Identification Of TMC1 Pathogenic Mutations In Chinese Families With Hereditary Hearing Loss

Hearing loss (HL) is the most common sensorineural defect in humans worldwide.The prevalence is 1/1000 in newborns and increases to 3.5 /1000 before 5 years old and to 5/1000 during adolescence. At least 60% of HL are caused by genetic factors, which are called hereditary HL, being classified as autosomal recessive non-syndromic HL(ARNSHL, account for77%), autosomal dominant non-syndromic HL(ADNSHL,22%), X-linked HL ,Y-linked HL and mitochondrial HL. Hereditary HL is a high heterogeneity and typical monogenic disorder, and 138 HL genes have been reported so far(http://hereditaryhearingloss.org/ 2017-3-17), among which 8 genes can cause ARNSHL and ADNSHL including COL11A2?GJB2?GJB6?MY06?MY07A?TBC1D24?TECTA?TMC1.The transmembrane channel-like 1 (TMC1, OMIM:606706) gene is expressed at the tips of the cochlear hair cell stereocilia and maintain theirs functions of mechanoelectrical transduction (MET). TMC1 mutations are implicated in the pathogenesis of both ARNSHL and ADNSHL, at DFNB7/11 and DFNA36 locus respectively. While the former appears mainly as congenital or pre-lingual severe profound HL, the latter shows post-lingual progressively aggravated HL. To date, 49 different kinds of homozygous DFBN7/11 mutations and 4 forms of DFNA36 mutations have been identified in hereditary HL families. The prevalence of TMC1 mutations among Pakistani ARNSHL families reach 3.4%, 19 of 557 families, 4.3%(4/93) to 8.1% (7/86) in Turkey families, 5.9% (5/85) in Tunisia, and 4.2% (1/24) in Europe. With the marked development of sequencing technology, next generation sequencing (NGS), which has the advantage of small samplesquantity, low cost, and high efficency, more and more TMC1 mutations are reported in multiple regions such as Ecuador, Algerian,Morocco, China and so on.Object: In this study, we will identify pathogenic mutations from four different HL families. Methods: NGS was performed using DNA of peripheral blood from the proband and other family members to search for probable deafness genes. Polymerase chain reaction and Sanger sequencing were used to check the candidate mutations in part of family members and normal control population. Pathogencity of these mutations were analyzed by co-segregation of phenotype and prediction of silico, SIFT,Polyphen2, and MutationTaster. Results: We identified four TMCI mutations,including three pathogenic mutations, c.797T>C, c.1714G>A, c.1253T>A, and one SNP,c.2276G>A. While the c.797T>C was a novel mutation at DFNB7/11 locus, the c.1714G>A and c.1253T>A were known mutations at DFNA36 locus. Co-segregation of the mutations and the deafness phenotype were verified within each family by Sanger sequencing. Conclusions: Three pathogenic mutations and one SNP of TMC1 were identified in four Chinese deafness families. The c.1253T>A (p.M418K), homologous to mutation of p.M412K in Beethoven mouse, was the second time reported in the world.