ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000022.10) (NC_000022.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17999358 Bondurand et al (2007) used a combination of semi-quantitative fluorescent multiplex polymerase chain reaction and FISH to search for SOX10 heterozygous deletions and describe the first characterization of SOX10 deletions in patients presenting with Waardenburg Syndrome Types 2 and 4. Both intragenic deletions and larger deletions involving SOX10 and surrounding genes were identified in individuals with both the WS4 and WS2 phenotypes, including individuals with neurologic involvement.
9462749 Pingault et al. (1998) describe two heterozygous, de novo nonsense mutations (E189X and Y83X) in two unrelated individuals with clinical diagnoses of WS4.
10077527 Southard-Smith et al. (1999) describes mutations identified in SOX10, including a heterozygous, de novo nonsense mutation (Y207X) in an individual with a clinical diagnosis of WS4.

Haploinsufficiency phenotype comments:

Mutations in SOX10 have been associated with Waardenburg syndrome type 4C (WS4C) and type 2E (WS2E). Both are characterized by pigmentary anomalies of the hair, skin, and eyes, as well as hearing loss. WS4C is distinguished by the addition of Hirschsprung disease, and WS2E is distinguished by the absence of 'dystopia canthorum,' the lateral displacement of the ocular inner canthi, which is seen in some other forms of WS. Mutations in SOX10 have also been associated with a neurologic variant of WS, also known as peripheral demyelinating neuropathy, central demyelination, Waardenburg syndrome, and Hirschsprung disease (PCWH). Most recently, loss of function mutations in SOX10 have also been associated with Kallman syndrome (PMID: 23643381) Regarding possible genotype-phenotype correlations between SOX10 mutations and neurologic/non-neurologic WS phenotypes: From OMIM entry 60229: "In 4 patients with...PCWH..., Inoue et al. (2004) identified truncating mutations in the SOX10 gene... All the mutations were located in the last exon (exon 5) in the 3-prime region of the SOX10 gene. Functional analysis showed that the truncating mutations suppressed the transcriptional activity of cotransfected wildtype SOX10 in a dose-dependent manner, suggesting that PCWH is caused by dominant-negative mutations. However, 2 truncating mutations (E189X; 602229.0001 and Y207X; 602229.0009) associated with the less severe WS4C phenotype ultimately showed different effects. Northern blot analysis demonstrated that WS4C-associated mutations, but not PCWH-associated mutations, lead to a reduction in mRNA via the nonsense-mediated decay (NMD) pathway, thereby causing haploinsufficiency and preventing a dominant-negative effect. Inoue et al. (2004) noted that the results were consistent with the NMD RNA surveillance pathway, which typically degrades only transcripts containing nonsense mutations that are followed by at least 1 intron (Carter et al., 1996; Nagy and Maquat, 1998), as usually occurs with WS4C-associated mutations. Accordingly, the PCWH-associated mutations that occur in SOX10 exon 5 are not followed by an intron, may escape NMD, and express large amounts of dominant-negative protein. Similar results were obtained for truncating mutations in the myelin protein zero gene (MPZ; 159440) that cause distinct myelinopathies. Inoue et al. (2004) suggested that, in general, the NMD mechanism may function protectively to convert dominant-negative effects to haploinsufficiency." Of note, Bondurand et al. (2007) (discussed above) and others (see PMID: 22842075) have reported large deletions involving SOX10 and other genes amongst individuals with the PCWH and individuals with the WS2E phenotypes. Also of note: Bondurand et al (2012) went on to describe a patient with Alu-mediated deletion of three enhancers of SOX10 in Waardenburg syndrome type 4 (PMID: 22378281).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Seeherunvong (2004) describe partial duplication of chromosome 22q (involving SOX10 and other genes) in a subject with MCA but nearly complete masculinization of the external genitaliaa and proposed that overexpression of SOX10, in the absence of SRY, might be a cause of sex reversal (PMID: 15108202). Polanco (2010) describe transgenic expression of Sox10 in gonads of XX mice resulted in development of testes and male physiology and propose that because over-expression of SOX10 alone is able to mimic the XX DSD phenotypes associated with duplication of human chromosome 22q13, SOX10 is functionally implicated in the etiology of DSDs (PMID: 19933217).