[Incomplete penetrance of SOX10 gene mutation in a family with Waardenburg syndrome type Ⅳ].

Objective

To detect the molecular etiology of a proband with Waardenburg syndrome type type Ⅳ（WS4） and their family members, explore the possible pathogenic mechanism of SOX10 gene mutation, analyze its incomplete penetrance combined with clinical phenotypes, and dicuss the potential molecular pathogenesis.

Methods

Clinical data of the proband and their family members were collected. Peripheral blood genomic DNA was extracted from the proband and family members, and all exons and flanking sequences were analyzed using a next-generation sequencing（NGS） -based deafness gene panel. Based on the high-throughput sequencing results, the mutation sites were verified and analyzed in the family members by Sanger sequencing.

Results

The proband was diagnosed with typical Waardenburg syndrome type type IVC（WS4C）, presenting with sensorineural hearing loss, Hirschsprung's disease（HD） and heterochromia iridis. Sanger sequencing revealed a pathogenic heterozygote c.127C>T mutation in the SOX10 gene of the proband, resulting in a substitution of arginine（Arg） tat codon 43 with a stop codon. The same mutation site was also identified in the proband's father, aunt and sister. The proband's sister had hearing impairment and heterochromatic iridis, presenting with a Waardenburg syndrome type type Ⅱ（WS2） phenotype, while the proband's father was phenotypically normal, and the proband's aunt had deafness but no heterochromia iridis.

Conclusion

The heterozygous c.127C>T mutation in SOX10 is the molecular pathological cause of WS4C in this proband. The clinical and genetic characteristics of this family illustrate the genetic heterogeneity and incomplete penetrance of WS4C.