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Original article
Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder
  1. Liang Zong1,
  2. Jing Guan1,
  3. Megan Ealy2,3,
  4. Qiujing Zhang1,
  5. Dayong Wang1,
  6. Hongyang Wang1,
  7. Yali Zhao1,4,
  8. Zhirong Shen5,
  9. Colleen A Campbell2,
  10. Fengchao Wang5,
  11. Ju Yang1,
  12. Wei Sun6,
  13. Lan Lan1,
  14. Dalian Ding6,
  15. Linyi Xie1,
  16. Yue Qi1,
  17. Xin Lou7,
  18. Xusheng Huang8,
  19. Qiang Shi8,
  20. Suhua Chang9,
  21. Wenping Xiong1,
  22. Zifang Yin1,
  23. Ning Yu1,
  24. Hui Zhao1,
  25. Jun Wang10,
  26. Jing Wang9,
  27. Richard J Salvi6,
  28. Christine Petit11,
  29. Richard J H Smith2,
  30. Qiuju Wang1
  1. 1Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
  2. 2Molecular Otolaryngology and Renal Research Laboratories and the Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA
  3. 3Department of Otolaryngology-Head & Neck Surgery, Stanford University School of Medicine, Stanford, California, USA
  4. 4Beijing Institute of Otorhinolaryngology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
  5. 5National Institute of Biological Sciences, Beijing, China
  6. 6Department of Communicative Disorders & Sciences, Center for Hearing and Deafness, University at Buffalo, Buffalo, New York, USA
  7. 7Department of Radiology, PLA General Hospital, Beijing, China
  8. 8Department of Neurology, PLA General Hospital, Beijing, China
  9. 9Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
  10. 10BGI-Shenzhen, Shenzhen, China
  11. 11Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, Collège de France, Paris, France
  1. Correspondence to Professor Qiuju Wang, Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, 28 Fuxing Road, Beijing 100853, China; wqcr301{at} Professor Richard JH Smith, Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA; richard-smith{at}


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.

  • Clinical genetics
  • Genetic heterogeneity
  • Mutation
  • Auditory neuropathy spectrum disorder

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