Targeted next-generation sequencing identified a novel variant of SOX10 in a Chinese family with Waardenburg syndrome type 2

Abstract

Objective Waardenburg syndrome type 2 (WS2) is an autosomal dominant syndrome, characterized by bright blue eyes, hearing loss, and depigmented patches of hair and skin. It exhibits high phenotypic and genetic heterogeneity. We explored the molecular etiology in a Chinese family with WS2. Methods We recruited a three-generation family with three affected members. Medical history was obtained from all family members who underwent detailed physical examinations and audiology tests. Genomic DNA was extracted from peripheral blood of each individual, and 139 candidate genes associated with hearing loss were sequenced using Illumina HiSeq 2000 (Illumina Inc., San Diego, CA, USA) and verified by Sanger sequencing. Results Genetic evaluation revealed a novel nonsense heterozygous variant, NM_006941.4: c.342G>A (p.Trp114Ter) in exon 2 of the SOX10 gene in the three affected patients; no unaffected family member carried the variation. We did not detect the variation in 500 Chinese individuals with normal hearing or in 122 unrelated Chinese families with hearing loss, suggesting that it was specific to our patients. Conclusions We identified a novel heterozygous nonsense variation in a family with syndromic hearing loss and WS2. Our findings expand the pathogenic spectrum and strengthen the clinical diagnostic role of SOX10 in patients with WS2.

Waardenburg syndrome type 4 coexisting with open-angle glaucoma: a case report

“…Approximately 400 mutations including missense/nonsense mutations, frameshift mutations, insertions/deletions, and copy number variants (CNVs) have been identified in genes associated with WS [ 33 – 35 ]. Three causative genes have been identified for WS4, WS 4A, and WS 4B, including mutation of EDNRB and EDN3 , respectively, while WS 4C is caused by heterogeneous mutation in the SOX10 gene, which plays a major role in the development and migration of neural crest cells [ 25 , 36 , 37 ]. The interaction of these genes during the formation and development of melanocytes could be the pathogenesis of WS and related diseases [ 4 , 19 , 34 ].…”

“…WS has an incidence rate of approximately 1 per 42,000 births [ 4 ]. Waardenburg syndrome has been described as four different types (WS 1–4) based on genotypic and phenotypic variations [ 5 , 6 ].…”

Deciphering potential causative factors for undiagnosed Waardenburg syndrome through multi-data integration

“…In large cohort or family studies, previous researchers mainly used targeted known WS pathogenic genes or deafness-related genes capture and next-generation sequencing for simultaneous single-nucleotide variants and copy number variation detection in WS [ 5 , 7 , 18 , 19 ]. However, targeted sequencing has a low-resolution rate compared to whole exome sequencing or whole genome sequencing, which could miss the other disease-related genes or variants, leaving some WS cases to remain unexplained at the molecular level.…”