Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder

J Med Genet. 2015 Aug;52(8):523-31. doi: 10.1136/jmedgenet-2014-102961. Epub 2015 May 18.


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.

Keywords: Auditory neuropathy spectrum disorder; Clinical genetics; Genetic heterogeneity; Mutation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Inducing Factor / chemistry
  • Apoptosis Inducing Factor / genetics
  • Chromosome Mapping
  • Cohort Studies
  • DNA Mutational Analysis
  • Exome / genetics
  • Female
  • Genes, X-Linked
  • Hearing Loss, Central / genetics*
  • Hearing Loss, Central / pathology
  • Humans
  • Male
  • Mice
  • Mutation, Missense
  • Pedigree
  • Protein Structure, Tertiary


  • AIFM1 protein, human
  • Apoptosis Inducing Factor

Supplementary concepts

  • Auditory neuropathy