Mutational Spectrum and Clinical Features of Patients with LOXHD1 Variants Identified in an 8074 Hearing Loss Patient Cohort

Abstract

Variants of the LOXHD1 gene, which are expressed in hair cells of the cochlea and vestibule, have been reported to cause a progressive form of autosomal recessive non-syndromic hereditary hearing loss, DFNB77. In this study, genetic screening was conducted on 8074 Japanese hearing loss patients utilizing massively parallel DNA sequencing to identify individuals with LOXHD1 variants and to assess their phenotypes. A total of 28 affected individuals and 21 LOXHD1 variants were identified, among which 13 were novel variants. A recurrent variant c.4212 + 1G > A, only reported in Japanese patients, was detected in 18 individuals. Haplotype analysis implied that this variation occurred in a mutational hot spot, and that multiple ancestors of Japanese population had this variation. Patients with LOXHD1 variations mostly showed early onset hearing loss and presented different progression rates. We speculated that the varying severities and progression rates of hearing loss are the result of environmental and/or other genetic factors. No accompanying symptoms, including vestibular dysfunction, with hearing loss were detected in this study. Few studies have reported the clinical features of LOXHD1-gene associated hearing loss, and this study is by far the largest study focused on the evaluation of this gene.

Cochlear Implantation From the Perspective of Genetic Background

“…A series of studies have shown that patients with LOXHD1 mutations show progressive hearing loss, leading to profound‐to‐severe non‐syndromic hearing loss (Mori et al, ; Maekawa et al, ). By examining a large cohort of hearing loss patients (n = 8,074), we have recently reported 28 patients with LOXHD1 mutations and clarified the clinical features (Maekawa et al, ). Concerning the audiogram configurations, most of the patients had high‐frequency hearing loss (Fig.…”

“…All CI patients, whose clinical data were available, showed a favorable outcome (Fig. ) (Maekawa et al, ). Therefore, patients with this gene mutation are good candidates for CI/EAS.…”

“…Now known as "auditory neuropathy spectrum disorder (ANSD)," AN was renamed in 2008 due to being a spectrum of associated symptoms (Roush et al, 2011 for review). Although the exact percentage of nonsyndromic ANSD is unclear, responsible genes continue to be identified, with mutations in the AUNA1, OTOF, PJVK, and GJB2 genes as well as in mitochondrial 12S rRNA reported to cause non-syndromic ANSD (Manchaiah et al, 2011). The OTOF gene (DFNB9) is predominantly expressed in the cochlear inner hair cells, and is essential for synaptic exocytosis at their ribbon synapses .…”

“…Congenital high-frequency involved hearing loss indicative for EAS. He was diagnosed with hearing loss at age 3 and started wearing hearing aids (Maekawa et al, 2019). Evaluated by serial audiograms, it was determined that he had progressive hearing loss.…”

“…Mean scores of the Japanese monosyllable, word, and sentence tests pre-CI and six months post-CI. The scores pre-CI are with hearing aids (Maekawa et al, 2019). monosyllable word sentence Fig.…”