title: Autosomal recessive non-syndromic hearing loss is caused by novel compound heterozygous mutations in TMC1 from a Tibetan Chinese family.
abstract: OBJECTIVE
  Hearing loss is the most common sensory disorder worldwide. Biallelic mutations in 42 different genes have been identified as associated with autosomal recessive non-syndromic hearing loss (ARNSHL). One of the common genes responsible for ARNSHL is TMC1. TMC1 mutations have been reported to cause non-syndromic hearing loss in a variety of populations. The current study is designed to investigate mutations prevalent among Chinese ethnic groups with ARNSHL.
  
  
  METHODS
  Targeted exome sequencing (TES) was employed to study the genetic causes of two siblings with ARNSHL in a Tibetan Chinese family. Variants identified by TES were further confirmed by Sanger sequencing.
  
  
  RESULTS
  We identified two distinct variants in the TMC1 gene in two deaf siblings of one Tibetan Chinese family using TES. Both siblings inherited a paternal allele containing a deletion of c.1396_1398AAC (p.Asn466del) and a maternal allele containing an insertion of c.2210_2211insCT (p.Glu737HisfsX2). The former disrupts a highly conserved residue in the large intracellular loop domain adjacent to the fourth transmembrane domain, and the latter causes a truncation of a portion of the C-terminal domain. These variants were compound heterzygous and segregated with the hearing impairment in this family.
  
  
  CONCLUSIONS
  The novel compound heterozygous mutant alleles of TMC1 identified in this study were responsible for the ARNSHL in this Tibetan Chinese family. Although compound heterozygous mutations in TMC1 occurring in different TMC1 domains have been previously described in Han Chinese; this result suggests that the TMC1 variants contributing to hereditary deafness in Chinese populations may be more complex than initially assumed and that sequence-based diagnostics will be required for a comprehensive evaluation of ARNSHL.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Fangzhu
authors.initials: F
authors.lastname: Lin
authors.affiliation: Center for Prenatal Diagnosis, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Dejun
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: School of Medicine, Tibet University, Lhasa 850000, China.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Fan
authors.affiliation: School of Medicine, Tibet University, Lhasa 850000, China.
authors.forename: Ji
authors.initials: J
authors.lastname: De
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, First Hospital of Jilin University, Changchun 130021, China. Electronic address: zhuwei30000@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
mesh_terms: D044466:Asian People / Q000235:genetics*; D003638:Deafness / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D059472:Exome; D005260:Female; D006579:Heterozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D035781:Siblings; D018609:Tibet
chemical_list: D008565:Membrane Proteins; C451751:TMC1 protein, human
keywords: ARNSHL; Non-syndromic hearing loss; TMC1; Tibetan Chinese