented on gene: KIF26A: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. These symptoms are likely caused by congenital cortical malformations. As reviewedpreviously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: KIF26A.
Malformations of cortical development v7.14 KIF26A Ida Ertmanska changed review comment from: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).
The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
Sources: Other; to: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).
The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Malformations of cortical development v7.14 KIF26A Ida Ertmanska commented on gene: KIF26A: Comment on list classification: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). 12/12 cases with brain MRI available showed congenital brain malformations, in particular ventriculomegaly/hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases.
KIF26A is associated with AR 'Cortical dysplasia, complex, with other brain malformations 11, 620156' in OMIM (accessed 31st Oct 2025). The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024). Based on the available evidence, this gene should be promoted to Green for Malformations of cortical development
Malformations of cortical development v7.14 KIF26A Ida Ertmanska Classified gene: KIF26A as Amber List (moderate evidence)
Malformations of cortical development v7.14 KIF26A Ida Ertmanska Gene: kif26a has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.13 KIF26A Ida Ertmanska gene: KIF26A was added
gene: KIF26A was added to Malformations of cortical development. Sources: Other
Q4_25_promote_green tags were added to gene: KIF26A.
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to 36228617; 36564622; 39305096
Phenotypes for gene: KIF26A were set to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332
Review for gene: KIF26A was set to GREEN
Added comment: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).
The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
Sources: Other
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska Phenotypes for gene: KIF26A were changed from GDNF-Ret in ENS development to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332
Paediatric pseudo-obstruction syndrome v2.3 KIF26A Ida Ertmanska Publications for gene: KIF26A were set to 19914172; 33542431
Paediatric pseudo-obstruction syndrome v2.2 KIF26A Ida Ertmanska Classified gene: KIF26A as Amber List (moderate evidence)
Paediatric pseudo-obstruction syndrome v2.2 KIF26A Ida Ertmanska Gene: kif26a has been classified as Amber List (Moderate Evidence).
Paediatric pseudo-obstruction syndrome v2.1 KIF26A Ida Ertmanska changed review comment from: 13 patients from have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 39305096

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/13, mild to moderate), cardiac defects (6/13), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 3 others had other gastrointestinal issues: megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/13 patients and corpus callosum agenesis / hypoplasia in 7/13 cases.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Post‐surgery, he had decreased stool frequency managed with macrogol; histopathological examination revealed features consistent with PIPO diagnosis. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137)

36228617 Q

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).; to: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

Note: several individuals died before certain clinical features could be assessed. The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/13 patients and corpus callosum agenesis / hypoplasia in 7/13 cases.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Post‐surgery, he had decreased stool frequency managed with macrogol; histopathological examination revealed features consistent with PIPO diagnosis. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
Paediatric pseudo-obstruction syndrome v2.1 KIF26A Ida Ertmanska reviewed gene: KIF26A: Rating: GREEN; Mode of pathogenicity: None; Publications: 36228617, 36564622, 39305096; Phenotypes: Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156, cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v4.4 FLNA Ida Ertmanska Classified gene: FLNA as Amber List (moderate evidence)
Ehlers Danlos syndrome with a likely monogenic cause v4.4 FLNA Ida Ertmanska Gene: flna has been classified as Amber List (Moderate Evidence).
Ehlers Danlos syndrome with a likely monogenic cause v4.3 FLNA Ida Ertmanska Publications for gene: FLNA were set to 28306229
Ehlers Danlos syndrome with a likely monogenic cause v4.2 FLNA Ida Ertmanska changed review comment from: PMID: 34863227 Billon et al., 2021
Summary report of 3 patient cohorts: 10 French female index cases from the Rare Vascular Diseases Centre, aged 14-66, 23 cases from the filaminopathies diagnostic lab, and a literature review of 59 cases - total of 92 cases with monoallelic variants in FLNA and periventricular nodular heterotopia type 1 (X-linked dominant).
50% of patients did not have neurological symptoms. Most patients presented with combined cardiovascular (CV) and connective tissue disorder (CTD) features. CV anomalies, e.g. aortic aneurysm and/or dilation, were present in 75% of patients. CTD features were present in 75% of patients - e.g. joints hyperlaxity and skin hyperelasticity.

Studies analysed in the literature review: PMIDs:11532987;15249610;15459826;15668422;15994863;15994863;16303888;16684786;19917821;20014127;20730588;20888935;21194575;21960593;22238415;22366253;23032111;24906659;26059841;27091362;27144976;27739212;28177866;28457522;29334594;29449050;30089473;30547349

PMID: 15668422 Sheen et al., 2005 - first report
2 families and 9 sporadic cases with periventricular nodular heterotopia associated with joint hyperlaxity, skin hyperelasticity, and aortic aneurysm/dissection. The authors suggested calling this condition Ehlers–Danlos variant of periventricular heterotopia.

FLNA is putatively linked to FG syndrome 2, 300321, and associated with 9 X-linked conditions: Cardiac valvular dysplasia, X-linked, 314400; Congenital short bowel syndrome, 300048; Frontometaphyseal dysplasia 1, 305620; Heterotopia, periventricular, 1, 300049; Intestinal pseudoobstruction, neuronal, 300048; Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I, 311300; Otopalatodigital syndrome, type II, 304120; Terminal osseous dysplasia, 300244 in OMIM (accessed 31st Oct 2025).; to: PMID: 34863227 Billon et al., 2021
Summary report of 3 patient cohorts: 10 French female index cases from the Rare Vascular Diseases Centre, aged 14-66, 23 cases from the filaminopathies diagnostic lab, and a literature review of 59 cases - total of 92 cases with monoallelic variants in FLNA and periventricular nodular heterotopia type 1 (X-linked dominant).
50% of patients did not have neurological symptoms. Most patients presented with combined cardiovascular (CV) and connective tissue disorder (CTD) features. CV anomalies, e.g. aortic aneurysm and/or dilation, were present in 75% of patients. CTD features were present in 75% of patients - e.g. joints hyperlaxity and skin hyperelasticity.

Studies analysed in the literature review: PMIDs:11532987;15249610;15459826;15668422;15994863;15994863;16303888;16684786;19917821;20014127;20730588;20888935;21194575;21960593;22238415;22366253;23032111;24906659;26059841;27091362;27144976;27739212;28177866;28457522;29334594;29449050;30089473;30547349

PMID: 15668422 Sheen et al., 2005 - first report
2 families and 9 sporadic cases with periventricular nodular heterotopia associated with joint hyperlaxity, skin hyperelasticity, and aortic aneurysm/dissection. The authors suggested calling this condition Ehlers–Danlos variant of periventricular heterotopia.

FLNA is putatively linked to FG syndrome 2, 300321, and associated with 9 X-linked conditions: Cardiac valvular dysplasia, X-linked, 314400; Congenital short bowel syndrome, 300048; Frontometaphyseal dysplasia 1, 305620; Heterotopia, periventricular, 1, 300049; Intestinal pseudoobstruction, neuronal, 300048; Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I, 311300; Otopalatodigital syndrome, type II, 304120; Terminal osseous dysplasia, 300244 in OMIM (accessed 31st Oct 2025).
Ehlers Danlos syndrome with a likely monogenic cause v4.2 FLNA Ida Ertmanska edited their review of gene: FLNA: 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)
Ehlers Danlos syndrome with a likely monogenic cause v4.2 FLNA Ida Ertmanska reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11532987, 15249610, 15459826, 15668422, 15994863, 15994863, 16303888, 16684786, 19917821, 20014127, 20730588, 20888935, 21194575, 21960593, 22238415, 22366253, 23032111, 24906659, 26059841, 27091362, 27144976, 27739212, 28177866, 28457522, 29334594, 29449050, 30089473, 30547349, 34863227; Phenotypes: Heterotopia, periventricular, 1, OMIM:300049; Mode of inheritance: None
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.19 HNRNPA1 Ida Ertmanska commented on gene: HNRNPA1: Comment on list classification: There are at least 7 unrelated individuals reported in literature with monoallelic variants in HNRNPA1 that presented with distal myopathy. Disease onset is either juvenile or in early adulthood. The affected individuals harboured stop-loss, missense, and frameshift variants, either de novo or shown to segregated with disease in an autosomal dominant manner. Other variants in this gene have been reported as causal for juvenile-onset ALS, multisystem proteinopathy, and distal hereditary motor neuropathy. There is currently little to no correlation between the location of the causative variant and the corresponding phenotype, and no precise understanding of the different disease mechanisms. Nonetheless, there is sufficient evidence for this gene-disease relationship. HNRNPA1 should be promoted to Green for Distal myopathies at the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v4.48 DNAJB13 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877.

There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs*3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877.

This gene is associated with 'Ciliary dyskinesia, primary, 34' phenotype in OMIM (MIM #617091) - OMIM accessed on 7 July 2025.

There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs*3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.
Respiratory ciliopathies including non-CF bronchiectasis v4.48 DNAJB13 Ida Ertmanska Publications for gene: DNAJB13 were set to 27486783; 35166991
Congenital myopathy v6.38 PNPLA2 Ida Ertmanska changed review comment from: Biallelic mutations in PNPLA2 are associated with Neutral lipid-storage disease with myopathy, OMIM:610717 (NLSDM) - phenotype accessed 30th Oct 2025).

PMID: 37620213 Fu et al., 2023 - literature review
11 childhood-onset and 82 adult-onset patients; only 6/11 childhood onset patients presented with muscle weakness. NLSDM is often diagnosed by presence of Jordan's anomaly on a peripheral blood smear and elevated CK - some cases asymptomatic until later life. Age of disease onset in the childhood cases ranged from shortly after birth to 11yo. However, the onset of myopathy occurred several years after the initial symptoms in all individuals (between 3-33 years after initial symptoms).; to: Biallelic mutations in PNPLA2 are associated with Neutral lipid-storage disease with myopathy, OMIM:610717 (NLSDM) - phenotype accessed 30th Oct 2025).

PMID: 37620213 Fu et al., 2023 - literature review
11 childhood-onset and 82 adult-onset patients; only 6/11 childhood onset patients presented with muscle weakness. NLSDM is often diagnosed by presence of Jordan's anomaly on a peripheral blood smear and elevated CK - some cases asymptomatic until later life. Age of disease onset in the childhood cases ranged from shortly after birth to 11yo. However, the onset of myopathy occurred several years after the initial symptoms in all individuals (between 3-33 years after initial symptoms).

PNPLA2 is already Green on the Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies panel.
Congenital myopathy v6.38 PNPLA2 Ida Ertmanska commented on gene: PNPLA2: Comment on list classification: The average age of onset for Neutral lipid-storage disease with myopathy is around 30 years old. Among childhood-onset patients, many do not initially present with myopathy. Based on the available evidence, this gene is not in scope of the Congenital myopathy panel and should remain Red.
Congenital myopathy v6.38 PNPLA2 Ida Ertmanska reviewed gene: PNPLA2: Rating: RED; Mode of pathogenicity: None; Publications: 21544567, 37620213, 40919432; Phenotypes: Neutral lipid-storage disease with myopathy, OMIM:610717; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.21 SPRTN Ronnie Wright gene: SPRTN was added
gene: SPRTN was added to Paediatric disorders - additional genes. Sources: Literature,NHS GMS
Mode of inheritance for gene: SPRTN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRTN were set to 12503110; 25261934
Phenotypes for gene: SPRTN were set to Ruijs-Aalfs syndrome, MIM# 616200
Penetrance for gene: SPRTN were set to Complete
Review for gene: SPRTN was set to GREEN
Added comment: 2 families in literature with progeroid phenotype and susceptibility to hepatocellular carcinoma.
DNA repair defects (chromosome breakage observed) in affected patients - PMID:25261934

1 family in NWGLH - IUGR & IGF abnormalities referral. Subsequently reported with hepatocellular carcinoma and described as progeroid - remarkably consistent phenotype with families in literature. Chromosome breakage studies being arranged.
(100KGP - https://cva.genomicsengland.nhs.uk/case/25972-1 - homozygous final exon nonsense/truncating variant)

3rd family = sufficient for green rating?
Sources: Literature, NHS GMS
Congenital myopathy v6.38 HNRNPA1 Ida Ertmanska reviewed gene: HNRNPA1: Rating: RED; Mode of pathogenicity: None; Publications: 34291734, 34722876, 35550112, 39072769; Phenotypes: Myopathy, distal, 3 , OMIM:610099, distal myopathy, MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.115 SCN4A Arina Puzriakova Tag Q2_25_expert_review was removed from gene: SCN4A.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.19 HNRNPA1 Ida Ertmanska Publications for gene: HNRNPA1 were set to 34291734; 34722876; 39072769
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.18 HNRNPA1 Ida Ertmanska Classified gene: HNRNPA1 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.18 HNRNPA1 Ida Ertmanska Gene: hnrnpa1 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.17 HNRNPA1 Ida Ertmanska edited their review of gene: HNRNPA1: Changed publications to: 34291734, 34722876, 35550112, 39072769
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.17 HNRNPA1 Ida Ertmanska changed review comment from: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.

HNRNPA1 is associated with AD Amyotrophic lateral sclerosis 20, OMIM:615426, as well as provisionally linked to AD Myopathy, distal, 3, OMIM:610099 and Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 (OMIM accessed 30th Oct 2025).
Sources: Other; to: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.

HNRNPA1 is associated with AD Amyotrophic lateral sclerosis 20, OMIM:615426, as well as provisionally linked to AD Myopathy, distal, 3, OMIM:610099 and Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 (OMIM accessed 30th Oct 2025).
Sources: Other
Distal myopathies v6.13 HNRNPA1 Ida Ertmanska edited their review of gene: HNRNPA1: Changed publications to: 34291734, 34722876, 35550112, 39072769
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.17 HNRNPA1 Ida Ertmanska gene: HNRNPA1 was added
gene: HNRNPA1 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Other
Q4_25_promote_green tags were added to gene: HNRNPA1.
Mode of inheritance for gene: HNRNPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HNRNPA1 were set to 34291734; 34722876; 39072769
Phenotypes for gene: HNRNPA1 were set to Myopathy, distal, 3 , OMIM:610099; distal myopathy, MONDO:0018949
Review for gene: HNRNPA1 was set to GREEN
Added comment: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.

HNRNPA1 is associated with AD Amyotrophic lateral sclerosis 20, OMIM:615426, as well as provisionally linked to AD Myopathy, distal, 3, OMIM:610099 and Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 (OMIM accessed 30th Oct 2025).
Sources: Other
Distal myopathies v6.13 HNRNPA1 Ida Ertmanska changed review comment from: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.
; to: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.

HNRNPA1 is associated with AD Amyotrophic lateral sclerosis 20, OMIM:615426, as well as provisionally linked to AD Myopathy, distal, 3, OMIM:610099 and Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 (OMIM accessed 30th Oct 2025).
Distal myopathies v6.13 HNRNPA1 Ida Ertmanska commented on gene: HNRNPA1: Comment on list classification: There are at least 7 unrelated individuals reported in literature with monoallelic variants in HNRNPA1 that presented with distal myopathy. Disease onset is either juvenile or in early adulthood. The affected individuals harboured stop-loss, missense, and frameshift variants, either de novo or shown to segregated with disease in an autosomal dominant manner. Other variants in this gene have been reported as causal for juvenile-onset ALS, multisystem proteinopathy, and distal hereditary motor neuropathy. There is currently little to no correlation between the location of the causative variant and the corresponding phenotype, and no precise understanding of the different disease mechanisms. Nonetheless, there is sufficient evidence for this gene-disease relationship. HNRNPA1 should be promoted to Green for Distal myopathies at the next GMS update.