The relationship between SDHD and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 4, 2022. The SDHD gene encodes the succinate dehydrogenase (SDH, mitochondrial respiratory chain complex II) subunit D, an integral membrane protein that anchors the SDH enzyme to the matrix side of the mitochondrial inner membrane. Defects of this protein lead to complex II deficiency.
The* SDHD* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 24367056). While various names have been given to the constellation of features seen in those with autosomal recessive SDHD-related disease, pathogenic variants in this gene cause a primary mitochondrial disease when inherited in an autosomal recessive manner. Therefore, the SDHD 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:10683).
Evidence supporting the relationship between SDHD and primary mitochondrial disease includes case-level data and experimental data. This curation included two missense variants and one start-loss variant in two cases from two publications (PMIDs: 24367056, 26008905). This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33162331). Mitochondrial dysfunction was recapitulated in a HEK293 knockout model (PMID: 34118887).
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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 4, 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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