A Novel Spontaneous Mutation of the SOX10 Gene Associated with Waardenburg Syndrome Type II

Abstract

Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss. It is responsible for 2-5% of congenital deafness. WS is classified into four types depending on the clinical phenotypes. Currently, pathogenic mutation of PAX3, MITF, EDNRB, EDN3, SNAI2, or SOX10 can cause corresponding types of WS. Among them, SOX10 mutation is responsible for approximately 15% of type II WS or 50% of type IV WS. We report the case of a proband in a Chinese family who was diagnosed with WS type II. Whole exome sequencing (WES) of the proband detected a novel heterozygous spontaneous mutation: SOX10 c.246delC. According to analysis based on nucleic acid and amino acid sequences, this mutation may produce a truncated protein, with loss of the HMG structure domain. Therefore, this truncated protein may fail to activate the expression of the MITF gene, which regulates melanocytic development and plays a key role in WS. Our finding expands the database of SOX10 mutations associated with WS and provides more information regarding the molecular mechanism of WS.

Figure 1

Family pedigree and clinical features of the proband. The (a) pedigree indicates that Family II-1 had a spontaneous heterozygous mutation (SOX10 c.246delC), which is marked black. Family I-1 only carried the mutation of the SLC26A4 gene. (b) The iris heterochromia in both eyes of the proband, which are blue. a, b, and c indicate the distance between the inner canthi, pupils, and outer canthi. WT: wild type.

Figure 2

Clinical audiology examination and temporal bone CT scan of the proband. (a) ASSR (auditory steady-state responses) of the left ear: 105 dB, 105 dB, and 90 dB at 1, 2, and 4 kHz, respectively; the remaining frequencies showed no response. (b) ASSR of the right ear: 90 dB, 105 dB, and 100 dB at 500 Hz, 1, and 4 kHz; the remaining frequencies showed no response. (c) Semicircular canal abnormalities shown on high-resolution axial CT in the red square (left ear). (d) Semicircular canal abnormalities shown on high-resolution axial CT in the red square (right ear).

Figure 3

Genetic sequencing results of the proband and his parents. The red arrow indicates the site of the base deletion or substitution.

Figure 4

Amino acid coding diagram for the proband and schematic diagram of the SOX10 gene domain. The red letters indicate the changed amino acids and the site of the stop codon. The mutation caused early termination of the coding sequence. If a deletion mutation occurs in front of the HMG domain, the HMG domain cannot combine with the promoter of the target gene (MITF).