Whole exome sequencing of six Chinese families with hereditary non-syndromic hearing loss

Abstract

Background:Hereditary non-syndromic hearing loss (NSHL) has a high genetic heterogeneity with >152 genes identi ed as associated molecular causes. The present study aimed to detect the possible damaging variants of the deaf probands from six unrelated Chinese families. Methods:After excluding the mutations in the most common genes, GJB2 and SLC26A4, 12 probands with prelingual deafness and autosomal recessive inheritance were evaluated by whole-exome sequencing (WES). All the candidate variants were veri ed by Sanger sequencing in all patients and their parents. Results:Biallelic mutations were identi ed in all deaf patients. Among these six families, 10 potentially causative mutations, including 3 reported and 7 novel mutations, in 3 different deafness-associated autosomal recessive (DFNB) genes (MYO15A, COL11A2, and CDH23) were identi ed. The mutations in MYO15A were frequent with 7/10 candidate variants. Sanger sequencing con rmed that these mutations segregated with the hearing loss of each family. Conclusions:Next-generation sequencing (NGS) approach becomes more cost-effective and e cient when analyzing large-scale genes compared to the conventional polymerase chain reaction-based Sanger sequencing, which is often used to screen common deafness-related genes. The current ndings further extend the mutation spectrum of hearing loss in the Chinese population, which has a positive signi cance for genetic counseling. gene (14.5%) are the second common pathogenic cause of DFNB in addition to the GJB2 gene (17.9%) [8,9]. Sanger sequencing to detect mutations in GJB2 and SLC26A4 is a routine method during genetic testing and counseling for deafness patients. However, for GJB2 or SLC26A4-negative patients, especially those from small-sized recessive families, the potential genetic causes for deafness are yet unclear.The genetic heterogeneity of hearing loss, with about 152 deafness-associated genes, identi ed to be associated with NSHL [10], makes conventional polymerase chain reaction (PCR)-based Sanger sequencing impractical for large-scale gene detection because of its cost-ine ciency and timeconsumption [11]. In recent years, next-generation sequencing (NGS) approach may make it possible to analyze multiple genes, including all the deafness-associated genes, in one test [12]. Whole exome sequencing (WES), a platform of NGS, offers powerful applications for diagnosis as well as identifying rare variants or new causative genes [13,14].In this study, we utilized WES to investigate the contributing genetic factors in patients from six unrelated Chinese families with autosomal recessive hearing loss but did not harbor GJB2 and SLC26A4 mutations. MethodsSix unrelated Chinese families (code as HL01-06) were recruited from the outpatient clinic of the

Recurrent missense variant identified in two unrelated families with MPZL2‐related hearing loss, expanding the variant spectrum associated with DFNB111

“…(Gln74*) truncating founder variant that has a minor allele frequency of 0.558% in the East Asian subpopulation. This variant was also recently reported in the homozygous state in five individuals of Chinese descent (Li et al, 2023).…”

“…An additional rare c.52C>T,p. (Leu18Phe) missense variant was recently reported in one patient (patient 34) who also carried the c.220C>T,(p.Gln74*) truncating variant (Li et al, 2023). The c.52C>T,p.…”

“…The CGPT clinical test identified a diagnosis of MPZL2‐ related hearing loss in 2.7% of those tested within the first 4 months of adding the gene to the test. Li et al (2023) reported that 1.3% (5/385) of individuals with hearing loss in a Chinese cohort provided whole‐exome testing had a confirmed diagnosis of MPZL2 ‐related hearing loss and another had two VUS, and Kim et al (2020) identified a diagnosis of MPZL2 related hearing loss in 10.8% of those with mild‐to‐moderate hearing loss analyzed in their cohort. Together, multiple reports since 2018 indicate that MPZL2 may be a more frequent genetic cause of autosomal recessive bilateral sensorineural hearing loss than previously thought, particularly in specific sub‐populations.…”

“…(Leu18Phe), was recently reported in the compound heterozygous state with the recurrent c.220C>T,p. (Gln74*) variant in an individual with late‐onset downsloping hearing loss (Li et al, 2023).…”

Mutation spectrum of hearing loss patients in Northwest China: Identification of 20 novel variants

“…The rapid development of next‐generation sequencing (NGS) makes it possible to analyse all genes in one test. Whole‐exome sequencing (WES), a platform of NGS, offers powerful applications for diagnosis as well as for identifying rare variants or new causative genes (Liang et al., 2021 ).…”