Genetic Analysis Of A Family With Autosomal Dominant Nonsyndromic Hearing Loss

Objective:To explore the genetic causes of a Chinese family with autosomal dominant non-syndromic hearing loss(family JSNY-023). Methods:Clinical data of the family were obtained through questionnaire. Peripheral blood samples were obtained from the 23 family members(9 affected and 14 unaffected). Genomic DNA was extracted with the routine method. Samples from 148 unrelated normal-hearing individuals and 53 sporadic non-syndromic hearing loss patients were also collected and served as controls. Firstly, the nine hot spots of four frequent deafness genes for the Chinese background were excluded in the proband by DNA microarray analysis. Three affected individuals and one family spouse were then selected for whole-exome sequencing and variation analysis. Secondly, primers for the candidate genes were designed for PCR amplification. Direct Sanger sequencing was conducted to identify base changes. Co-segregation analysis was performed to confirm the causative gene. Finally, Sanger sequencing of the controls was conducted to exclude single nucleotide polymorphism, and bioinformatic analysis was performed to predict whether the variant is damaging. Results:There were 51 candidate genes identified by whole-exome sequencing and variation analysis. Sanger-sequencing confirmed a novel EYA4 missense mutation(c.T1301A;p.I434K) co-segregating with the phenotype of the family. The mutation was absent in the 148 unrelated control subjects and 53 sporadic patients of Chinese background, and is predicted to be damaging by bioinformatic analysis. Conclusions:1. The c.T1301 A mutation in EYA4 gene is responsible for the hearing loss in JSNY-023 family.2. Missense mutation in the eya-homologous region can also lead to nonsyndromic hearing loss.