Five Novel Mutations in LOXHD1 Gene Were Identified to Cause Autosomal Recessive Nonsyndromic Hearing Loss in Four Chinese Families

Abstract

Hearing loss is one of the most common sensory disorders in newborns and is mostly caused by genetic factors. Autosomal recessive nonsyndromic hearing loss (ARNSHL) is usually characterized as a severe-to-profound congenital sensorineural hearing loss and later can cause various degrees of defect in the language and intelligent development of newborns. The mutations in LOXHD1 gene have been shown to cause DFNB77, a type of ARNSHL. To date, there are limited reports about the association between LOXHD1 gene and ARNSHL. In this study, we reported six patients from four Chinese families suffering from severe-to-profound nonsyndromic hearing loss. We performed targeted next generation sequencing in the six affected members and identified five novel pathogenic mutations in LOXHD1 including c.277G>A (p.D93N), c.611-2A>T, c.1255+3A>G, c.2329C>T (p.Q777 ^∗ ), and c.5888delG (p.G1963Afs ^∗ 136). These mutations were confirmed to be cosegregated with the hearing impairment in the families by Sanger sequencing and were inherited in an autosomal recessive pattern. All of the five mutations were absent in 200 control subjects. There were no symptoms of Fuchs corneal dystrophy in the probands and their blood-related relatives. We concluded that these five novel mutations could be involved in the underlying mechanism resulting in the hearing loss, and this discovery expands the genotypic spectrum of LOXHD1 mutations.

Figure 1

Pedigrees of the hearing loss families and identified pathogenic variants. Black squares represent members with hearing loss. Genotypes are marked below each member. Arrow shows the proband. Asterisks indicate the families with LOXHD1 mutations identified in the present study.

Figure 2

Audiograms of some members participating in this study in the four Chinese families. Blue crosses and red circles represent the air conduction hearing threshold levels of left and right ears, respectively. Asterisks indicate the families with LOXHD1 mutations identified in this study. Gender and age are shown below the audiogram of each individual.

Figure 3

Sanger sequencing results of the probands in the four families. Red arrows point to the positions of the LOXHD1 mutations.

Figure 4

All identified pathogenic variants in LOXHD1 gene associated with DFNB77. (a) Isoform 1 represents LOXHD1 protein NP_653213.6. (b) Schematic representation of PLAT protein domain. (c) Isoform 2 represents LOXHD1 protein NP_001138944.1. Two variants (L635P and splice site variants K646K) only affect the shorter isoform 2. The blue label represents the previously reported mutations causing DFNB77 deafness, while the red label represents novel mutations in this work [14].