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).
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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