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SOX3 is implicated in X-linked Septooptic dysplasia with limited clinical evidence. Four probands were reported: two male siblings with a seven-alanine expansion and one unrelated individual with a nonfunctional p.Arg5Gln variant, plus a female with an 18-bp deletion in the polyalanine tract (c.726_743del (p.Ala243_Ala248del)); segregation in the sibship supports X-linked recessive inheritance with one additional affected relative ([PMID:21289259]).
Functional assays demonstrate that the del6PA allele exhibits a twofold increase in transcriptional activation and retains repression of β-catenin–mediated transcription, whereas expansions impair β-catenin repression, suggesting a dosage-sensitive gain-of-function mechanism ([PMID:21289259]). However, the small number of cases and lack of independent replication limit the current diagnostic utility. Key take-home: SOX3 polyalanine tract variants may contribute to septooptic dysplasia via altered transcriptional activity, but further studies are required for clinical validation.
Gene–Disease AssociationLimited4 probands across one study, single segregating family, concordant functional data ([PMID:21289259]) Genetic EvidenceLimited4 probands with X-linked polyalanine tract deletion/expansion; segregation in one sibship ([PMID:21289259]) Functional EvidenceModerateIn vitro assays show increased transactivation for del6PA and impaired β-catenin repression for expansions ([PMID:21289259]) |