Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder

Abstract

BackgroundMany hearing-loss diseases are demonstrated to have Mendelian inheritance caused by mutations in single gene. However, many deaf individuals have diseases that remain genetically unexplained. Auditory neuropathy is a sensorineural deafness in which sounds are able to be transferred into the inner ear normally but the transmission of the signals from inner ear to auditory nerve and brain is injured, also known as auditory neuropathy spectrum disorder (ANSD). The pathogenic mutations of the genes responsible for the Chinese ANSD population remain poorly understood.MethodsA total of 127 patients with non-syndromic hearing loss (NSHL) were enrolled in Guangxi Zhuang Autonomous Region. A hereditary deafness gene mutation screening was performed to identify the mutation sites in four deafness-related genes (GJB2, GJB3, 12S rRNA, and SLC26A4). In addition, whole-exome sequencing (WES) was applied to explore unappreciated mutation sites in the cases with the singularity of its phenotype.ResultsWell-characterized mutations were found in only 8.7% (11/127) of the patients. Interestingly, two mutations in the OTOF gene were identified in two affected siblings with ANSD from a Chinese family, including one nonsense mutation c.1273C > T (p.R425X) and one missense mutation c.4994 T > C (p.L1665P). Furthermore, we employed Sanger sequencing to confirm the mutations in each subject. Two compound heterozygous mutations in the OTOF gene were observed in the two affected siblings, whereas the two parents and unaffected sister were heterozygous carriers of c.1273C > T (father and sister) and c.4994 T > C (mother). The nonsense mutation p.R425X, contributes to a premature stop codon, may result in a truncated polypeptide, which strongly suggests its pathogenicity for ANSD. The missense mutation p.L1665P results in a single amino acid substitution in a highly conserved region.ConclusionsTwo mutations in the OTOF gene in the Chinese deaf population were recognized for the first time. These findings not only extend the OTOF gene mutation spectrum for ANSD but also indicate that whole-exome sequencing is an effective approach to clarify the genetic characteristics in non-syndromic ANSD patients. Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0400-0) contains supplementary material, which is available to authorized users.

Genetic analysis of 106 sporadic cases with hearing loss in the UAE population

“…In sample 8, we detected two potential HL-associated variants within the OTOF gene in a heterozygous state. It's noteworthy that compound heterozygous mutations in the OTOF gene are frequently observed and have been implicated in many cases of hearing loss [38][39][40][41][42][43][44].…”

Comprehensive functional network analysis and screening of deleterious pathogenic variants in non-syndromic hearing loss causative genes

“…In the GJB2 mutant condition, the functional gap junction channel formation is defective [18]. The researchers have been reported the role of GJB2 mutations in the pathogenesis of NSHL through different experimental analyses [6,[19][20][21][22][23]. Though GJB2 is the most common mutation worldwide in different populations, other important genes include SLC26A4, GJB3, GJB6, MYO15A, MYO7A, TMC1, CDH23 etc.…”

Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry

“…The allelic spectrum of PLP ARNSHI variants in EAS is unique, the GJB2 p.(G12fs) (c.35delG) variant, which is highly prevalent in all other populations is absent, while GJB2 founder variant p.(L79fs) (c.235delC) [31] and OTOF variant p.(E1700Q) are highly present (Fig. 2) [32].…”

“…Individuals that are homozygous for this variant usually have high frequency HI and therefore many affected individuals may go undiagnosed. SLC26A4 [p.(L117F)] [42] and OTOF [p.(E1700Q)] [32] variants were also included in this study since they are considered pathogenic by a large number of sources, including recent evaluations by clinical laboratories. It should be noted that SLC26A4 [p.(L117F)] has been reported for both non-syndromic HI and Pendred syndrome in ClinVar.…”