Abstract
BackgroundGenetic tests for hereditary hearing loss inform clinical management of patients and can provide the first step in the development of therapeutics. However, comprehensive genetic tests for deafness genes by Sanger sequencing is extremely expensive and time-consuming. Next-generation sequencing (NGS) technology is advantageous for genetic diagnosis of heterogeneous diseases that involve numerous causative genes.MethodsGenomic DNA samples from 58 subjects with hearing loss from 15 unrelated Japanese families were subjected to NGS to identify the genetic causes of hearing loss. Subjects did not have pathogenic GJB2 mutations (the gene most often associated with inherited hearing loss), mitochondrial m.1555A>G or 3243A>G mutations, enlarged vestibular aqueduct, or auditory neuropathy. Clinical features of subjects were obtained from medical records. Genomic DNA was subjected to a custom-designed SureSelect Target Enrichment System to capture coding exons and proximal flanking intronic sequences of 84 genes responsible for nonsyndromic or syndromic hearing loss, and DNA was sequenced by Illumina GAIIx (paired-end read). The sequences were mapped and quality-checked using the programs BWA, Novoalign, Picard, and GATK, and analyzed by Avadis NGS.ResultsCandidate genes were identified in 7 of the 15 families. These genes were ACTG1, DFNA5, POU4F3, SLC26A5, SIX1, MYO7A, CDH23, PCDH15, and USH2A, suggesting that a variety of genes underlie early-childhood hearing loss in Japanese patients. Mutations in Usher syndrome-related genes were detected in three families, including one double heterozygous mutation of CDH23 and PCDH15.ConclusionTargeted NGS analysis revealed a diverse spectrum of rare deafness genes in Japanese subjects and underscores implications for efficient genetic testing.
Highlights
Genetic tests for hereditary hearing loss inform clinical management of patients and can provide the first step in the development of therapeutics
OTOF mutations are common in patients with auditory neuropathy, which is characterized by normal outer hair cell function and abnormal neural conduction [5]
Subjects with auditory neuropathy were tested for OTOF mutations, which are associated with auditory neuropathy [12], and subjects with OTOF mutations were excluded
Summary
Genetic tests for hereditary hearing loss inform clinical management of patients and can provide the first step in the development of therapeutics. 50% of congenital hearing loss cases and 70% of childhood hearing loss cases are attributed to genetic mutations [1]. GJB2 mutations are the most common cause of childhood hearing loss worldwide [1], followed by SLC26A4 mutations [4]. The prevalence of childhood hearing loss patients with mutations in other deafness-related genes is likely to be less than 1% [1]. Such high heterogeneity of hearing loss makes it impractical to perform genetic tests by Sanger sequencing. This is the case for some types of syndromic hearing loss. Nine genes have been reported to cause Usher syndrome, and all are large and difficult to analyze using Sanger sequencing
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