The relationship between SDHAF1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 4, 2023. The SDHAF1 gene encodes succinate dehydrogenase (complex II) assembly factor 1. Defects of this protein have been associated with autosomal recessive complex II deficiency.
The SDHAF1 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19465911), in one family with features consistent with Leigh syndrome spectrum (LSS) and in another family with leukoencephalopathy. While various names have been given to the constellation of features seen in those with SDHAF1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the SDHAF1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, SDHAF1 was previously curated by this GCEP on January 13, 2020 (SOP Version 7) as having a limited association with LSS. The scope of this current curation encompassed cases of primary mitochondrial disease, which includes LSS.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (three missense, three stop-gained variants) from four publications (PMIDs: 19465911, 22995659, 31130284, 26642834). In addition to LSS and leukoencephalopathy, affected individuals also had spastic paraplegia, dystonia, failure to thrive, and sensorineural hearing loss. Muscle biopsies showed complex II deficiency.
This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, yeast knockdown showing complex II deficiency, and rescue of complex II activity in patient cells by wild-type protein (PMIDs: 19465911, 26749241, 33162331).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. 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 December 4, 2023 (SOP Version 10).
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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