A novel dominant GJB2 (DFNA3) mutation in a Chinese family

Abstract

To decipher the phenotype and genotype of a Chinese family with autosomal dominant non-syndromic hearing loss (ADNSHL) and a novel dominant missense mutation in the GJB2 gene (DFNA3), mutation screening of GJB2 was performed on the propositus from a five-generation ADNSHL family through polymerase chain reaction amplification and Sanger sequencing. The candidate variation and the cosegregation of the phenotype were verified in all ascertained family members. Targeted genes capture and next-generation sequencing (NGS) were performed to explore additional genetic variations. We identified the novel GJB2 mutation c.524C > A (p.P175H), which segregated with high frequency and was involved in progressive sensorineural hearing loss. One subject with an additional c.235delC mutation showed a more severe phenotype than did the other members with single GJB2 dominant variations. Four patients diagnosed with noise-induced hearing loss did not carry this mutation. No other pathogenic variations or modifier genes were identified by NGS. In conclusion, a novel missense mutation in GJB2 (DFNA3), affecting the second extracellular domain of the protein, was identified in a family with ADNSHL.Mutations in the gene GJB2, which encodes the gap junction protein connexin 26, play a key role in hereditary hearing loss and represent the most common cause of non-syndromic hearing loss 1 . Variations in GJB2 may cause either autosomal dominant or recessive non-syndromic hearing loss (NSHL) as well as syndromic hearing loss (SHL). The inheritance pattern is ultimately determined by how the variation affects the expression and function of the connexin 26 protein. More than two hundred mutations in GJB2 (DFNB1, MIM220290) have been found to be related to autosomal recessive non-syndromic hearing loss 2 , whereas only nineteen GJB2 mutations have been associated with hereditary autosomal dominant non-syndromic deafness (DFNA3, MIM601544). Previous studies of dominant GJB2 mutations are rare and have been limited to cases or simplex families. In this study, via traditional PCR and Sanger sequencing, a novel GJB2 heterozygous mutation was identified in a Chinese family with autosomal dominant non-syndromic hearing loss (ADNSHL). Results Clinical description. From Family 304, a total of 32 family members, including 16 clinically affected and 16unaffected individuals, were included in this study (Fig. 1). Among the 16 affected cases, 4 subjects had explicit noise exposure history. In this family, the 12 affected members without noise exposure history showed symmetrical and bilateral non-syndromic sensorineural hearing loss, but no clear onset age was described (although the ages of identification were generally within childhood). The propositus (IV:2) was a 26-year-old male with bilateral progressive hearing loss when he first visited our outpatient clinic in 2004. The hearing impairment initially presented at high frequencies. He showed moderate or mild hearing loss at 0.5 kHz and 1 kHz and severe or profound hearing loss at 2 kHz, 4 kHz and ...

Prelingual Sensorineural Hearing Loss Caused by a Novel GJB2 Dominant Mutation in a Chinese Family

“…For recessive pathogenic variants, differences in hotspot variants have been shown to be a characteristic of different nationalities. In contrast, there are currently 40 dominant pathogenic variants related to hearing loss or syndromic hearing loss [1][2][3], with no evidence of racial differences. Here, we describe a novel dominant pathogenic variant of GJB2 (c.205 T > C; p.Phe69Leu) associated with prelingual nonsyndromic sensorineural hearing loss in a Chinese family.…”