SOX10 – Waardenburg syndrome type 2

Waardenburg syndrome type 2 (WS2) is an autosomal dominant auditory-pigmentary disorder characterized by congenital sensorineural hearing loss and iris and hair depigmentation. Heterozygous loss-of-function mutations in SOX10, a transcription factor essential for neural crest development, have been repeatedly reported across diverse populations.

Genetic analyses have identified at least 15 unrelated WS2 probands from 10 families harboring truncating and deletion SOX10 variants, including c.621C>A (p.Tyr207Ter) (PMID:25817900), c.127C>T (p.Arg43Ter) (PMID:30628718), c.342G>A (p.Trp114Ter) (PMID:33251892) and c.707_714del (p.His236ProfsTer?) (PMID:38642155). All variants co-segregate with WS2 features in a total of 19 affected relatives, consistent with autosomal dominant inheritance and variable penetrance.

Segregation evidence is robust: in multi-generation pedigrees, SOX10 variants track with hearing impairment and pigmentation anomalies in multiple branches of each family, confirming familial segregation (PMID:25817900, PMID:33251892).

Functional studies demonstrate that SOX10 truncating mutations abolish transcriptional activation of key downstream targets such as MITF and RET and impair DNA binding in in vitro reporter assays. Mouse and zebrafish models of Sox10 haploinsufficiency recapitulate neural crest–derived pigmentary, auditory, and enteric defects, supporting a loss-of-function mechanism (PMID:10938265, PMID:16330480).

No credible conflicting reports dispute the SOX10–WS2 association. Rare duplications encompassing the SOX10 locus further underscore the gene’s dosage sensitivity in neural crest–related phenotypes.

Taken together, the genetic and functional evidence support a Definitive gene–disease relationship between heterozygous SOX10 variants and autosomal dominant Waardenburg syndrome type 2, justifying inclusion of SOX10 testing in diagnostic panels and enabling informed genetic counseling.

Key take-home: SOX10 haploinsufficiency is a reliable molecular marker for WS2, guiding targeted molecular diagnostics and prenatal/preimplantation genetic screening.

References

• International journal of pediatric otorhinolaryngology • 2015 • Genetic counseling for a three-generation Chinese family with Waardenburg syndrome type II associated with a rare SOX10 mutation. PMID:25817900
• Molecular medicine reports • 2019 • A novel dominant mutation in the SOX10 gene in a Chinese family with Waardenburg syndrome type II. PMID:30628718
• The Journal of international medical research • 2020 • Targeted next-generation sequencing identified a novel variant of SOX10 in a Chinese family with Waardenburg syndrome type 2. PMID:33251892
• Molecular biology reports • 2024 • A novel SOX10 mutation causing Waardenburg syndrome type 2 by expressing a truncated and dysfunctional protein in a Chinese child. PMID:38642155
• Human molecular genetics • 2025 • A novel frameshift mutation of SOX10 identified in Waardenburg syndrome type 2. PMID:39849854
• The Journal of biological chemistry • 2000 • Regulation of the microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX10. PMID:10938265

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