Abstract
Hearing loss is the most common sensory deficit in humans. Identifying the genetic cause and genotype-phenotype correlation of hearing loss is sometimes challenging due to extensive clinical and genetic heterogeneity. In this study, we applied targeted next-generation sequencing (NGS) to resolve the genetic etiology of hearing loss in a Chinese Han family with multiple affected family members. Targeted sequencing of 415 deafness-related genes identified the heterozygous c.481C>T (p.R161C) mutation in SOX10 and the homozygous c.235delC (p.L79Cfs∗3) mutation in GJB2 as separate pathogenic mutations in distinct affected family members. The SOX10 c.481C>T (p.R161C) mutation has been previously reported in a Caucasian patient with Kallmann syndrome that features congenital hypogonadotropic hypogonadism with anosmia. In contrast, family members carrying the same p.R161C mutation in this study had variable Waardenburg syndrome-associated phenotypes (hearing loss and/or hair hypopigmentation) without olfactory or reproductive anomalies. Our results highlight the importance of applying comprehensive diagnostic approaches such as NGS in molecular diagnosis of hearing loss and show that the p.R161C mutation in SOX10 may be associated with a wide range of variable clinical manifestations.
Highlights
Hearing loss is the most prevalent neurosensory impairment in humans, affecting over half a billion people worldwide [1, 2]
Sanger sequencing validated the presence of this variant in IV-1, III-1, and II-1, three individuals with Waardenburg syndrome (WS)-associated phenotypes (Figure 2(a))
We identified two separate genetic causes of hearing loss in distinct affected members, including the recessive c.235delC (p.L79Cfs∗3) mutation in GJB2 (III-2) and the dominant c.481C>T (p.R161C) mutation in SOX10 (II-1, III-1, and IV-1)
Summary
Hearing loss is the most prevalent neurosensory impairment in humans, affecting over half a billion people worldwide [1, 2]. Many previous reports have already shown that HCs can be injured due to genetic factors, noise, ototoxic drugs, aging, or inflammation [6,7,8,9,10,11,12,13]; and it is estimated that 50%-60% of early-onset hearing loss is due to genetic factors [14, 15]. Based on the association with other clinical features, approximately 70% of genetic hearing loss is nonsyndromic and 30% is syndromic. More than 100 genes for nonsyndromic hearing loss have been identified, and over 700 different forms of syndromic hearing impairment have been described [16, 17]. The extremely high genetic and phenotypic heterogeneity sometimes makes the diagnosis of genetic hearing loss challenging
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