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

Karuna Maekawa,Satoshi Iwasaki,Natsumi Uehara,Yumiko Kobayashi,Shin-Ichi Goto,Mayuri Okami,Hajime Sano,Shin-Ichi Usami,Shin-Ya Nishio,Chie Oshikawa,Shin-Ichiro Oka,Masayuki Shirakura,Yohei Honkura,Naoko Sakuma,Satoko Abe,Yukihiko Kanda

doi:10.3390/genes10100735

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.

Highlights

One of the most common sensory impairments is hearing loss (HL), affecting one in 500 to 700 newborns [1]
We identified 21 possibly disease-causing LOXHD1 variants, 13 of which were novel variants (Table 1)
The novel variants consisted of 7 missense variants, 1 nonsense variant, 4 splicing variants and 1 frameshift deletion variant

Summary

Introduction

One of the most common sensory impairments is hearing loss (HL), affecting one in 500 to 700 newborns [1]. Roughly a hundred genes have been reported as associated with inherited non-syndromic HL, and at least half of prelingual HL cases account for genetic factors [1,2]. Among these reported genes, around 65% are a cause for autosomal recessive sensorineural hearing loss (ARSNHL), and over 70 causative genes have been identified [2]. Less common causative genes such as LOXHD1 are rarely detected in SNHL patients, making it difficult to diagnose.

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Conclusion