Gene-disease assertions not curated here (add link or write note):
Disease | SIX6-related colobomatous optic disc-macular atrophy-chorioretinopathy syndrome |
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Inheritance | Autosomal recessive |
Prevalence | Unknown Source: Orphanet |
Rapid or full curation? | Rapid Full |
CLINGEN - No curations by GCEPs, no evidence for haploinsufficiency/triplosensitivity (curation from 2012). In scope for Glaucoma and neuro-ophthalmology GCEP. GenCC - Strong (Invitae and PanelApp Australia. Limited by Ambry, for AR colobomatous optic disc-macular atrophy-chorioretinopathy syndrome. No BabySeq curations. Several variants in HGMD to review (see next section below) | |
Clinical Validity Scoring Notes and points |
Zamani 2022 PMID: 35754085. c.445C>T p.Q149* (absent gnomAD) in table 2 and in P42 shown in table 3, HOM for the variant. This individual had optic disk anomalies w/ retinal and/or macular dystrophy, Horizontal nystagmus, microphthalmia, photophobia, macular coloboma, microcornea. This variant is predicted to undergo NMD (in exon 1 of 2, not in the last 50 nt). 2 POINTS CASE EVIDENCE Panagiotou 2022 - PMID: 35693420 - C.547G>C p.Asp183His (absent gnomAD) found in family MEP68 with nystagmus, microcornea, opacity/sclerocornea, coloboma, cataracts, normal fundus. Found in three affected sibs, only one parent genotyped as a het carrier and family consangineous. Found via WES. due to consanguinity only counting 2 SEGREGATIONS. c.-227_572+235del1034 found HOM in 1 affected individual from family F1332, with anterior segment anomalies and microphthalmia. This is a deletion of exon 1, 227bp of the 5’UTR, and 235 bp of the first intron of SIX6, unlikely that transcription would occur NMD+. 2 CASE POINTS Aldahmesh 2013 PMID: 23167593. c.532_536delAACCG p.(Asn178Profs*142) - absent gnomAD, extension variant. Consangineous family from Syria, parents het with two homozygous affected children. Phenotype is mirophthlamia with coloboma. Counting as an NMD- variant since a large amount of the reading frame is disrupted. 0.5 CASE POINTS, 1 SEGREGATION Deepthi 2021 PMID: 33108933 - c.532_536delAACCG p.(Asn178Profs*142) - absent gnomAD, extension variant, same as article above. This is a family from Syria, but based on text description, it sounds like they are separate families, as they compare their cases to the two previously reported siblings. 0.5 CASE POINTS, 1 SEGREGATION LI 2002 PMID: 12130660 - Mouse model - deficienct in Six6 homeodomain factor by homologous recombination, and Six6 protein absence was confirmed by Western blot. Homozygous mutant mice had hypoplastic pituitary gland and ariable degrees of retinal hypoplasia often with absence of optic chiasm and optic nerve. Six6 regulates early progenitor cell proliferation during mammalian retinogenesis and pituitary development. MOUSE MODEL 2 POINTS SEGREGATIONS - 1 POINT (4 TOTAL AFFECTED, AR) Stopping here, reached at least moderate
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Clinical Validity Points Total | 8 Source: 35754085, 35693420, 23167593, 33108933, 12130660 |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Moderate (could continue curation to try to reach strong/definitive, but stopping in the interest of time) Source: |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function Two LOF variants + 1 null mouse model (see scoring notes above) PMID: 35754085, 35693420, 12130660
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Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) | Unknown Source: |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Congenital |
Severity | Moderate |
Clinical Features | Microphthalmia/anophthalmia, nystagmus, abnormal retinal morphology (retinal dystrophy, retinal detachment, horizontal macular abnormalities), abnormality of the optic disc (including optic nerve coloboma), Developmental cataract Sources: PMID: 33108933 |
HPO Terms |
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Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary | The SIX6 gene is associated with autosomal recessive colobomatous optic disc-macular atrophy-chorioretinopathy syndrome (PMID: 35754085, 35693420, 23167593, 33108933, 12130660). Clinical features include microphthalmia/anophthalmia, nystagmus, abnormal retinal morphology (retinal dystrophy, retinal detachment, horizontal macular abnormalities), abnormality of the optic disc (including optic nerve coloboma), and developmental cataract. |
Case ID, Curator name, Date, Jira ticket link | D-170702391-BH-3973-P-A, Andrea Oza, 10.25.23 |