The relationship between SSBP1 and optic atrophy with negative Electroretinograms, an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of May, 2021. SSBP1 encodes the single-stranded DNA-binding protein 1. It is a housekeeping gene involved in mitochondrial biogenesis and is a subunit of a single-stranded DNA (ssDNA)-binding complex. optic atrophy with negative Electroretinograms (also referred to as Optic atrophy 13 with retinal and foveal abnormalities) is characterized by bilateral optic atrophy, foveopathy, loss of vision/color vision and retinal pigmentary defects, in some cases (Jurkute t al, 2019; PMID: 31298765).
SSBP1 was first reported in relation to autosomal dominant optic atrophy with negative Electroretinograms in 2019. (Jurkute et al; PMID: 31298765). At least 8 missense variants have been reported in humans thus far. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 13 probands in 4 publications ( PMID: 31298765, 31550237, 31550240, 31479473). Variants segregated with disease in several (>40) additional family members. All variants reported are missense, and are found to recur across families. A founder effect has not been reported, but is likely. The mechanism for disease is expected to be dominant negative resulting in a loss of function of the wild-type protein.
Summary of experimental data (3.5 points): This gene-disease association is supported by in vitro functional assays and animal models. SSBP1 is found to be ubiquitously expressed, and is especially abundant in the retina (PMID: 31298765, 31550237). SSBP1 alterations affect mitochondrial morphogenesis as seen experimentally and in patients (PMID: 28638454). Several groups have studied the effects of SSBP1 variation in zebrafish models, which recapitulate the human phenotype (PMID: 31298765, 31550237, 31550240). Re-introduction of wild-type SSBP1 rescues the phenotype in the zebrafish model (PMID: 31298765).
In summary, there is strong evidence to support the relationship between SSBP1 and autosomal dominant optic atrophy with negative Electroretinograms. Three years must elapse from the first proposal of the association to reach a definitive classification.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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