The relationship between SDHB and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2022. The SDHB gene encodes the succinate dehydrogenase complex iron sulphur subunit B. Defects of this protein lead to complex II deficiency.
The SDHB gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22972948). While various names have been given to the constellation of features seen in those with autosomal recessive SDHB-related disease, pathogenic variants in this gene cause a primary mitochondrial disease when inherited in an autosomal recessive manner. Therefore, the SDHB phenotype has been split, with one disease entity being autosomal recessive primary mitochondrial disease, according to the ClinGen Lumping and Splitting Framework. Of note, this gene has also been implicated in autosomal dominant hereditary pheochromocytoma-paraganglioma. This gene disease relationship has been assessed separately (https://search.clinicalgenome.org/kb/genes/HGNC:10681).
Evidence supporting the relationship between SDHB and primary mitochondrial disease includes case-level data and experimental data. This curation included five missense variants in eight cases from five reports (PMIDs: 22972948, 26925370, 26642834, 27604842, 32124427). Of note, the c.143A>T (p.Asp48Val) was associated with disease in six probands, including four cases in a homozygous state and two cases in a compound heterozygous state. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33162331). Mitochondrial dysfunction and developmental alterations associated with PMD were recapitulated in knockout animal models including round worm (Caenorhabditis elegans), fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio) (PMIDs: 32859697, 17056719, 33156815).
In summary, there is definitive evidence to support the relationship between SDHB and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 7, 2022 (SOP Version 8).
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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