Non-syndromic enlarged vestibular aqueduct caused by novel compound mutations of the SLC26A4 gene: a case report and literature review

Abstract

Enlarged vestibular aqueduct is an autosomal genetic disease mainly caused by mutations in the SLC26A4 gene and includes non-syndromic and syndromic types. This study aimed to identify genetic defects in a Chinese patient with non-syndromic enlarged vestibular aqueduct (NSEVA) and to investigate the impact of variants on the severity of non-syndromic enlarged vestibular aqueduct. A male patient with NSEVA, aged approximately 6 years, was recruited for this study. The clinical characteristics and results of auxiliary examinations, including laboratory and imaging examinations, were collected, and 127 common hereditary deafness genes were detected by chip capture high-throughput sequencing. Protein structure predictions, the potential impact of mutations, and multiple sequence alignments were analyzed in silico. Compound heterozygote mutations c.1523_1528delinsAC (p.Thr508Asnfs*3) and c.422T>C (p.Phe141Ser) in the SLC26A4 gene were identified. The novel frameshift mutation c.1523_1528delinsAC produces a severely truncated pendrin protein, and c.422T>C has been suggested to be a disease-causing mutation. Therefore, this study demonstrates that the novel mutation c.1523_1528delinsAC in compound heterozygosity with c.422T>C in the SLC26A4 gene is likely to be the cause of NSEVA. Cochlear implants are the preferred treatment modality for patients with NSEVA and severe-to-profound sensorineural hearing loss Genetic counseling and prenatal diagnosis are essential for early diagnosis. These findings expand the mutational spectrum of SLC26A4 and improve our understanding of the molecular mechanisms underlying NSEVA.

Keywords: SLC26A4; compound mutations; non-syndromic enlarged vestibular aqueduct; pendrin; sensorineural hearing loss.

FIGURE 1

Craniocerebral CT and MRI results of the patient. (A, B) CT results indicated bilateral enlarged vestibular aqueduct (red arrow). (C, D) MRI results indicated bilateral endolymph sac effusion and enlarged vestibular aqueduct (red arrow).

FIGURE 2

Chip capture high-throughput sequencing result in the patient. (A) Sequencing map of heterozygous c.1523_1528delinsAC mutation (Mutation start point is shown by red arrows). (B) Sequencing map of the heterozygous c.422T>C mutation (The mutation site is indicated by the red arrow).

FIGURE 3

Prediction of the mutations and multiple sequence alignments for the patient’s two mutations. (A) The ribbon protein models of wild-type and c.1523_ 1528delinsAC mutant forms are displayed. The mutant protein exhibits a severely truncated form (red arrow). (B) The PolyPhen2 score was 1.000, predicted to be “PROBABLY DAMAGING” for c.422T > C. (C) Multiple sequence alignments revealed that these two mutations were located in the highly conserved amino acid region in different species (red boxes).