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Retinal disorders v9.19 IDUA Siying Lin gene: IDUA was added
gene: IDUA was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: IDUA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IDUA were set to 42838055
Phenotypes for gene: IDUA were set to Retinitis pigmentosa; atteunated MPS I
Mode of pathogenicity for gene: IDUA was set to Other
Review for gene: IDUA was set to GREEN
Added comment: Biallelic hypomorphic IDUA variants have been shown to cause late-onset retinal-predominant disease, including apparently non-syndromic retinitis pigmentosa, in a multi-centre cohort of 14 affected individuals from 12 unrelated families, supported by functional and biochemical validation.
Sources: Literature
Retinal disorders v9.17 VWA8 Ida Ertmanska changed review comment from: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish

PMID: 42120427 Kong et al., 2026 - Functional evidence
Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice.
The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation.; to: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish

PMID: 42120427 Kong et al., 2026 - Functional evidence - same research group as first patient report in PMID: 37012052
Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice.
The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation.
Retinal disorders v9.17 VWA8 Ida Ertmanska changed review comment from: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish.; to: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish

PMID: 42120427 Kong et al., 2026 - Functional evidence
Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice.
The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation.
Retinal disorders v9.17 VWA8 Ida Ertmanska changed review comment from: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.; to: PMID: 40638000 Chacon-Camacho et al., 2025
Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.

PMID: 34660594 Umair et al., 2021
Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs.
Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish.
Retinal disorders v9.17 DHX16 Ida Ertmanska Added comment: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). Moreover, retinitis pigmentosa was the main / presenting finding in some patients. Hence, this gene should be promoted to Green for Retinal disorders at the next update.
Retinal disorders v9.16 DHX16 Ida Ertmanska gene: DHX16 was added
gene: DHX16 was added to Retinal disorders. Sources: Literature
Q3_26_promote_green tags were added to gene: DHX16.
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX16 were set to 31256877; 36212160; 36211162; 37574199; 37664979; 40141454; 41555919
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890
Review for gene: DHX16 was set to GREEN
Added comment: PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40326698 Clay et al., 2025
3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy.

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).

PMID: 36212160 Park et al., 2022
Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported.

PMID: 31256877 Paine et al., 2019
Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome.
P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC.
P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His.
P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL.
P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; Tapetoretinal degeneration and total vision loss; SNHL; contractures.
Sources: Literature
Retinal disorders v9.14 FBN2 Ida Ertmanska changed review comment from: PMID: 24899048 Ratnapriya et al., 2014
Summary copied from OMIM: "Reported a family in which a father and 4 sons had early-onset macular dystrophy. Clinical features varied among the 5 affected individuals. The father was diagnosed with macular degeneration at 69 years of age, and examination at age 75 showed large areas of pigment epithelial atrophy in the macula of both eyes. The eldest son reported a history of distorted vision in his left eye from the age of 46 years; examination at age 52 confirmed pigmentary changes of the left macula. Another son had a history of choroidal neovascularization in the right eye at age 35. Two more sons exhibited clinical findings consistent with atrophic macular disease in their forties. There was no history of skeletal, joint, or muscle abnormalities in these patients."
A heterozygous FBN2 c.3430G>A, p.Glu1144Lys variant was posed to be causal. MAF in gnomAD v4 = 0.0001761. Conflicting in ClinVar (VUS/B).
Sources: Literature; to: PMID: 24899048 Ratnapriya et al., 2014
Summary copied from OMIM: "Reported a family in which a father and 4 sons had early-onset macular dystrophy. Clinical features varied among the 5 affected individuals. The father was diagnosed with macular degeneration at 69 years of age, and examination at age 75 showed large areas of pigment epithelial atrophy in the macula of both eyes. The eldest son reported a history of distorted vision in his left eye from the age of 46 years; examination at age 52 confirmed pigmentary changes of the left macula. Another son had a history of choroidal neovascularization in the right eye at age 35. Two more sons exhibited clinical findings consistent with atrophic macular disease in their forties. There was no history of skeletal, joint, or muscle abnormalities in these patients."
A heterozygous FBN2 c.3430G>A, p.Glu1144Lys variant segregated with disease and was posed to be causal. MAF in gnomAD v4 = 0.0001761. Conflicting in ClinVar (VUS/B).
Sources: Literature
Retinal disorders v9.14 FBN2 Ida Ertmanska gene: FBN2 was added
gene: FBN2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: FBN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBN2 were set to 24899048
Phenotypes for gene: FBN2 were set to Macular degeneration, early-onset, OMIM:616118; macular degeneration, early-onset, MONDO:0014501
Review for gene: FBN2 was set to RED
Added comment: PMID: 24899048 Ratnapriya et al., 2014
Summary copied from OMIM: "Reported a family in which a father and 4 sons had early-onset macular dystrophy. Clinical features varied among the 5 affected individuals. The father was diagnosed with macular degeneration at 69 years of age, and examination at age 75 showed large areas of pigment epithelial atrophy in the macula of both eyes. The eldest son reported a history of distorted vision in his left eye from the age of 46 years; examination at age 52 confirmed pigmentary changes of the left macula. Another son had a history of choroidal neovascularization in the right eye at age 35. Two more sons exhibited clinical findings consistent with atrophic macular disease in their forties. There was no history of skeletal, joint, or muscle abnormalities in these patients."
A heterozygous FBN2 c.3430G>A, p.Glu1144Lys variant was posed to be causal. MAF in gnomAD v4 = 0.0001761. Conflicting in ClinVar (VUS/B).
Sources: Literature
Retinal disorders v9.10 XXYLT1 Siying Lin gene: XXYLT1 was added
gene: XXYLT1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: XXYLT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XXYLT1 were set to PMID: 42530953
Phenotypes for gene: XXYLT1 were set to Retinal dystrophy
Mode of pathogenicity for gene: XXYLT1 was set to Other
Review for gene: XXYLT1 was set to GREEN
Added comment: Biallelic XXYLT1 variants were identified in 7 affected individuals from 5 unrelated families (4 Finnish and 1 UK) with autosomal recessive inherited retinal disease. The recurrent splice variant was supported by RNA studies demonstrating aberrant splicing and loss of function, while the independent UK family harboured a distinct homozygous missense variant. These findings support XXYLT1 is a novel cause of autosomal recessive inherited retinal disease.
Sources: Literature
Retinal disorders v9.4 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic. Authors pose that LOF variants lead to dominant hearing loss.
Retinal disorders v9.4 COL11A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variabel reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome / Marshall syndrome / isolated hearing loss, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variable reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Retinal disorders v9.3 COL11A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variabel reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. Hence, the MOI should be 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.; to: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variabel reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Retinal disorders v9.3 COL11A1 Ida Ertmanska commented on gene: COL11A1: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variabel reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. Hence, the MOI should be 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.
Retinal disorders v9.3 LOXL3 Ida Ertmanska changed review comment from: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including retinal disease in 4 individuals from 3 unrelated families. Retinal findings included foveal hypoplasia, chorioretinal lattice degeneration, and non-specific retinal changes. A mouse model with a knock-in missense variant in LOXL3 recapitulated Stickler syndrome features, including progressive visual degeneration. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including retinal disease in 4 individuals from 3 unrelated families. Retinal findings included foveal hypoplasia, chorioretinal lattice degeneration, and peripheral retinal degeneration. A mouse model with a knock-in missense variant in LOXL3 recapitulated Stickler syndrome features, including progressive visual degeneration. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v9.3 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including retinal disease in 4 individuals from 3 unrelated families. Retinal findings included foveal hypoplasia, chorioretinal lattice degeneration, and non-specific retinal changes. A mouse model with a knock-in missense variant in LOXL3 recapitulated Stickler syndrome features, including progressive visual degeneration. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v9.1 BBIP1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in abnormal retinal development. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 3 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in abnormal retinal development. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v9.1 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).
Retinal disorders v8.120 LRRC32 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals with 3 different homozygous LRRC32 variants and retinal disease. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now more than 3 unrelated individuals with 3 different homozygous LRRC32 variants and retinal disease. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v8.117 LRRC32 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with 3 different homozygous LRRC32 variants and retinal disease. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v8.115 COQ5 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic COQ5 variants and retinopathy due to COQ10 deficiency. Hence, this gene should be promoted to Green for Retinal disorders.
Retinal disorders v8.112 RDH11 Ida Ertmanska changed review comment from: Comment on list classification: There are now more than 10 unrelated individuals reported in literature with biallelic variants in RDH11 and retinal disease (RP and progressive night blindness). Hence, this gene should be promoted to Green for Retinal disorders.; to: Comment on list classification: There are now more than 3 unrelated individuals reported in literature with biallelic variants in RDH11 and retinal disease (RP and progressive night blindness). Hence, this gene should be promoted to Green for Retinal disorders.
Retinal disorders v8.112 RDH11 Ida Ertmanska Added comment: Comment on list classification: There are now more than 10 unrelated individuals reported in literature with biallelic variants in RDH11 and retinal disease (RP and progressive night blindness). Hence, this gene should be promoted to Green for Retinal disorders.
Retinal disorders v8.111 RDH11 Ida Ertmanska changed review comment from: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).; to: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life. 70% of cases had some ocular involvement.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Retinal disorders v8.111 RDH11 Ida Ertmanska changed review comment from: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Neurodevelopmental impairment, juvenile-onset cataract, and retinal dystrophy were confirmed as common features. Microcephaly and distinct craniofacial traits were also recurrent.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).; to: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Retinal disorders v8.104 BBIP1 Ida Ertmanska Added comment: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in abnormal retinal development. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v8.101 INTS11 Ida Ertmanska Added comment: Comment on list classification: There are at least 3 unrelated families with individuals harbouring biallelic INTS11 variants affected by retinal disease. Hence, this gene should be updated to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Retinal disorders v8.100 INTS11 Ida Ertmanska changed review comment from: PMID: 41810893 Lin et al., 2026
Report of four affected individuals with biallelic INTS11 variants from two unrelated families.
Retinal phenotype: mild optic disc pallor; severe thinning of the inner retinal layers with preserved outer retinal layers, generalized rod and cone system dysfunction localized to the inner retina or post-phototransduction.
Individuals A-1 and A-2 were compound heterozygous for missense INTS11 variants c.34G > A; p.(Gly12Ser) and c.1219C > T; p.(Pro407Ser), as previously described. Novel compound het INTS11 variants (c.721G > A, p.(Ala241Thr) and c.983T > A, p.(Leu328Gln)) were identified in individuals B-3 and B-4.

PMID: 37054711 Tepe et al., 2023
15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. 5 patients were noted to have optic atrophy, and 2 had retinal dystrophy.; to: PMID: 41810893 Lin et al., 2026
Report of four affected individuals with biallelic INTS11 variants from two unrelated families.
Retinal phenotype: mild optic disc pallor; severe thinning of the inner retinal layers with preserved outer retinal layers, generalized rod and cone system dysfunction localized to the inner retina or post-phototransduction.
Individuals A-1 and A-2 were compound heterozygous for missense INTS11 variants c.34G > A; p.(Gly12Ser) and c.1219C > T; p.(Pro407Ser), as previously described. Novel compound het INTS11 variants (c.721G > A, p.(Ala241Thr) and c.983T > A, p.(Leu328Gln)) were identified in individuals B-3 and B-4.

PMID: 37054711 Tepe et al., 2023
15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. 5 patients were noted to have optic atrophy, and 2 had retinal dystrophy. Less specific ocular findings included myopia, astigmatism, and strabismus.
Retinal disorders v8.92 TEAD1 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated individuals of varied ancestry with heterozygous TEAD1 variants and retinal disease. There is good evidence of dominant segregation within pedigrees. Hence, TEAD1 should be promoted to Green at the next GMS update.
Retinal disorders v8.91 FSD1L Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated families reported in literature where affected individuals have a retinal phenotype and habrour biallelic FDS1L variants. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are more than 3 unrelated families reported in literature where affected individuals have a syndromic phenotype including retinal disease, and habrour biallelic FDS1L variants. In milder cases, retinitis pigmentosa was reported as the only symptom. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v8.89 FSD1L Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated families reported in literature where affected individuals have a retinal phenotype and habrour biallelic FDS1L variants. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v8.88 FSD1L Ida Ertmanska changed review comment from: PMID: 41720098 Serpieri et al., 2026
Report of eleven individuals (including five fetuses) from six unrelated families harbouring biallelic FSD1L variants. Seq method: exome sequencing. Consanguinity was confirmed in 4/6 families, and suspected in the fifth.
Phenotype spectrum: severe intellectual disability (5/5 assessed from 3 families), epilepsy (5 individuals from 3 families), severe hydrocephalus (3 families), vision deficit due to optic nerve hypoplasia/atrophy (3 families), spastic tetraparesis (2 families) corpus callosum hypoplasia/agenesis on MRI (5/5 families assessed),

Variants detected - largely nonsense type:
Family A - homozygous c.409T>G (p.Leu137Val);
Family B - 3 affected fetuses homozygous for c.1411C>T (p.Gln471Ter);
Family C - sibs compound het for c.1228T>G (p.Phe410Val) and c.1251_1252insTAA (p.Thr418Ter);
Family D - affected individuals (1 fetal case) homozygous for c.1366G>C (p.Asp456His) - shown to impact splicing (r.406_442del), resulting in predicted p.Ser136LeufsTer19 change;
Family E - affected child with homozygous c.835C>T (p.Arg279Ter) change;
Family F - fetus homozygous for c.1260G>A (p.Trp420Ter);

Functional evidence: Fsd1l depletion in mouse embryos recapitulated the ventricular dilation observed in affected fetuses.

FSD1L is not yet associated with a phenotype in OMIM or Gene2Phenotype.; to: PMID: 41720098 Serpieri et al., 2026
Report of eleven individuals (including five fetuses) from six unrelated families harbouring biallelic FSD1L variants. Seq method: exome sequencing. Consanguinity was confirmed in 4/6 families, and suspected in the fifth.
Phenotype spectrum: severe intellectual disability (5/5 assessed from 3 families), epilepsy (5 individuals from 3 families), severe hydrocephalus (3 families), vision deficit due to optic nerve hypoplasia/atrophy (3 families), spastic tetraparesis (2 families) corpus callosum hypoplasia/agenesis on MRI (5/5 families assessed),

Variants detected - largely nonsense type:
Family A - homozygous c.409T>G (p.Leu137Val);
Family B - 3 affected fetuses homozygous for c.1411C>T (p.Gln471Ter);
Family C - sibs compound het for c.1228T>G (p.Phe410Val) and c.1251_1252insTAA (p.Thr418Ter);
Family D - affected individuals (1 fetal case) homozygous for c.1366G>C (p.Asp456His) - shown to impact splicing (r.406_442del), resulting in predicted p.Ser136LeufsTer19 change;
Family E - affected child with homozygous c.835C>T (p.Arg279Ter) change;
Family F - fetus homozygous for c.1260G>A (p.Trp420Ter);

Functional evidence: Fsd1l depletion in mouse embryos recapitulated the ventricular dilation observed in affected fetuses.

PMID 41720099 Lin et al., 2026
FSD1L variants detected:
Family A: 2 sibs compound het for c.1049G>A (p.Arg350Gln) and c.1428del (p.Phe476Leufs∗22)
Family B: individual comp het for c.488G>A (p.Arg163His), c.488G>A & c.745C>T (p.Arg249∗)
Family C: 2 sibs compound het for c.488G>A (p.Arg163His) & c.226_227del (p.Ser77Argfs∗4)
Family D: individual compound het for c.1037_1038delinsT (p.Pro346Leufs∗8) and c.1025+624_1025+649del
Sibs from family A had mild neurological involvement (mild ID, spastic diplegia in one sibling).
Authors note that "specific combination and functional severity of the two alleles likely determines the clinical outcome", with non-LoF variants causing a milder effect (e.g., isolated retinal phenotype).

FSD1L is not yet associated with a phenotype in OMIM or Gene2Phenotype.
Retinal disorders v8.88 FSD1L Ida Ertmanska changed review comment from: PMID: 41720098 Serpieri et al., 2026
Report of eleven individuals (including five fetuses) from six unrelated families harbouring biallelic FSD1L variants. Seq method: exome sequencing. Consanguinity was confirmed in 4/6 families, and suspected in the fifth.
Phenotype spectrum: severe intellectual disability (5/5 assessed from 3 families), epilepsy (5 individuals from 3 families), severe hydrocephalus (3 families), vision deficit due to optic nerve hypoplasia/atrophy (3 families), spastic tetraparesis (2 families) corpus callosum hypoplasia/agenesis on MRI (5/5 families assessed),

Variants detected:
Family A - homozygous c.409T>G (p.Leu137Val);
Family B - 3 affected fetuses homozygous for c.1411C>T (p.Gln471Ter);
Family C - sibs compound het for c.1228T>G (p.Phe410Val) and c.1251_1252insTAA (p.Thr418Ter);
Family D - affected individuals (1 fetal case) homozygous for c.1366G>C (p.Asp456His) - shown to impact splicing (r.406_442del), resulting in predicted p.Ser136LeufsTer19 change;
Family E - affected child with homozygous c.835C>T (p.Arg279Ter) change;
Family F - fetus homozygous for c.1260G>A (p.Trp420Ter);

Functional evidence: Fsd1l depletion in mouse embryos recapitulated the ventricular dilation observed in affected fetuses.

FSD1L is not yet associated with a phenotype in OMIM or Gene2Phenotype.; to: PMID: 41720098 Serpieri et al., 2026
Report of eleven individuals (including five fetuses) from six unrelated families harbouring biallelic FSD1L variants. Seq method: exome sequencing. Consanguinity was confirmed in 4/6 families, and suspected in the fifth.
Phenotype spectrum: severe intellectual disability (5/5 assessed from 3 families), epilepsy (5 individuals from 3 families), severe hydrocephalus (3 families), vision deficit due to optic nerve hypoplasia/atrophy (3 families), spastic tetraparesis (2 families) corpus callosum hypoplasia/agenesis on MRI (5/5 families assessed),

Variants detected - largely nonsense type:
Family A - homozygous c.409T>G (p.Leu137Val);
Family B - 3 affected fetuses homozygous for c.1411C>T (p.Gln471Ter);
Family C - sibs compound het for c.1228T>G (p.Phe410Val) and c.1251_1252insTAA (p.Thr418Ter);
Family D - affected individuals (1 fetal case) homozygous for c.1366G>C (p.Asp456His) - shown to impact splicing (r.406_442del), resulting in predicted p.Ser136LeufsTer19 change;
Family E - affected child with homozygous c.835C>T (p.Arg279Ter) change;
Family F - fetus homozygous for c.1260G>A (p.Trp420Ter);

Functional evidence: Fsd1l depletion in mouse embryos recapitulated the ventricular dilation observed in affected fetuses.

FSD1L is not yet associated with a phenotype in OMIM or Gene2Phenotype.
Retinal disorders v8.86 MDM1 Arina Puzriakova edited their review of gene: MDM1: Added comment: PMID: 41742423 (2026) - 6 individuals from 5 unrelated families with biallelic predicted null variants in MDM1 (aka SAXO6). Ophthalmic examination revealed retinitis pigmentosa in 4 individuals and cone-rod dystrophy in 2 individuals.
SAXO6 was shown to co-localise with distinct ciliary microtubules from the immotile cilium present in rod and cone photoreceptors in human retina, and mass spectrometry demonstrated an interaction with α-tubulin, supporting its classification as a microtubule inner protein.

This gene is not yet associated with any phenotype in OMIM or G2P.; Changed rating: GREEN; Changed publications to: 41742423; Changed phenotypes to: Retinal dystrophy, HP:0000556; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.86 MDM1 Siying Lin gene: MDM1 was added
gene: MDM1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: MDM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDM1 were set to PMID: 41742423
Phenotypes for gene: MDM1 were set to Retinal dystrophy
Penetrance for gene: MDM1 were set to unknown
Mode of pathogenicity for gene: MDM1 was set to Other
Review for gene: MDM1 was set to GREEN
Added comment: Recent publication (PMID: 41742423) reporting 6 affected individuals from 5 families with biallelic loss of function variants in MDM1 (also known as SAXO6) and retinal dystrophy
Sources: Literature
Retinal disorders v8.86 FSD1L Siying Lin gene: FSD1L was added
gene: FSD1L was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: FSD1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FSD1L were set to 41720099
Phenotypes for gene: FSD1L were set to Retinitis pigmentosa; retinal dystrophy
Penetrance for gene: FSD1L were set to unknown
Mode of pathogenicity for gene: FSD1L was set to Other
Review for gene: FSD1L was set to GREEN
Added comment: Lin, Cancellieri, Cao et al (PMID 41720099) describe 6 affected individuals from 4 families with retinitis pigmentosa. 2 affected siblings had both retinitis pigmentosa and a mild neurodevelopmental phenotype; the remaining four individuals had apparent isolated retinal dystrophy, including one individual who underwent a full neurological evaluation, including brain neuroimaging, which revealed no evidence of central nervous system involvement. This suggests that FSD1L-associated disease may therefore span a broad phenotypic spectrum, ranging from severe neurodevelopmental syndromes to, at its mildest, non-syndromic retinal dystrophy.
Sources: Literature
Retinal disorders v8.86 MORC2 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Siying Lin, there are more than 3 individuals reported in literature with heterozygous MORC2 variants, presenting with retinal disease. The retinal phenotype ranged from mild pigmentary changes reported in childhood to severe retinitis pigmentosa in adulthood. Based on available evidence, this gene should be updated to Green for Retinal disease.; to: Comment on list classification: As reviewed by Siying Lin, there are more than 3 individuals reported in literature with heterozygous MORC2 variants, presenting with syndromic retinal disease. The retinal phenotype ranged from mild pigmentary changes reported in childhood to severe retinitis pigmentosa in adulthood. Based on available evidence, this gene should be updated to Green for Retinal disease.
Retinal disorders v8.86 MORC2 Ida Ertmanska commented on gene: MORC2: Comment on list classification: As reviewed by Siying Lin, there are more than 3 individuals reported in literature with heterozygous MORC2 variants, presenting with retinal disease. The retinal phenotype ranged from mild pigmentary changes reported in childhood to severe retinitis pigmentosa in adulthood. Based on available evidence, this gene should be updated to Green for Retinal disease.
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 v8.78 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 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).
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
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 v8.74 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 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 v8.73 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 v8.71 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 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 v8.69 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 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 v8.67 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 v8.65 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
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
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
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).
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 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 v8.39 VSX2 Ida Ertmanska changed review comment from: Biallelic VSX2 variants often result in microphthalmia, anophthalmia, coloboma (MAC):

PMID: 21976963 Reis et al., 2011
2 unrelated consanguineous families with AR isolated bilateral microphthalmia.
Pakistani family - affected individuals homozygous for c.668G>C (p.G223A).
Iranian family - affected individuals homozygous for c.249delG (p.Leu84SerfsX57). ERG performed on 2 sisters in this family showed inner retinal dysfunction in both.

As reviewed by Beisi Xu, there are also at least three different VSX2 variants reported in three unrelated patients with retinopathy and no reported MAC phenotype.

PMID: 36264558 Smirnov et al., 2022: 3 patients from 2 unrelated non-consanguineous Turkish families, harbouring homozygous missense variants: c.595C>T, p.(Arg199Cys) and c.698C>T, p.(Pro233Leu). All 3 patients presented with infantile nystagmus, low stable visual acuity, myopia and night blindness, cause by retinopathy with lens luxation.

PMID: 24001013 Khan et al., 2013: Case study - Female, 3yo, Saudi Arabian. Phenotype: Poor vision from birth, chorioretinal atrophy, retinal dysfunction; superior lens subluxation and smooth iris. Homozygous for c.773delA; p.(Lys258Serfs*44); variant heterozygous in unaffected brother and consanguineous parents. Homozygous frameshift BCAP29 variant also identified in patient - not much known about this gene.
Functional studies in mice and human retinal organoids indicate that the reported VSX2 variants have a variable effect on VSX2’s DNA binding properties, which may explain the phenotypic heterogeneity observed in patients (PMID: 23028343; 35831950; 38994775).

This gene is not yet associated with retinal disorders in OMIM or Gene2Phenotype.; to: Biallelic VSX2 (formerly CHX10) variants often result in microphthalmia, anophthalmia, coloboma (MAC).

PMID: 21976963 Reis et al., 2011
2 unrelated consanguineous families with AR isolated bilateral microphthalmia.
Pakistani family - affected individuals homozygous for c.668G>C (p.G223A).
Iranian family - affected individuals homozygous for c.249delG (p.Leu84SerfsX57). ERG performed on 2 sisters in this family showed inner retinal dysfunction in both.

As reviewed by Beisi Xu, there are also at least three different VSX2 variants reported in three unrelated patients with retinopathy and no reported MAC phenotype:

PMID: 36264558 Smirnov et al., 2022: 3 patients from 2 unrelated non-consanguineous Turkish families, harbouring homozygous missense variants: c.595C>T, p.(Arg199Cys) and c.698C>T, p.(Pro233Leu). All 3 patients presented with infantile nystagmus, low stable visual acuity, myopia and night blindness, cause by retinopathy with lens luxation.

PMID: 24001013 Khan et al., 2013: Case study - Female, 3yo, Saudi Arabian. Phenotype: Poor vision from birth, chorioretinal atrophy, retinal dysfunction; superior lens subluxation and smooth iris. Homozygous for c.773delA; p.(Lys258Serfs*44); variant heterozygous in unaffected brother and consanguineous parents. Homozygous frameshift BCAP29 variant also identified in patient - not much known about this gene.

Functional studies in mice and human retinal organoids indicate that the reported VSX2 variants have a variable effect on VSX2’s DNA binding properties, which may explain the phenotypic heterogeneity observed in patients (PMID: 23028343; 35831950; 38994775).
PMID: 8630490 Burmeister et al., 1996: Mice homozygous for a premature stop codon in VSX2/CHX10 are blind, with obvious microphthalmia, cataractous lens, a thin retina, and no optic nerve. Study notes that loss of VSX2CHX10 leads both to reduced proliferation of retinal progenitors and to a specific absence of differentiated bipolar cells - supportive of MAC / retinal degeneration phenotype seen in patients.

This gene is not yet associated with retinal disorders in OMIM or Gene2Phenotype.
Retinal disorders v8.39 PDE6H Achchuthan Shanmugasundram changed review comment from: There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with ncomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.; to: There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with incomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.
Retinal disorders v8.38 PDE6H Achchuthan Shanmugasundram commented on gene: PDE6H: There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with ncomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.
Retinal disorders v8.25 CYP2U1 Ida Ertmanska commented on gene: CYP2U1: Comment on list classification: As reviewed by Cassandra Smith, individuals with biallelic variants in CYP2U1 may present with retinal abnormalities, which fits into the scope of this panel - there at least 8 unrelated individuals reported in literature. The retinal disease has a variable age of onset (ranging from 6 to 32 years old in reported cases), sometimes appearing as the first symptom, before spasticity. Based on the available evidence, CYP2U1 should be rated Green for Retinal disorders.
Retinal disorders v8.25 CYP2U1 Ida Ertmanska commented on gene: CYP2U1: CYP2U1 is known to cause hereditary spastic paraplegia, with a variable spectrum of other symptoms being reported: intellectual disability, dystonia, pseudoxanthoma elasticum, and visual impairments (pigmentary degenerative maculopathy, loss of visual acuity, photophobia). There are at least 8 unrelated individuals with retinal abnormalities with biallelic variants in CYP2U1, harbouring missense, stop-gained, splice-altering, and frameshift variants (PMID: 23176821, 26914923, 33107650, 34828401, 38058766, 39605873). The retinal disease has a variable age of onset (ranging from 6 to 32 years old in reported cases) – sometimes appearing as the first symptom, before spasticity (e.g. PMID:26914923, 39605873).

FUNCTIONAL EVIDENCE: A Cyp2u1−/− mouse model recapitulated the retinal impairments observed in patients – mice exhibited a late-onset (18 mo) ophthalmologic phenotype characterized by a cone dystrophy (PMID: 34546337 Pujol et al., 2021). Skin fibroblasts of an individual with c.61_73del, p.(Leu21Trpfs∗19) in CYP2U1 showed reduced oxygen consumption compared to controls, as well as structural abnormalities of the mitochondrial membrane (PMID: 23176821 Tesson et al., 2012). Expressing CYP2U1 with missense variants in HEK293T cells demonstrated that most missense variants were functionally inactive, due to loss of proper heme binding or destabilization of the protein structure (PMID: 29034544 Durand et al., 2018). Thus, the proposed disease mechanism is LoF leading to mitochondrial dysfunction - a common driver for degenerative retinal disease. Based on the available evidence, CYP2U1 should be rated Green for Retinal disorders.

The gene is associated with Spastic paraplegia 56, autosomal recessive (OMIM:615030, accessed 17th Sep 2025). It is also Definitive for CYP2U1-related spastic paraplegia in G2P (G2P00349).
Retinal disorders v8.14 CFI Ida Ertmanska changed review comment from: PMID: 25986072 – Two families with carriers of CFI:c.1234G>A p.(Val412Met). 24yo heterozygous carrier Fam3-01 displayed early-onset drusen maculopathy. Individual Fam1-01, 68yo, had advanced age-related macular degeneration – time of onset unknown. 10/200 unrelated Tunisian Jewish controls were reported to carry for the variant (5% allele freq) - too high to cause the disorder. The variant is also present in gnomAD v4.1.0: highest allele freq = 0.0004954 (Middle Eastern population; no homozygotes).
OMIM reports a gene association with disease susceptibility (OMIM:615439 Macular degeneration, age related, 13, susceptibility to; accessed 20th Aug 2025).; to: PMID: 25986072 – Two families with carriers of CFI:c.1234G>A p.(Val412Met). 24yo heterozygous carrier Fam3-01 displayed early-onset drusen maculopathy. Individual Fam1-01, 68yo, had advanced age-related macular degeneration – time of onset unknown. 10/200 unrelated Tunisian Jewish controls were reported to carry for the variant (5% allele freq) - too high to cause the disorder. The variant is also present in gnomAD v4.1.0: highest allele freq = 0.0004954 (Middle Eastern population; no homozygotes).
OMIM reports a gene association with disease susceptibility (OMIM:615439 Macular degeneration, age related, 13, susceptibility to; accessed 20th Aug 2025).
Retinal disorders v8.5 TBC1D32 Achchuthan Shanmugasundram gene: TBC1D32 was added
gene: TBC1D32 was added to Retinal disorders. Sources: Literature
dd_review, Q2_25_ promote_green tags were added to gene: TBC1D32.
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 37768732
Phenotypes for gene: TBC1D32 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: TBC1D32 was set to GREEN
Added comment: PMID:37768732 reported the identification of biallelic variants in TBC1D32 gene in four individuals from three unrelated families with retinitis pigmentosa. In addition, data from Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models also support the disease association.

This gene is not yet associated with any phenotypes in OMIM.
Sources: Literature
Retinal disorders v8.4 DYRK1A Siying Lin gene: DYRK1A was added
gene: DYRK1A was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: DYRK1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DYRK1A were set to PMID: 40405340; 36736451
Phenotypes for gene: DYRK1A were set to FEVR
Mode of pathogenicity for gene: DYRK1A was set to Other
Review for gene: DYRK1A was set to GREEN
Added comment: PMID 36736451: one individual with DYRK1A syndrome and anomalous retinal vasculature.
PMID 40405340: two individuals with FEVR-like presentations and later likely disease-causing DKRY1A variants identified; the retinal phenotype can be the presenting feature of DYRK1A syndrome
Sources: Literature
Retinal disorders v7.8 AP5B1 Siying Lin gene: AP5B1 was added
gene: AP5B1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: AP5B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP5B1 were set to PMID 40081374
Phenotypes for gene: AP5B1 were set to Macular dystrophy
Mode of pathogenicity for gene: AP5B1 was set to Other
Review for gene: AP5B1 was set to GREEN
Added comment: 2 individuals from 2 families with biallelic loss of function variants and macular dystrophy
Sources: Literature
Retinal disorders v7.2 GPATCH11 Achchuthan Shanmugasundram changed review comment from: PMID:39572588 reported 12 individuals from six unrelated families presenting with a syndromic disease and they were identified with biallelic variants in GPATCH11 gene. Intellectual disability was present in three unrelated families, while global developmental delay was reported in all.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39572588 reported 12 individuals from six unrelated families presenting with a syndromic disease and they were identified with biallelic variants in GPATCH11 gene. Retinal dystrophy and mild foveolar hypoplasia were reported in one family, whereas macular atrophy was reported in a different family. Signs of retinitis pigmentosa was reported in another family.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Retinal disorders v7.2 GPATCH11 Achchuthan Shanmugasundram gene: GPATCH11 was added
gene: GPATCH11 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: GPATCH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPATCH11 were set to 39572588
Phenotypes for gene: GPATCH11 were set to neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: GPATCH11 was set to GREEN
Added comment: PMID:39572588 reported 12 individuals from six unrelated families presenting with a syndromic disease and they were identified with biallelic variants in GPATCH11 gene. Intellectual disability was present in three unrelated families, while global developmental delay was reported in all.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Retinal disorders v7.1 C19orf44 Andrew Webster gene: C19orf44 was added
gene: C19orf44 was added to Retinal disorders. Sources: Research
Mode of inheritance for gene: C19orf44 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: C19orf44 were set to retinal dystrophy; macular dystrophy; cone-rod dystrophy; rod-cone dystrophy
Penetrance for gene: C19orf44 were set to unknown
Mode of pathogenicity for gene: C19orf44 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: C19orf44 was set to GREEN
Added comment: Publication accepted by Genetics In Medicine, involving four LOF alleles in 15 affected individuals from 11 families, with four centres contributing (Israel, Boston, Basel, London (UCL/MEH)).

GENETMED-D-24-00741R2
Biallelic null variants in C19orf44 cause a unique late onset retinal dystrophy
phenotype characterized by patchy perifoveal chorioretinal atrophy
Sources: Research
Retinal disorders v6.18 COQ8B Achchuthan Shanmugasundram changed review comment from: PMID:39226897 reported the identification of compound heterozygous variants in COQ8B gene in five individuals from four different families with non-syndromic retinitis pigmentosa. In total, five different variants were identified from these patients (p.Arg63Trp, p.Trp189Ter, p.Asp386Asn, p.Val442Met and p.Trp520Ter). In addition, cell-based analysis of recombinant proteins deriving from these genotypes showed in all cases a significant decrease in ligand-protein interaction compared to the wild type.; to: PMID:39226897 reported the identification of compound heterozygous variants in COQ8B gene in five individuals from four different families with non-syndromic retinitis pigmentosa. In total, five different variants were identified from these patients (p.Arg63Trp, p.Trp189Ter, p.Asp386Asn, p.Val442Met and p.Trp520Ter). In addition, cell-based analysis of recombinant proteins deriving from these genotypes showed in all cases a significant decrease in ligand-protein interaction compared to the wild type.

This gene has not yet been associated with retinal phenotype either in OMIM or in Gene2Phenotype.
Retinal disorders v6.18 COQ8B Achchuthan Shanmugasundram commented on gene: COQ8B: PMID:39226897 reported the identification of compound heterozygous variants in COQ8B gene in five individuals from four different families with non-syndromic retinitis pigmentosa. In total, five different variants were identified from these patients (p.Arg63Trp, p.Trp189Ter, p.Asp386Asn, p.Val442Met and p.Trp520Ter). In addition, cell-based analysis of recombinant proteins deriving from these genotypes showed in all cases a significant decrease in ligand-protein interaction compared to the wild type.
Retinal disorders v6.5 MAN2B1 Siying Lin gene: MAN2B1 was added
gene: MAN2B1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: MAN2B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2B1 were set to PMID:29859105
Phenotypes for gene: MAN2B1 were set to Retinal dystrophy
Mode of pathogenicity for gene: MAN2B1 was set to Other
Review for gene: MAN2B1 was set to GREEN
Added comment: Retinal dystrophy can be a feature of the systemic alpha-mannosidosis phenotype, and can be the presenting feature in apparent non-syndromic retinal dystrophy (one individual in the Moorfields cohort)
Sources: Literature
Retinal disorders v6.4 STX3 Achchuthan Shanmugasundram gene: STX3 was added
gene: STX3 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: STX3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STX3 were set to 33974130
Phenotypes for gene: STX3 were set to Retinal dystrophy and microvillus inclusion disease, OMIM:619446
Review for gene: STX3 was set to GREEN
Added comment: PMID:33974130 assembled a cohort of ten individuals from eight families with microvillus inclusion disease (MVID), which included follow up of five previously reported individuals and five new individuals. All of them had homozygous loss-of-function nonsense variants in STX3 gene. Eight of them presented with a novel syndrome consisting of MVID and early-onset severe retinal dystrophy (EOSRD). All six different variants identified in individuals with MVID and EOSRD are located in exons shared between the STX3A and the STX3B transcripts, while the single variant (p.Arg247Ter) present in other two individuals with MVID only is located in exon 9A and it spares STX3B transcript.

Functional studies showed that STX3B transcript is highly expressed in human retina and that the protein is enriched in the inner and outer segments of photoreceptors and in ribbon synapses of the human retina. The study also showed that the inactivation of Stx3 in murine rod photoreceptors leads to a progressive degeneration of photoreceptors, corroborating a recently published study that used a different Stx3 knockout mouse line.

In summary, biallelic variants affecting both STX3A and STX3B transcripts cause MVID and EOSRD, while variants affecting only STX3A transcript cause MVID.

This gene has been associated with both phenotypes in OMIM (MIMs #619445 & #619446), but not yet in Gene2Phenotype.
Sources: Literature
Retinal disorders v5.5 PQLC2 Achchuthan Shanmugasundram gene: PQLC2 was added
gene: PQLC2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: PQLC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PQLC2 were set to 35486108
Phenotypes for gene: PQLC2 were set to Retinitis pigmentosa, MONDO:0019200
Review for gene: PQLC2 was set to GREEN
Added comment: PMID:35486108 reported whole-exome sequencing with targeted analysis of SLC genes in 913 cases from 785 families with inherited retinal dystrophy. This identified 2 different homozygous variants in SLC66A1 in three individuals from two families with adult-onset retinal dystrophy.

Olinger et al. (2024) (https://www.sciencedirect.com/science/article/pii/S2949774424009804) reported CNV analysis of trio and non-trio WGS data from Genomics England 100K genomes project. This identified homozygous 21kb deletion spanning nearly entire SLC66A1 gene in 2 siblings with adult-onset rod-cone dystrophy, while parents are heterozygous carriers. Review of cohort data then identified homozygous loss-of-function variants (1 nonsense, 2 frameshift) in another 3 unrelated individuals with rod-cone dystrophy.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Retinal disorders v4.71 ATXN7_CAG Siying Lin STR: ATXN7_CAG was added
STR: ATXN7_CAG was added to Retinal disorders. Sources: Literature
Mode of inheritance for STR: ATXN7_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: ATXN7_CAG were set to PMID: 27632585,
Phenotypes for STR: ATXN7_CAG were set to Maculopaty; Cone-Rod Dystrophy
Review for STR: ATXN7_CAG was set to GREEN
Added comment: PMID: 27632585 (father of proband), this ARVO abstract ( https://iovs.arvojournals.org/article.aspx?articleid=2768575) and cases from our clinical cohort, demonstrate that affected individuals can present with a seemingly isolated maculopathy or cone-rod dystrophy that precedes the onset of neurological symptoms
Sources: Literature
Retinal disorders v4.71 SAMD7 Siying Lin gene: SAMD7 was added
gene: SAMD7 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: SAMD7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SAMD7 were set to PMID: 38272031
Phenotypes for gene: SAMD7 were set to Macular dystrophy; cone dystrophy
Penetrance for gene: SAMD7 were set to unknown
Mode of pathogenicity for gene: SAMD7 was set to Other
Review for gene: SAMD7 was set to GREEN
Added comment: 5 different variants identified in homozygosity in 6 families from varying ethnicities (Pakistani, African, Yemenite Jewish, Berber/Morocccan) segregating with disease. All affected individuals presented with macular dystrophy, a few had additional cone system involvement. Immunofluorescence studies show SAMD7 localisation to inner and outer nuclear layers of the human retina.
Sources: Literature
Retinal disorders v4.50 VWA8 Arina Puzriakova Added comment: Comment on list classification: New gene added by Hannah Knight. A single family (PMID: 37012052) with 11 individuals all presenting initial symptoms of visual defects which later progressed to macular changes, including macular degeneration and dystrophy. Two variants (c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter)) on the same allele of the VWA8 gene were found to segregate with disease. Expression studies showed reduced protein expression. Zebrafish knockdown model displayed a similar phenotype to that of humans.

Although there is only one family reported to date, multi-generational segregation with disease and concordant phenotype in a knockdown zebrafish model supports pathogenicity and therefore rating Amber with a 'watchlist' tag.
Retinal disorders v4.36 CFAP20 Zornitza Stark gene: CFAP20 was added
gene: CFAP20 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: CFAP20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP20 were set to 36329026
Phenotypes for gene: CFAP20 were set to Retinitis pigmentosa (MONDO:0019200)
Review for gene: CFAP20 was set to GREEN
Added comment: Describe 8 individuals from 4 independent families with damaging biallelic variants (homozygous or compound heterozygous) in CFAP20 that segregate with retinal dystrophy. All variants cluster to one side of the protein, with two of the residues directly contacting alpha-tubullin.

Family 1 - consanguineous set of 3 siblings from Sudan, homozygous for CFAP20 c.305G>A; p.Arg102His (they also had a homozygous variant in DYNC1LI2 however CFAP20 was considered the better candidate.
Family 2 - 3 siblings from Spain, 2 with retinal dystrophy, 1 genetically tested and has c.337C>T; p.(Arg113Trp) and c.397delC; p.(Gln133Serfs*5)
Family 3 - single affected family member compound het for c.164+1G>A and c.457A>G; p.(Arg153Gly).
Family 4 - 3 affected siblings with generalised retinopathy and variable neurological deficits with c.164+1G>A and c.257G>A; p.(Tyr86Cys)

For all families, no individuals had signs of polycystic kidney disease; however, not all individuals had kidney imaging. Visual defecit phenotype presented between adolescence and adulthood (17-56 years old).

Used HEK293T cell expression studies to demonstrate a statistically significant decline of mutated CFAP20 protein levels (with the exception of p.Arg102His). To test the specific variants, they used the C.elegans orthologues.

CFAP20 is a ciliopathy candidate. Demonstrate in zebrafish that cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development.
Sources: Literature
Retinal disorders v4.20 MPDZ Siying Lin changed review comment from: PMID 28556411: 3 families with affected individuals with biallelic MPDZ variants and congenital hydrocephalus with retinohoroidal coloboma, macular hypoplasia and foveal hypoplasia
PMID 36594712: 2 siblings with biallelic MPDZ variants and macular colobomas
PMID 36429029: proband with biallelic MPDZ variants and macular coloboma
Sources: Literature; to: PMID 28556411: 3 families with affected individuals with biallelic MPDZ variants and congenital hydrocephalus with retinohoroidal coloboma, macular hypoplasia and foveal hypoplasia
PMID 36594712: 2 siblings with biallelic MPDZ variants and macular colobomas
PMID 36429029: proband with biallelic MPDZ variants and macular coloboma
Sources: Literature
Retinal disorders v4.20 MPDZ Siying Lin gene: MPDZ was added
gene: MPDZ was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: MPDZ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPDZ were set to PMID 28556411, 36594712, 36429029
Mode of pathogenicity for gene: MPDZ was set to Other
Added comment: PMID 28556411: 3 families with affected individuals with biallelic MPDZ variants and congenital hydrocephalus with retinohoroidal coloboma, macular hypoplasia and foveal hypoplasia
PMID 36594712: 2 siblings with biallelic MPDZ variants and macular colobomas
PMID 36429029: proband with biallelic MPDZ variants and macular coloboma
Sources: Literature
Retinal disorders v4.12 PYGM Siying Lin gene: PYGM was added
gene: PYGM was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: PYGM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PYGM were set to PMID 30316539
Phenotypes for gene: PYGM were set to Macular dystrophy, retinopathy
Mode of pathogenicity for gene: PYGM was set to Other
Review for gene: PYGM was set to GREEN
Added comment: Mahroo et al (PMID 30316539) report on 4 individuals with McArdle disease and biallelic variants in PYGM and similar retinopathy affecting the macula. Screening results for mutations in a number of macular dystrophy genes were negative, supporting the association of this retinopathy with McArdle disease
Sources: Literature
Retinal disorders v3.34 SGSH Siying Lin gene: SGSH was added
gene: SGSH was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: SGSH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGSH were set to PMID 31718697
Mode of pathogenicity for gene: SGSH was set to Other
Review for gene: SGSH was set to GREEN
Added comment: Reports of late onset retinal dystrophy with mild systemic involvement (attenuated MPS phenotype) associated with biallelic genotypes which include likely hypomorphic alleles. Also two individuals identified in our clinical cohort with retinal dystrophy associated with biallelic SGSH variants.
Sources: Literature
Retinal disorders v2.273 FRMD7 Ivone Leong changed review comment from: Comment on list classification: New gene added by Mohammed Derar (University of Leeds). This gene is associated with a disease in OMIM and Gene2Phenotype.

PMID: 35157951 found patients with FRMD7 variants had grade 1 foveal hypoplasia or normal foveal morphology.

PMID: 30025138 did not perform any tests to look at foveal hypoplasia.

PMID: 33531592 showed a an FRMD7 variant in one sibling (proband) of a dizygotic twin pair. The other sibling is unaffected. The family reported nystagmus in another male sibling and the maternal grandfather; however, it is unclear whether these two individuals were also tested for FRMD7 variant. The proband had foveal hypoplasia. As it does not appear all patients with variants

PMID: 30015830 identified causative variants in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. Retinal OCT was conducted and was found to be normal.

As foveal hypoplasia does not appear to affect all individuals with FRMD7 variants, this gene has been referred to NHS GMS working group to determine if this gene is appropriate for this panel.; to: Comment on list classification: New gene added by Mohammed Derar (University of Leeds). This gene is associated with a disease in OMIM and Gene2Phenotype.

PMID: 35157951 found patients with FRMD7 variants had grade 1 foveal hypoplasia or normal foveal morphology.

PMID: 30025138 did not perform any tests to look at foveal hypoplasia.

PMID: 33531592 showed a an FRMD7 variant in one sibling (proband) of a dizygotic twin pair. The other sibling is unaffected. The family reported nystagmus in another male sibling and the maternal grandfather; however, it is unclear whether these two individuals were also tested for FRMD7 variant. The proband had foveal hypoplasia. As it does not appear all patients with variants

PMID: 30015830 identified causative variants in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. Retinal OCT was conducted and was found to be normal.

Nystagmus is the presenting feature and foveal hypoplasia does not appear to affect all individuals with FRMD7 variants. This gene is already Green on the "Albinism or congenital nystagmus" (version 1.23) panel; therefore, this gene will remain as Amber for now.
Retinal disorders v2.269 FRMD7 Ivone Leong Added comment: Comment on list classification: New gene added by Mohammed Derar (University of Leeds). This gene is associated with a disease in OMIM and Gene2Phenotype.

PMID: 35157951 found patients with FRMD7 variants had grade 1 foveal hypoplasia or normal foveal morphology.

PMID: 30025138 did not perform any tests to look at foveal hypoplasia.

PMID: 33531592 showed a an FRMD7 variant in one sibling (proband) of a dizygotic twin pair. The other sibling is unaffected. The family reported nystagmus in another male sibling and the maternal grandfather; however, it is unclear whether these two individuals were also tested for FRMD7 variant. The proband had foveal hypoplasia. As it does not appear all patients with variants

PMID: 30015830 identified causative variants in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. Retinal OCT was conducted and was found to be normal.

As foveal hypoplasia does not appear to affect all individuals with FRMD7 variants, this gene has been referred to NHS GMS working group to determine if this gene is appropriate for this panel.
Retinal disorders v2.241 PAK2 Arina Puzriakova gene: PAK2 was added
gene: PAK2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: PAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAK2 were set to 33693784
Phenotypes for gene: PAK2 were set to Knobloch 2 syndrome
Review for gene: PAK2 was set to RED
Added comment: 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.
Sources: Literature
Retinal disorders v2.236 ALPK1 Neringa Jurkute changed review comment from: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individuals shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.

PMID: 30967659; 31053777; 31939038; 34159509; to: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individuals shared overlapping phenotype with retinal changes, chronic disc swelling observed in majority of cases.

OMIM: 614979

PMID: 30967659; 31053777; 31939038; 34159509
Retinal disorders v2.236 ALPK1 Neringa Jurkute changed review comment from: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individual shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.

PMID: 30967659; 31053777; 31939038; 34159509; to: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individuals shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.

PMID: 30967659; 31053777; 31939038; 34159509
Retinal disorders v2.220 ARL3 Ivone Leong Added comment: Comment on publications: PMID:30269812 describes 2 unrelated consanguineous families (Saudi and Pakistani). Both have phenotype resembling Joubert syndrome (night blindness, rod-cone dystrophy, mild dysmorphic features, hypotonia (only in 1 family), ataxia, cerebellar vernis hypoplasia). Both are homozygous missense for the same amino acid residue (R149C, R149H). The authors performed some in vitro functional analysis.

PMID:16565502 describes a knockout mouse model of Arl3. The homozygous knockouts developed ciliary disease affecting kidney, biliary tract, pancreas and retina. However, there was no mention of a brain phenotype.

PMID:31743939 describes 2 large consanguineous Pakastani families with the same homozygous variant (Arg99Ile). There are 8 affected individuals in total and 7/8 had cone-rod dystrophy and no features of Joubert syndrome.

PMID:33748123 describes a Chinese family. Proband is compound het (c.91A>G, p.T31A; c.353G>T, p.C118F) and has retinal dystrophy. Heterozygous father has late onset and mild rode-cone dystrophy. Mother and sister (het) are normal. All family members did not have any other phenotypes.

PMID:26964041 describes a family with affected mother, son and daughter with retinitis pigmentosa. Affected patients were heterozygosity for Y90C. The mother's parents do not have the variant suggesting that it is a de novo event in the mother. No functional studies of the variant were performed.

PMID:30932721 reports a case where a patient has a de novo Y90C variant and has RP.

PMID:34485303 reports a heterozygous Asp67Val variant segregating in an Ashkenazi Jewish family with a dominant inherited retinal degenerations.
Retinal disorders v2.219 BEST1 Eleanor Williams changed review comment from: Review of mode of inheritance:
Macular dystrophy, vitelliform, 2 OMIM:153700 - many heterozygous cases reported

OMIM also lists Bestrophinopathy, autosomal recessive OMIM:611809 and Retinitis pigmentosa, concentric and Retinitis pigmentosa-50 OMIM:613194 but with no inheritance pattern listed.

Reports for 11 biallelic cases:

PMID: 18179881 Burgess et al 2008 - report on the analysis of the BEST1 gene in 7 affected individuals from 5 unrelated families of European ethnicity. Clinical electrophysiology of affected individuals showed abnormal full-field ERGs in addition to a severe reduction in the electrooculogram (EOG) light rise analogous to that seen with dominant BEST1 mutations that cause both Best disease and autosomal-dominant vitreoretinochoroidopathy. In all families homozygous or compound het variants in BEST1 were found (6 missense, 1 nonsense). 10 asymptomatic heterozygotes were examined in detail and were found to have a normal retinal examination, ERG responses, and EOG light rise.

PMID: 34327816 - Nowomiejska et al 2021 - in retrospective variant-phenotype analysis they report 6 patients with either homozygous or compound het variants in BEST1, aswell as 24 patients with heterozygous variants.; to: Review of mode of inheritance:
Macular dystrophy, vitelliform, 2 OMIM:153700 - many heterozygous cases reported

OMIM also lists Bestrophinopathy, autosomal recessive OMIM:611809 and Retinitis pigmentosa, concentric and Retinitis pigmentosa-50 OMIM:613194 but with no inheritance pattern listed.

Reports for 11 biallelic cases:

PMID: 18179881 Burgess et al 2008 - report on the analysis of the BEST1 gene in 7 affected individuals from 5 unrelated families of European ethnicity. Clinical electrophysiology of affected individuals showed abnormal full-field ERGs in addition to a severe reduction in the electrooculogram (EOG) light rise analogous to that seen with dominant BEST1 mutations that cause both Best disease and autosomal-dominant vitreoretinochoroidopathy. In all families homozygous or compound het variants in BEST1 were found (6 missense, 1 nonsense). 10 asymptomatic heterozygotes were examined in detail and were found to have a normal retinal examination, ERG responses, and EOG light rise.

PMID: 34327816 - Nowomiejska et al 2021 - in a retrospective variant-phenotype analysis they report 6 patients with either homozygous or compound het variants in BEST1, aswell as 24 patients with heterozygous variants.
Retinal disorders v2.216 IRX5 Eleanor Williams changed review comment from: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of function/gene
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
; to: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of gene/small variants
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
Retinal disorders v2.213 SPTLC2 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is associated with a phenotype in OMIM and Gene2Phenotype.

PMID: 31509666 reported on 2 unrelated families (family 1 and 2) and 3 unrelated individuals (patients 1, 2 and 3) who have HSAN1 and have variants in SPTLC1 (2 families and patient 1 have the same heterozygous variant C133Y, and patient 2 and 3 have C133W, also heterozygous). Those with the C133Y variant have HSAN1 and macular telangiectasia type 2 and those with C133W variant only have HSAN1 and no eye phenotype. The authors note that patients with C133W both patients were under the age of 50 and had been treated with serine supplementation.

Affected members of family 3 was diagnosed with HSAN1C and were heterozygous for S384F in SPTLC2 and macular telangiectasia type 2.

As there is only one case, there is not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Retinal disorders v2.211 SPTLC1 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype.

PMID: 31509666 reported on 2 unrelated families (family 1 and 2) and 3 unrelated individuals (patients 1, 2 and 3) who have HSAN1 and have variants in SPTLC1 (2 families and patient 1 have the same heterozygous variant C133Y, and patient 2 and 3 have C133W, also heterozygous). Those with the C133Y variant have HSAN1 and macular telangiectasia type 2 and those with C133W variant only have HSAN1 and no eye phenotype. The authors note that patients with C133W both patients were under the age of 50 and had been treated with serine supplementation.

Affected members of family 3 was diagnosed with HSAN1C and were heterozygous for S384F in SPTLC2 and macular telangiectasia type 2.

While there appears to be a link between this gene and macular telangiectasia type 2, all affected families/individuals have the same variant. Therefore, there is currently enough evidence to support a gene-disease association. This gene has been given an Amber rating until more information is available.
Retinal disorders v2.208 LRP1 Zornitza Stark gene: LRP1 was added
gene: LRP1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: LRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRP1 were set to 33776059
Phenotypes for gene: LRP1 were set to Macular drusen
Review for gene: LRP1 was set to RED
Added comment: PMID: 33776059 - 2x unrelated individuals with compound heterozygous missense variants and inherited retinal disorder/macular drusen. No functional data.
Sources: Literature
Retinal disorders v2.205 ALDH3A2 Arina Puzriakova gene: ALDH3A2 was added
gene: ALDH3A2 was added to Retinal disorders. Sources: Literature
Q3_21_rating tags were added to gene: ALDH3A2.
Mode of inheritance for gene: ALDH3A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH3A2 were set to 25784589; 29071827; 29183715; 31273323
Phenotypes for gene: ALDH3A2 were set to Sjogren-Larsson syndrome, OMIM:270200
Review for gene: ALDH3A2 was set to GREEN
Added comment: Biallelic variants in this gene are associated with Sjogren-Larsson syndrome (MIM# 270200). Some affected individuals exhibit ocular manifestations which include a distinctive retinal abnormality characterised by macular degeneration with perifoveal crystalline inclusions (also referred to as glistening white dots) which develop in the first few years of life. There are also some reports of patients with retinal pigmentary degeneration in the macular region and thinning of the retinal layers.
Sources: Literature
Retinal disorders v2.193 IRX5 Eleanor Williams changed review comment from: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition.

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of function/gene
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
; to: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of function/gene
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
Retinal disorders v2.193 IRX5 Eleanor Williams changed review comment from: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition.

Cone dystrophy
-------------------
PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa. ; to: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition.

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of function/gene
---------
PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
Retinal disorders v2.192 IRX5 Eleanor Williams changed review comment from: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition.

Cone dystrophy
-------------------
PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.; to: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition.

Cone dystrophy
-------------------
PMID: 33891002 - Khol et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.
Retinal disorders v2.182 ACBD5 Arina Puzriakova commented on gene: ACBD5: A fourth individual was identified by Dr Helen Brittain (Genomics England Clinical Fellow) who presented with retinal dystrophy, ataxia and developmental regression at 2 yrs old
Retinal disorders v2.91 MSTO1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and not in Gene2Phenotype. There are at least 7 unrelated cases who are biallelic for variants in this gene and 1 family of patients (4 affected) who are monoallelic for variants in this gene.

For patients who are biallelic, there are 3 cases that reported pigmentary retinopathy. 5 out of 7 cases had growth impairments. For patients who are monoallelic there are no ophthalmological findings and growth impairment was only reported for 1 affected individual.

As not all affected individuals with biallelic variants showed a retinal disorder this gene has been given an Amber rating. Whether there is enough evidence to support a gene-disease association and for this gene to be rated Green should be reviewed by the GMS specialist group.
Retinal disorders v2.52 AP3B2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with an eye phenotype in Gene2Phenotype but not in OMIM. PMID:27889060 describes 1 out of 8 families where individuals who have variants in this gene had retinitis pigmentosa and mild optic disc pallor. This gene is also Amber on the Optic neuropathy panel (Version 2.29).

Therefore, there is currently not enough evidence to support a gene-disease association, this gene has been given a Red rating.
Retinal disorders v2.33 SLC6A6 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. There are 2 unrelated cases with early retinal degeneration and a mouse model that replicates the human phenotype. Therefore, there is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. There are 2 unrelated cases with early retinal degeneration and a mouse model that replicates the human phenotype. PMID: 29886034 did not look at the eyes of patients so therefore unsure if the affected individual with a variant in SLC6A6 has an eye phenotype.

Therefore, there is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Retinal disorders v2.20 WDPCP Zornitza Stark changed review comment from: Two families reported; the first one with a BBS phenotype, and in the second one affected individual had polysyndactyly and tongue hamartomas, so phenotype consistent with OFD rather than BBS. Note this gene has discordant ratings on multiple panels.; to: Four families reported, with different ciliopathy phenotypes including BBS, OFD and syndromic retinopathy.
Retinal disorders v2.20 TUBB4B Zornitza Stark gene: TUBB4B was added
gene: TUBB4B was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: TUBB4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBB4B were set to 29198720
Phenotypes for gene: TUBB4B were set to Leber congenital amaurosis with early-onset deafness MIM#617879
Review for gene: TUBB4B was set to GREEN
gene: TUBB4B was marked as current diagnostic
Added comment: At least 5 affected individuals from 4 families with Leber congenital amaurosis and early-onset deafness with heterozygosity for 2 missense (R391H, R391C). Functional analysis demonstrated that the mutations have a significant dampening impact on microtubular growth.
Sources: Expert list
Retinal disorders v2.20 RIMS2 Zornitza Stark gene: RIMS2 was added
gene: RIMS2 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: RIMS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIMS2 were set to 32470375
Phenotypes for gene: RIMS2 were set to Cone-rod synaptic disorder syndrome, congenital nonprogressive, MIM# 618970
Review for gene: RIMS2 was set to GREEN
gene: RIMS2 was marked as current diagnostic
Added comment: Biallelic LoF variants reported with syndromic congenital cone-rod synaptic disease in 7 individuals from 4 families.
Sources: Expert list
Retinal disorders v2.17 ACBD5 Zornitza Stark changed review comment from: 2 families reported and supporting in vitro functional assays demonstrating ACBD5 deficiency leading to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation

PMID: 27799409: 1 individual who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. Functional assay supports ACBD5 deficiency leads to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation

PMID: 23105016: 1 family retinal dystrophy.; to: 2 families reported and supporting in vitro functional assays demonstrating ACBD5 deficiency leading to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation

PMID: 27799409: 1 individual who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. Functional assay supports ACBD5 deficiency leads to accumulation of very long-chain fatty acids due to impaired peroxisomal β-oxidation

PMID: 23105016: 1 family with retinal dystrophy.
Retinal disorders v1.147 IDH3A Ivone Leong gene: IDH3A was added
gene: IDH3A was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: IDH3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IDH3A were set to 28412069; 30478029
Phenotypes for gene: IDH3A were set to Retinitis Pigmentosa; Pseudocoloboma
Review for gene: IDH3A was set to GREEN
Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 28412069 reported on 7 individuals from 4 unrelated familes (Netherlands, Israel and South Africa) diagnosed have retinitis pigmentosa who have compound heterozygous/homozygous variants in IDHA3. PMID: 30478029 reported on a Idha3 mouse model that develops retinal degeneration. Therefore, there is enough evidence to promote this gene to green status.
Sources: Expert list