Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
SDHAF1 is an autosomal recessive assembly factor for succinate dehydrogenase (complex II) whose biallelic variants cause early‐onset mitochondrial disease characterized by infantile leukoencephalopathy. SDHAF1 mutations impair Fe–S cluster incorporation into the SDHB subunit, leading to complex II deficiency, elevated succinate and lactate levels, and white matter lesions on MR spectroscopy. Genetic and functional studies converge to establish a robust gene–disease relationship supporting clinical diagnostic use.
In a retrospective cohort of nine children with biochemically confirmed complex II deficiency, five patients from three unrelated families harbored homozygous SDHAF1 variants with segregation of disease alleles (three novel, two recurrent) and leukoencephalopathy with succinate accumulation (PMID:22995659). The affected relatives included five children with consistent phenotypes and MRI abnormalities. No SDHAF1 variants were found in four children with non‐leukoencephalopathic presentations, underscoring genotype–phenotype specificity (PMID:22995659).
To date, six distinct SDHAF1 variants have been reported: three predicted loss‐of‐function alleles (c.22C>T (p.Gln8Ter), c.28C>T (p.Gln10Ter), c.156C>A (p.Tyr52Ter)) and three missense changes at conserved residues (c.164G>C (p.Arg55Pro), c.169G>C (p.Gly57Arg), c.170G>A (p.Gly57Glu)) (PMID:22995659). These variants disrupt key LYR and arginine‐rich motifs required for SDHB binding. There is no evidence for founder alleles in specific populations.
Functional assays in yeast and patient fibroblasts demonstrated that pathogenic SDHAF1 variants abolish binding to SDHB’s Fe–S peptide, prevent holo‐SDHB maturation, and trigger LONP1‐mediated SDHB degradation (PMID:26749241). Riboflavin supplementation in vivo and in vitro enhances flavinylation of SDHA, reduces succinate and HIF‐1α accumulation, and ameliorates neurologic symptoms, revealing potential therapeutic avenues (PMID:26749241).
Earlier identification of SDHAF1 via yeast complementation and fibroblast rescue established its role as the first LYR‐motif complex II assembly factor; expression of wild-type SDHAF1 restored SDH activity and OXPHOS‐dependent growth (PMID:19465911). These concordant genetic, biochemical, and cellular findings define a clear loss‐of‐function mechanism.
Collectively, the strong segregation data, diverse variant spectrum, and mechanistic insights support a Strong clinical validity classification for SDHAF1 in mitochondrial disease. SDHAF1 genetic testing is recommended for infants presenting with early leukoencephalopathy and elevated succinate, and riboflavin therapy may improve outcomes. Key take-home: SDHAF1 biallelic variants reliably predict complex II deficiency and guide targeted metabolic and genetic interventions.
Gene–Disease AssociationStrong5 probands from 3 families with bi-allelic SDHAF1 variants, segregation confirmed and consistent leukoencephalopathy phenotype Genetic EvidenceStrongFive probands in three families with homozygous LoF and missense variants showing segregation and phenotype specificity Functional EvidenceStrongYeast complementation, patient fibroblast rescue, and Fe–S transfer assays demonstrate loss-of-function mechanism and therapeutic rescue |