SSBP1

Inheritance Pattern: AD

Disease ID:MONDO:0008135

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0008135

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0008135

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SSBP1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 24, 2021. The SSBP1 gene encodes the mitochondrial single-stranded DNA-binding protein that binds and protects single-stranded mitochondrial DNA at the replication fork from damage, prevents the formation of DNA secondary structures, and prevents inappropriate binding of DNA metabolizing enzymes. The SSBP1 gene was first reported in relation to de novo dominant Leigh syndrome spectrum in 2019 (PMID: 31479473). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one de novo variant in one case in one publication (PMID: 31479473). This case had a single large scale mitochondrial DNA deletion (SLSMD) that was suspected to be related to the SSBP1 pathogenic variant. The patient’s phenotype was consistent with SLSMD syndrome. SSBP1 variants have also been reported to be associated with optic atrophy, retinal degeneration and hearing loss in other cases who did not have LSS. No segregation data were available. The mechanism of disease (loss or gain of function) is still being elucidated but is proposed to involve impaired mitochondrial DNA replication as a result of altered mitochondrial single-stranded DNA-binding. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, and animal models (PMIDs: 27977873, 25613900, 31550240). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 24, 2021 (SOP Version 7).

Inheritance Pattern: AD

Disease ID:MONDO:0008135

Submitter: ClinGen

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.