title: Phenotypic Heterogeneity in a DFNA20/26 family segregating a novel ACTG1 mutation.
abstract: BACKGROUND
  Genetic factors play an important role in hearing loss, contributing to approximately 60% of cases of congenital hearing loss. Autosomal dominant deafness accounts for approximately 20% of cases of hereditary hearing loss. Diseases with autosomal dominant inheritance often show pleiotropy, different degrees of penetrance, and variable expressivity.
  
  
  METHODS
  A three-generation Chinese family with autosomal dominant nonsyndromic hearing impairment (ADNSHI) was enrolled in this study. Audiometric data and blood samples were collected from the family. In total, 129 known human deafness genes were sequenced using next-generation sequencing (NGS) to identify the responsible gene mutation in the family. Whole Exome Sequencing (WES) was performed to exclude any other variant that cosegregated with the phenotype.
  
  
  RESULTS
  The age of onset of the affected family members was the second decade of life. The condition began with high-frequency hearing impairment in all family members excluding III:2. The novel ACTG1 c.638A > G (p.K213R) mutation was found in all affected family members and was not found in the unaffected family members. A heterozygous c.638A > G mutation in ACTG1 and homozygous c.109G > A (p.V37I) mutation in GJB2 were found in III:2, who was born with hearing loss. The WES result concurred with that of targeted sequencing of known deafness genes.
  
  
  CONCLUSIONS
  The novel mutation p.K213R in ACTG1 was found to be co-segregated with hearing loss and the genetic cause of ADNSHI in this family. A homozygous mutation associated with recessive inheritance only rarely co-acts with a dominant mutation to result in hearing loss in a dominant family. In such cases, the mutations in the two genes, as in ACTG1 and GJB2 in the present study, may result in a more severe phenotype. Targeted sequencing of known deafness genes is one of the best choices to identify the genetic cause in hereditary hearing loss families.
authors.affiliation: Department of Otolaryngology, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China. yyymzh@163.com.|Department of Otolaryngology, Hainan Branch of PLA General Hospital, Sanya, 572000, People's Republic of China. yyymzh@163.com.
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Otolaryngology, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China. mixueer0110@126.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Otolaryngology, Hainan Branch of PLA General Hospital, Sanya, 572000, People's Republic of China. bangqing6@163.com.
authors.forename: Bangqing
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, 30322-3030, USA. jqlu@otogenetics.com.
authors.forename: Jingqiao
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Otolaryngology, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China. wjcmu@163.com.
authors.forename: Guojian
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, 30322-3030, USA. xlin2@emory.edu.
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Third hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050051, People's Republic of China. quyan1589@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Otolaryngology, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China. daipu301@vip.sina.com.
authors.forename: Pu
authors.initials: P
authors.lastname: Dai
mesh_terms: D000199:Actins / Q000737:chemistry / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D002648:Child; D000072259:Connexin 26; D017630:Connexins; D004252:DNA Mutational Analysis; D005260:Female; D006319:Hearing Loss, Sensorineural; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D055815:Young Adult
chemical_list: C000594243:ACTG1 protein, human; D000199:Actins; D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26
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