SOX10 – PCWH syndrome

SOX10 encodes an HMG-domain transcription factor essential for neural crest and glial cell development. Heterozygous SOX10 variants cause PCWH syndrome (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease) in an autosomal dominant manner. Clinical features include sensorineural hearing loss, hypopigmentation, enteric aganglionosis, and combined peripheral and central myelin defects.

Genetic evidence includes at least five unrelated PCWH probands with de novo loss-of-function SOX10 variants: c.671C>G (p.Ser224Ter) (PMID:22246888), p.Asp293GlyfsTer10 (PMID:21822601), p.Gln377Ter (PMID:22963253), de novo exon 5 deletion (PMID:24311220), and dosage sensitivity confirmed by 22q11.2q13 duplication including SOX10 (PMID:28328136). No multiplex familial segregation has been reported, supporting autosomal dominant inheritance.

The variant spectrum is dominated by truncating alleles—nonsense, frameshift, and exon-level deletions—as well as gene duplications. Representative variant c.671C>G (p.Ser224Ter) abolishes the C-terminal transactivation domain and has been observed in a classic PCWH case.

Functional studies demonstrate that truncating SOX10 proteins lack transcriptional activation of neural crest target promoters (e.g., MITF, EDNRB) and exert dominant-negative effects when escaping nonsense-mediated decay (PMID:9722528, PMID:15004559). Animal and cellular models corroborate a dominant-negative mechanism: murine and avian studies reveal that C-terminal truncations impair neural crest and oligodendrocyte development (PMID:20308050, PMID:16330480).

No convincing conflicting evidence has been reported. Collectively, genetic and experimental data support a Moderate ClinGen classification for the SOX10–PCWH association.

Key take-home: Heterozygous SOX10 loss-of-function or duplication variants cause autosomal dominant PCWH syndrome; genetic testing enables definitive diagnosis, prognosis, and informed genetic counseling.

References

• European journal of pediatrics • 2011 • A novel SOX10 mutation in a patient with PCWH who developed hypoxic-ischemic encephalopathy after E. coli sepsis. PMID:21822601
• The Journal of dermatology • 2012 • Pediatric case report: clinical profile of a patient with PCWH with p.Q377X nonsense mutation in the SOX10 gene. PMID:22963253
• Muscle & nerve • 2012 • SOX10 mutation with peripheral amyelination and developmental disturbance of axons. PMID:22246888
• American Journal of Medical Genetics Part A • 2017 • 22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease. PMID:28328136
• The Journal of Biological Chemistry • 1998 • Functional analysis of Sox10 mutations found in human Waardenburg-Hirschsprung patients. PMID:9722528
• Nature Genetics • 2004 • Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. PMID:15004559
• Human Molecular Genetics • 2010 • SOX10 structure-function analysis in the chicken neural tube reveals important insights into its role in human neurocristopathies. PMID:20308050
• Human Molecular Genetics • 2006 • Deletion of long-range sequences at Sox10 compromises developmental expression in a mouse model of Waardenburg-Shah (WS4) syndrome. PMID:16330480

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