SDHC – Carney-Stratakis syndrome

Carney-Stratakis syndrome (CSS) is a rare, autosomal dominant condition characterized by the dyad of gastrointestinal stromal tumors (GISTs) and paragangliomas (PGLs), arising from germline inactivating variants in succinate dehydrogenase subunit genes. SDHC, encoding a membrane‐anchoring subunit of mitochondrial complex II, has been implicated in CSS through multiple independent reports demonstrating loss-of-function variants in affected individuals.

Three unrelated CSS probands harboring distinct germline SDHC loss-of-function variants have been documented: a canonical splice-site mutation c.405+1G>A in a large family with multiple PGLs and GISTs (PMID:38021081), a nonsense variant c.43C>T (p.Arg15Ter) in a 45-year-old woman with bilateral paragangliomas and multifocal gastric GIST (PMID:32944103), and a novel SDHC frameshift resulting from exon 3 deletion in a pediatric patient with multifocal GIST (PMID:31883676).

Segregation analysis in one two-generation family confirmed cosegregation of the c.405+1G>A SDHC variant with PGL and GIST in an affected father and daughter (1 additional relative) (PMID:38021081).

The SDHC variant spectrum in CSS includes canonical splice-site mutations (c.405+1G>A) and early truncating alleles (c.43C>T (p.Arg15Ter)), all predicted to abolish protein function. No recurrent or founder SDHC alleles have been reported to date.

Functional studies demonstrate concordant complex II deficiency: SDHC-mutant tumors show absence of SDHB immunostaining, reflecting secondary SDHB destabilization (PMID:21173220), and enzymatic assays confirm diminished succinate dehydrogenase activity in SDHC-deficient GIST samples. Yeast complementation models of SDHC orthologs further validate the pathogenicity of analogous missense and splice variants (PMID:17636259).

Integration of genetic and functional data supports a ClinGen Moderate clinical validity classification for SDHC in CSS. Germline testing for SDHC variants is recommended in patients presenting with concurrent PGL and GIST, enabling early surveillance for associated tumors and facilitating cascade testing in at-risk relatives.

Key Take-home: Germline loss-of-function variants in SDHC underlie Carney-Stratakis syndrome through haploinsufficiency of mitochondrial complex II; genetic diagnosis enables targeted surveillance and family counseling.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2011 • Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. PMID:21173220
• Radiology case reports • 2020 • Carney-Stratakis syndrome: A dyad of familial paraganglioma and gastrointestinal stromal tumor. PMID:32944103
• Cancer genetics • 2020 • Pediatric gastrointestinal stromal tumor: Report of two novel patients harboring germline variants in SDHB and SDHC genes. PMID:31883676
• Journal of the Endocrine Society • • Aberrant Splicing of SDHC in Families With Unexplained Succinate Dehydrogenase-Deficient Paragangliomas. PMID:33195952
• The Journal of biological chemistry • 2007 • Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate. PMID:17636259

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