SOX9 – Campomelic Dysplasia

Campomelic dysplasia (CD; MONDO:0007251) is an autosomal dominant skeletal dysplasia characterized by bent long bones, hypoplastic scapulae, bell-shaped thorax and XY sex reversal in ~75% of 46,XY cases. Heterozygous loss-of-function variants in SOX9 (HGNC:11204) underlie CD via haploinsufficiency (PMID:8001137).

Genetic analyses across large cohorts have identified over 150 heterozygous SOX9 variants in CD, including missense changes in the high-mobility group (HMG) domain, frameshift and nonsense mutations truncating the C-terminal transactivation domain, and splice-site alterations (PMID:7485151). De novo mutations predominate, although germline mosaicism accounts for familial recurrence in some pedigrees (PMID:8894698). A representative coding frameshift is c.736dup (p.Gln246fs).

Familial segregation and parental mosaicism have been documented: one family exhibited three affected siblings of paternal germline mosaicism (PMID:8894698), and maternal mosaicism has been described in cases with mild parental phenotypes (PMID:29542186).

Functional studies reveal that SOX9 mutations disrupt DNA-binding, cooperative dimerization, and C-terminal transactivation, establishing haploinsufficiency as the primary mechanism. The A76E dimerization domain variant abrogates chondrocyte enhancer activation but preserves monomeric sex-determining function (PMID:12837698). Mouse models further corroborate dosage-sensitive roles in chondrogenesis and gonadal differentiation.

Long-range cis-regulatory deletions and translocations upstream of SOX9 delineate enhancers essential for tissue-specific expression, including a distal element 1.1 Mb upstream responsive to GLI1/SHH signaling (PMID:17409199), linking perturbations of noncoding regions to CD phenotypes.

Hypomorphic missense variants retaining residual DNA-binding associate with the non-lethal acampomelic variant of CD, often lacking campomelia or sex reversal, expanding the genotype-phenotype spectrum (PMID:20513132).

Together, genetic and experimental data establish a definitive SOX9–campomelic dysplasia association, with diverse loss-of-function and regulatory variants causing disease via reduced transcriptional activation of cartilage and sex-development genes. Additional evidence from variant-dedicated animal models and enhancer perturbation studies further supports this conclusion.

Key take-home: Clinical genetic testing for SOX9 haploinsufficiency is critical for accurate diagnosis and management of campomelic dysplasia and related skeletal or gonadal anomalies.

References

• Cell • 1994 • Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. PMID:8001137
• American Journal of Human Genetics • 1995 • Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. PMID:7485151
• Human Molecular Genetics • 1996 • A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal. PMID:8894698
• Human Molecular Genetics • 2003 • Dimerization of SOX9 is required for chondrogenesis, but not for sex determination. PMID:12837698
• Human Molecular Genetics • 2007 • SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway. PMID:17409199
• Human Mutation • 2010 • Heterozygous SOX9 mutations allowing for residual DNA-binding and transcriptional activation lead to the acampomelic variant of campomelic dysplasia. PMID:20513132
• Journal of clinical research in pediatric endocrinology • 2025 • Novel SOX9 Gene Variant Associated with Campomelic Dysplasia: Effects on Sex Phenotypes. PMID:40492130

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