A Missense Mutation in POU4F3 Causes Midfrequency Hearing Loss in a Chinese ADNSHL Family

Abstract

Hereditary nonsyndromic hearing loss is extremely heterogeneous. Mutations in the POU class 4 transcription factor 3 (POU4F3) are known to cause autosomal dominant nonsyndromic hearing loss linked to the loci of DFNA15. In this study, we describe a pathogenic missense mutation in POU4F3 in a four-generation Chinese family (6126) with midfrequency, progressive, and postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining targeted capture of 129 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified POU4F3 c.602T>C (p.Leu201Pro) as the disease-causing variant. This variant cosegregated with hearing loss in other family members but was not detected in 580 normal controls or the ExAC database and could be classified as a "pathogenic variant" according to the American College of Medical Genetics and Genomics guidelines. We conclude that POU4F3 c.602T>C (p.Leu201Pro) is related to midfrequency hearing loss in this family. Routine examination of POU4F3 is necessary for the genetic diagnosis of midfrequency hearing loss.

Figure 1

Pedigree, mutational analysis, and audiogram of Chinese family 6126 with ADNSHI. (a) The proband is indicated by an arrow. Subjects II:1, II:3 and III:1 were tested by NGS. (b) DNA sequencing profile showing the POU4F3 c.602T>C cosegregated with the hearing loss. (c) Audiogram showed bilateral sensorineural hearing impairment of affected subjects II:1, III:1, and IV:1 (red: right ear; blue: left ear).

Figure 2

Conservation analysis and genomic structure of POU4F3 based on the open reading frame (NM_002700.2) containing 2 exons (black rectangles). (a) The position of POU4F3 c.602T>C (p.Leu201Pro) is highlighted in red and shown both at the gene (top) and the protein level (bottom). The protein diagram depicts the predicted functional domains and sequence motifs. (b) Protein alignment showing POU4F3 p.Leu201 occurred at evolutionarily conserved amino acids (in red box) across twelve species.