Mutations in LOXHD1 Gene Cause Various Types and Severities of Hearing Loss

Abstract

Objective We present two families that were identified with novel mutations in LOXHD1, as a cause of non-progressive hearing loss. Methods One thousand three hundred fourteen (1,314) Japanese subjects with sensorineural hearing loss from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known non-syndromic hearing loss genes were performed to identify the genetic cause of hearing loss. Results Two patients in one family affected with homozygous mutation; c.879+1G>A in LOXHD1, showed profound congenital hearing loss, whereas two patients in the other family with compound heterozygous mutations; c.5869G>T (p.E1957X) and c.4480C>T (p.R1494X) showed moderate to severe hearing loss. Conclusion Mutations in LOXHD1 are extremely rare, and these cases are the first identified in a Japanese population. The genotype-phenotype correlation in LOXHD1 is still unclear. The differences of phenotypes in each patient might be the result of the nature of the mutations, or the location at the gene, or be influenced by genetic modifier.

Further audiovestibular characterization of DFNB77, caused by deleterious variants in LOXHD1, and investigation into the involvement of Fuchs corneal dystrophy

“…Severity varied from mild to profound and progression varied from stable to progressive HI in some frequencies. This phenotypic variability and audiogram configuration is in line with previous research on DFNB77 (Table ) …”

“…It is not unlikely that the individuals with non‐congenital HI in fact have congenital HI, but that delayed diagnosis occurred due to lack of neonatal hearing screening or inconclusive test results. In literature, the reported onset of HI is mainly congenital, but varies from congenital to 8 years old (Table ) . One individual, described by Eppsteiner et al, had progressive HI that started at the age of 40 years .…”

“…Mice with homozygous Loxhd1 missense variants are profoundly deaf from an early age . To date, 41 cases with DFNB77 from 22 families have been reported worldwide, harboring 27 different disease‐causing variants . In 17 of these families, the auditory characteristics have been described, showing different audiometric phenotypes, varying from mild to profound and stable to progressive sensorineural HI .…”

Navigating genetic diagnostics in patients with hearing loss

“…Their diagnoses included 20 genes and they estimated a diagnostic rate of 40% if they had not preselected their patient population [25]. They also provided an in-depth phenotypic analysis that adds to our knowledge of the clinical presentation associated with several genes, including LRTOMT, P2RX2, POU3F4, PTPRQ , and USH2A [26–30]. …”

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, ).…”