SOX10 – Waardenburg syndrome type 4C

SOX10 (HGNC:11190) has been implicated in Waardenburg syndrome type 4C (MONDO:0013202), an autosomal dominant neurocristopathy characterized by pigmentary abnormalities, sensorineural hearing loss, intestinal aganglionosis, hypogonadotropic hypogonadism, and anosmia. A single Japanese female proband presented with bilateral iris depigmentation, bilateral sensorineural hearing impairment, Hirschsprung disease, hypogonadotropic hypogonadism, and anosmia; genetic analysis identified a de novo heterozygous frameshift variant c.124delC (p.Leu42CysfsTer67) in SOX10 (PMID:33082981). Transcriptional assays of SOX10 mutations found in Waardenburg–Hirschsprung patients demonstrated that truncating variants abolish transactivation and synergy with partner factors, consistent with haploinsufficiency as a mechanism of pathogenicity (PMID:9722528). No additional familial segregation data are reported. This association remains limited by evidence from a single case, but functional studies support a loss-of-function mechanism. Key take-home: heterozygous SOX10 truncating variants should be considered in patients presenting with Waardenburg syndrome features plus enteric and endocrine involvement.

References

• Human genome variation • 2020 • A novel SOX10 variant in a Japanese girl with Waardenburg syndrome type 4C and Kallmann syndrome. PMID:33082981
• The Journal of biological chemistry • 1998 • Functional analysis of Sox10 mutations found in human Waardenburg-Hirschsprung patients. PMID:9722528

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