title: Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder.
abstract: BACKGROUND
  Auditory neuropathy spectrum disorder (ANSD) is a form of hearing loss in which auditory signal transmission from the inner ear to the auditory nerve and brain stem is distorted, giving rise to speech perception difficulties beyond that expected for the observed degree of hearing loss. For many cases of ANSD, the underlying molecular pathology and the site of lesion remain unclear. The X-linked form of the condition, AUNX1, has been mapped to Xq23-q27.3, although the causative gene has yet to be identified.
  
  
  METHODS
  We performed whole-exome sequencing on DNA samples from the AUNX1 family and another small phenotypically similar but unrelated ANSD family.
  
  
  RESULTS
  We identified two missense mutations in AIFM1 in these families: c.1352G>A (p.R451Q) in the AUNX1 family and c.1030C>T (p.L344F) in the second ANSD family. Mutation screening in a large cohort of 3 additional unrelated families and 93 sporadic cases with ANSD identified 9 more missense mutations in AIFM1. Bioinformatics analysis and expression studies support this gene as being causative of ANSD.
  
  
  CONCLUSIONS
  Variants in AIFM1 gene are a common cause of familial and sporadic ANSD and provide insight into the expanded spectrum of AIFM1-associated diseases. The finding of cochlear nerve hypoplasia in some patients was AIFM1-related ANSD implies that MRI may be of value in localising the site of lesion and suggests that cochlea implantation in these patients may have limited success.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zong
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Guan
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories and the Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA Department of Otolaryngology-Head & Neck Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Ealy
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Qiujing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Dayong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China Beijing Institute of Otorhinolaryngology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National Institute of Biological Sciences, Beijing, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories and the Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Campbell
authors.affiliation: National Institute of Biological Sciences, Beijing, China.
authors.forename: Fengchao
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Communicative Disorders & Sciences, Center for Hearing and Deafness, University at Buffalo, Buffalo, New York, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Lan
authors.affiliation: Department of Communicative Disorders & Sciences, Center for Hearing and Deafness, University at Buffalo, Buffalo, New York, USA.
authors.forename: Dalian
authors.initials: D
authors.lastname: Ding
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Linyi
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Radiology, PLA General Hospital, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lou
authors.affiliation: Department of Neurology, PLA General Hospital, Beijing, China.
authors.forename: Xusheng
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Neurology, PLA General Hospital, Beijing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Suhua
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Wenping
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Zifang
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Communicative Disorders & Sciences, Center for Hearing and Deafness, University at Buffalo, Buffalo, New York, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Salvi
authors.affiliation: Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, Collège de France, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories and the Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China.
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000737:chemistry / Q000235:genetics; D002874:Chromosome Mapping; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D050172:Genes, X-Linked; D006313:Hearing Loss, Central / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor
keywords: Auditory neuropathy spectrum disorder; Clinical genetics; Genetic heterogeneity; Mutation