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

TLDR

Auditory neuropathy spectrum disorder (ANSD) causes distorted inner‑ear to brain‑stem transmission and speech perception deficits, yet its molecular basis and lesion site remain largely unknown, including the X‑linked form mapped to Xq23‑q27.3. The authors performed whole‑exome sequencing on DNA from an X‑linked ANSD family and a phenotypically similar unrelated family to identify causative variants. They discovered multiple missense mutations in AIFM1 across families and sporadic cases, with bioinformatics and expression data confirming AIFM1 as a common cause of ANSD, and noted cochlear nerve hypoplasia suggesting MRI utility and limited cochlear implant success.

Abstract

<h3>Background</h3> 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. <h3>Methods</h3> We performed whole-exome sequencing on DNA samples from the AUNX1 family and another small phenotypically similar but unrelated ANSD family. <h3>Results</h3> We identified two missense mutations in <i>AIFM1</i> in these families: c.1352G&gt;A (p.R451Q) in the AUNX1 family and c.1030C&gt;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 <i>AIFM1</i>. Bioinformatics analysis and expression studies support this gene as being causative of ANSD. <h3>Conclusions</h3> Variants in <i>AIFM1</i> gene are a common cause of familial and sporadic ANSD and provide insight into the expanded spectrum of <i>AIFM1</i>-associated diseases. The finding of cochlear nerve hypoplasia in some patients was <i>AIFM1</i>-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.