Genotyping and audiological characteristics of infants with a single-allele SLC26A4 mutation.

Objectives: To identify second-allele variant in infants with a known single-allele mutation of the SLC26A4 gene and to determine the frequency of their occurrence; and to investigate the clinical audiological characteristics of infants with bi-allelic mutations in SLC26A4.

Methods: The study subjects were 371 patients with a single-allele SLC26A4 mutation detected by neonatal deafness gene screening (4 genes and 9 pathogenic variants) who were treated at the otology outpatient department of Beijing Tongren Hospital. The exonic and flanking splice site regions of the SLC26A4 gene were sequenced for all patients. All patients with bi-allelic SLC26A4 mutations underwent audiological evaluation, and some also underwent temporal bone computed tomography and/or inner ear magnetic resonance imaging.

Results: Of the 371 patients, 314 (84.64%) had an c.919-2A > G heterozygous mutation and 57 (15.36%) had a c.2168A > G (p.H723R) heterozygous mutation. 13 patients (3.50%) had a second-allele variant, including 11 (2.96%) with pathogenic mutations and 1 (0.27%) with a likely benign variant. Of the 13 patients with bi-allelic mutations, 11 had hearing loss and 2 had normal hearing, the latter of whom had c.919-2A > G/c.1766A > G and c.919-2A > G/c.757A > G compound heterozygous mutations, respectively. Four of the 13 patients with bi-allelic mutations had passed the universal newborn hearing screening, including 2 cases (15.38%) with hearing loss. The most prevalent degree of hearing loss was profound (40.91%), followed by severe (36.36%). The most prevalent audiometric configuration was sloping hearing loss (50.00%), followed by flat-type hearing loss (40.91%).

Conclusions: This is the first report in China of the frequency of occurrence of second-allele variant in infants with a known single-allele mutation of the SLC26A4 gene; the frequency was 3.50% for any type of variant and 2.96% for pathogenic mutations. A novel variant, c.1766A > G (p.Q589R), which is likely benign, was identified. The pathogenicity of c.757A > G (p.I253V) mutation deserves more in-depth research. For infants with bi-allelic SLC26A4 mutations, the degree of hearing loss was mainly severe-to-profound and the audiometric configuration was mainly sloping.