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Recessive GJA1 (connexin 43) mutations have been implicated in a Hallermann-Streiff syndrome (HSS)/ODDD spectrum phenotype. A single proband with HSS/ODDD features was found to carry a homozygous c.227G>A (p.Arg76His) variant, with clinically unaffected heterozygous parents, consistent with autosomal recessive inheritance ([PMID:14974090]). No additional affected relatives or multiplex families have been reported, and no functional studies specific to p.Arg76His have been performed. A separate full-blown HSS case lacked GJA1 mutations, indicating genetic heterogeneity. As such, the clinical validity of GJA1 in HSS is currently classified as Limited; further case series and functional validation are required to establish diagnostic utility. Key take-home: Hypomorphic recessive GJA1 variants may underlie HSS/ODDD spectrum but evidence remains limited for clinical decision-making.
Gene–Disease AssociationLimitedSingle homozygous missense variant in one proband, parental segregation only Genetic EvidenceLimitedOne AR proband with homozygous c.227G>A (p.Arg76His), no additional families Functional EvidenceLimitedNo variant-specific functional assays for p.Arg76His; general Cx43 loss-of-function data available |