Abstract
Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous disease involving more than 70 pathogenic genes. However, most ARNSHL families have small-sized pedigrees with limited genetic information, rendering challenges for the molecular diagnosis of these patients. Therefore, we attempted to establish a strategy for identifying deleterious variants associated with ARNSHL by applying proband whole-exome sequencing (proband-WES). Aside from desiring to improve molecular diagnostic rates, we also aimed to search for novel deafness genes shared by patients with similar phenotype, making up for the deficiency of small ARNSHL families. In this study, 48.5% (16/33) families were detected the pathogenic variants in eight known deafness genes, including 10 novel variants identified in TMPRSS3 (MIM 605551), MYO15A (MIM 602666), TMC1 (MIM 606706), ADGRV1 (MIM 602851), and PTPRQ (MIM 603317). Apart from six novel variants with a truncating effect (nonsense, deletion, insertion, and splice-site), four novel missense variants were not found in 200 unrelated control population by using Sanger sequencing. It is important to note that none of novel genes were shared across different pedigrees, indicating that a larger sample size might be needed. Proband-WES is a cost-effective and precise way of identifying causative variants in nuclear families with ARNSHL. This economical strategy may be appropriated as a clinical application to provide molecular diagnostics, genetic counseling, and individualized health maintenance measures for patients with ARNSHL at hearing clinics.
Highlights
Hearing loss (HL) is one of the most common sensory disorders, affecting nearly 328 million adults and 32 million children worldwide (WHO, 2017)
To ensure the pedigrees from a homogeneous population with Autosomal recessive non-syndromic hearing loss (ARNSHL), we used the following inclusion criteria: 1) the probands had other affected sibling(s); 2) patients’ parents were asymptomatic; 3) all affected individuals suffered from congenital or prelingual deafness with a severity ranging from severe to profound; and 4) HL was the sole symptom of all patients
55.6% (10/18) were novel variants that apart from six novel variants with a truncating effect, the other four were missense variants detected in TMPRSS3 and MYO15A, respectively, which were undetected in 200 unrelated control subjects
Summary
Hearing loss (HL) is one of the most common sensory disorders, affecting nearly 328 million adults and 32 million children worldwide (WHO, 2017). It is estimated that approximately 30,000 Chinese infants are born with congenital non-syndromic HL (NSHL) annually (Ouyang et al, 2009). Approximately 70% are NSHL, for which hearing impairment is the exclusive phenotype (Niu et al, 2017; Deng et al, 2018). It is reported that almost 80% of NSHL cases involve autosomal-recessive inheritance with high genetic heterogeneity (Angeli et al, 2012). The major symptom of autosomal-recessive NSHL (ARNSHL) is bilaterally symmetric, severe-to-profound, and prelingual sensorineural HL, which is known to be caused mainly by monogenic mutations (Wu et al, 2016; Deng et al, 2018)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
