SOX4 – Coffin-Siris Syndrome

SOX4, encoding an HMG-box transcription factor, has been implicated in Coffin-Siris syndrome (CSS) through a novel de novo missense variant identified in a Chinese patient presenting classic CSS features including growth delay, dysmorphic facial shape, hypoplastic nails, and tooth agenesis. Whole-exome sequencing and Sanger validation revealed a heterozygous c.1255C>G (p.Leu419Val) variant in SOX4 (1 proband)[PMID:38684576]. A larger genotype–phenotype registry study of 208 CSS individuals confirmed SOX4 as one of the BAF complex genes contributing to CSS phenotype variability (PMID:34205270).

Functional follow-up using murine single-cell RNA sequencing, fluorescence in situ hybridization, and WGCNA demonstrated high Sox4 expression in tooth primordia and central network positioning in pathways related to cell–substrate junctions, focal adhesion, and RNA splicing, supporting a role in dental development concordant with the human tooth agenesis phenotype. The aggregate evidence—de novo missense variant, concordant developmental expression, and network analyses—supports a limited but emerging association. Key take-home: heterozygous SOX4 variants warrant inclusion in genetic testing for CSS, especially when tooth agenesis is present, to inform diagnosis and potential therapeutic strategies.

References

• Clinical oral investigations • 2024 • Identification of a novel de novo mutation in SOX4 for syndromic tooth agenesis. PMID:38684576
• Genes • 2021 • Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome. PMID:34205270

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