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In a cohort of 21 individuals meeting full or partial Cowden syndrome diagnostic criteria, comprehensive sequencing of PTEN, SDHB, SDHC, and SDHD revealed pathogenic PTEN, SDHB, and SDHD variants but identified no disease-causing SDHC mutations despite plasma succinate measurements being performed^( [PMID:22261759] ). Elevated plasma succinate was observed in 13/21 mutation-positive individuals compared with 5/32 controls, supporting a shared biochemical alteration in PTEN and SDHx mutation carriers but not implicating SDHC genetically in Cowden syndrome^( [PMID:22261759] ).
Collectively, genetic evidence for SDHC in Cowden syndrome remains limited: no SDHC probands, no segregation data, and no reported SDHC functional assays in Cowden cases. While succinate accumulation suggests SDH complex dysfunction, the lack of direct SDHC variant associations constrains clinical validity. Key take-home: routine SDHC testing is not recommended in Cowden syndrome diagnostics without additional supportive data.
Gene–Disease AssociationLimitedNo pathogenic SDHC variants identified in Cowden syndrome cases; study sequenced 21 individuals without SDHC findings Genetic EvidenceLimitedSequencing of SDHC in Cowden cohort (n=21) revealed no disease-causing variants Functional EvidenceLimitedNo direct functional studies of SDHC in Cowden syndrome; inference only from SDH complex activity |