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SOX9 is a high-mobility-group transcription factor central to chondrogenesis and testis determination. Heterozygous mutations in SOX9, including coding loss-of-function and upstream regulatory deletions, have been linked to campomelic dysplasia and 46,XY complete gonadal dysgenesis (SOX9, 46,XY complete gonadal dysgenesis).
An autosomal dominant 349 kb deletion located 353 kb upstream of SOX9 segregated with 46,XY complete gonadal dysgenesis in three siblings, two of whom developed gonadoblastoma. SOX9 mRNA levels were significantly decreased in affected individuals, confirming a regulatory haploinsufficiency mechanism (PMID:24907458).
Screening of nine patients with campomelic dysplasia and sex reversal identified five distinct SOX9 mutations, including the splice-acceptor variant c.432-2A>C found in two unrelated 46,XY individuals presenting complete gonadal dysgenesis. All mutations acted dominantly and are predicted to abolish normal SOX9 function (PMID:7485151).
Autosomal dominant inheritance is supported by de novo and familial variants with variable penetrance; the regulatory deletion was inherited from an apparently unaffected father, indicating reduced penetrance and expressivity.
Functional assays show that upstream deletions reduce SOX9 transcript abundance in patient cells. Coding loss-of--function mutations eliminate SOX9 DNA binding and transactivation activity in vitro, consistent with a haploinsufficiency model for gonadal development.
Collectively, five probands across two independent pedigrees with SOX9 regulatory or splice-site variants, segregation of disease in an AD pattern, and concordant functional data yield a Moderate ClinGen gene–disease validity classification. SOX9 analysis should be integrated into diagnostic workflows for 46,XY complete gonadal dysgenesis to guide genetic counseling and management.
Gene–Disease AssociationModerateFive probands across two unrelated pedigrees with segregating SOX9 variants and consistent functional data Genetic EvidenceModerate5 probands with heterozygous deletion or splice-site variants in AD pattern Functional EvidenceSupportingSOX9 expression reduction in patients and loss of transactivation in mutant proteins |