Identification Of TMPRSS3 Variations In Large CGDC Deafness Cohort

Deafness is one of the major public health problems in the world.Hearing protection is a major demand of China's social and economic development.Among all kinds of etiology,genetic defect is the major cause of deafness.For congenital deafness with high heredity,the key step to reduce the rate of birth defect is to discover the molecular etiology of deafness and to explain its mechanism.Among hereditary hearing loss,70% are non-syndromic,and autosomal recessive non-syndromic deafness(DFNB)is usually characterized by severe to profound prelingual sensorineural hearing loss.The TMPRSS3 gene encodes a transmembrane serine protease,underlying both DFNB8 and DFNB10 non-syndromic deafness.At present,76 pathogenic variations have been reported in TMPRSS3.In the previous project started in September 2013,our team joined more than 50 scientific teams engaged in deafness research and otology and led the establishment of Chinese Deafness Genetics Consortium(CDGC).CDGC deafness cohort has collected 22599 deafness cases covering 41 nationalities in 31 provinces,municipalities and autonomous regions of China.Approximately 30% of genetic causes were identified by prescreening of GJB2,SLC26A4 and MT-RNR1.Massively parallel sequencing(MPS)of 785 deafness-related genes was performed in 12247 cases with unknown etiology and 3752 geographically matched controls with normal hearing.By inhouse bioinformatic analysis pipeline,MPS data of TMPRSS3 gene were extracted from 12247 cases,and genetic variations were identified.CNVplex analysis was performed in 87 cases with single heterozygous mutation in TMPRSS3.Homozygous or compound heterozygous variations in TMPRSS3 were detected in 52 cases by MPS,CNVplex,real-time PCR,long-range PCR,Sanger sequencing and breakpoint analysis involving 43 variations.Pathogenicity of the detected variations was analyzed according to the recommendations for the interpretation of sequence variants of American College of Medical Genetics and Genomics(ACMG).A total of 39 pathogenic variations including 24 missense mutations,3 frameshift mutations,5 splice site mutations,3 nonsense mutations and 4 copy number variants were identified by pathogenicity analysis.A total of 49 cases were diagnosed as TMPRSS3-caused deafness.We summarized the clinical characteristics of the diagnosed cases,such as age of onset,type of deafness,severity of deafness,audiograms,etc.We described the genotype-phenotype correlation between TMPRSS3 and DFNB8/DFNB10 deafness.Auditory and speech scales were applied to evaluate the effect of cochlear implantation in nine TMPRSS3-cases.Eight of the nine cases who underwent cochlear implantation showed good performance.In this study,the mutational spectrum of TMPRSS3 in Chinese deaf population is comprehensively identified in a large cohort,showing that TMPRSS3 is a significant contributor to non-syndromic deafness in Chinese population,especially in the cases of autosomal recessive deafness with residual hearing in low frequencies and profound hearing loss in mid-to-high frequencies.For cases whose genetic etiology is not identified in MPS,the detection of copy number variation should be regarded as a follow-up choice.Especially for those cases who have not been diagnosed by other deafness genes and carry heterozygous pathogenic mutation,copy number variation should be routinely detected and validated by integrative approaches.Cases with TMPRSS3-caused deafness are proper candidates for cochlear implantation.