Genetic Analysis And Initial Exploration Of The Pathogenic Gene In An Autosomal Dominant Nonsyndromic Deafness Kindred

Background Hearing loss(HL) is the most common sensory defect, and it is estimated that278million people worldwide suffer from HL, affecting approximately one in500newborns. HL of children affects the growth of the auditory system, education, social activities and quality of life. With the development of modern medicine, environmental factors are contributing less to deafness, nearly60%of HL cases are attributed to hereditary factors. To identify all the genes that cause deafness is a hard and challenging work.Approximately70%of all genetic HL are non-syndromic hearing loss (NSHL), of which50%are considered to be monogenic diseases, NSHL is inherited in a recessive mode in approximately80%of cases, in a dominant mode in approximately20%, and is either X-linked or mitochondrial in origin in1%to3%. To date, many studies have identified143loci responsible for NSHL. The identification of NSHL disease-causing genes which have been reported is mainly based on families, so the work of collection, preservation and analysis traits of familial HL is critical for genetic research for deafness.Objective:To investigate the audiological and genetical features of a large Chinese pedigree with autosomal dominant nonsydromic hearing loss, and to explore its underlying disease-causing gene.Methods:We collected the detailed medical history informations of the all family members. Otoscopy, physical examination, and pure-tone audiometry were performed. Blood samples were collected and well preserved after obtaining in formed consent from all participants. Genetic characteristics of the family was evaluated by audiology materials and pedigree; Genomic DNA was isolated from the peripheral leukocytes of the subjects. Screening the commonly deafness gene (GJB2, GJB3, COCH, EYA4, PDS, MT) to exclude well known pathogenic mutations in the candidate genes; We decided to apply whole-exome sequencing, A new generational sequencing technique, to explore disease-causing gene of the family.Results:We collected a five-generations family from Hunan Province of China with autosomal dominant sensorineural hearing loss, the family have53members, of which42members were alive and14members’blood samples were collected.11patients, including7males and4females, were found to be hearing-impaired, the oldest subject is78years old, and the youngest is27years old. Audiogram showed bilateral symmetric, progressive and sensorineural hearing loss which occured in first to third decade, progressing fist at high-frequencies, and ultimately expended to mid and low frequency in the forty or fifty decade, leading to severe-profound hearing loss. Audiometric configuration is steeply sloping or island type. The mode of inheritance appeared to be autosomal dominant based upon the pedigree. We did not any known deafness-associated gene mutations by screening57exons in common deafness genes and MTDNA sequences, we found42missense mutations which have been reported as single nucleotide polymorphism(SNP), the other single nucleotide variants of COCH was excluded. We performed whole-exome sequencing in two affected and one normal individuals. Finally, we predicted344possible pathogenic mutations, combined with the genes’function and pattern of inheritance, We found10probably causative mutation, which did not include the known deafness genes of NSHL.Conclusions:1. We collected a large autosomal dominant non-syndromic hearing loss kindred, in which affected subjects showed post-lingual, symmetry, progressive hearing impairment.2. Through screening for the crowd common deafness genes’ mutations, including GJB2, GJB3, COCH, EYA4, PDS and mitochondrial genome, we ruled out the possibility of these genes to cause the hearing loss in this family.3. We predicted10candidate genes by using whole exon sequencing in three individuals.