Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study

Orphanet Journal of Rare Diseases

Tatsuo Matsunaga²  Kenjiro Kosaki¹  Kimitaka Kaga⁴  Jun Kudoh⁶  Noriko Morimoto⁵  Kazunori Namba²  Chiharu Torii¹  Atsushi Shimizu³  Naohiro Suzuki²  Hideki Mutai² 

[1] Center for Medical Genetics Keio University School of Medicine, Tokyo, Japan;Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8902, Japan;Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan;National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan;Department of Otorhinolaryngology, National Center for Child Health and Development, Tokyo, Japan;Laboratory of Gene Medicine, Keio University School of Medicine, Tokyo, Japan

关键词: Heterogeneity;    Deafness gene;    Target gene capture;    Hereditary hearing loss;   

Others  :  863437
DOI  :  10.1186/1750-1172-8-172

 received in 2013-07-18, accepted in 2013-10-05,  发布年份 2013

【 摘 要 】

Background

Genetic 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.

Methods

Genomic 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.

Results

Candidate 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.

Conclusion

Targeted NGS analysis revealed a diverse spectrum of rare deafness genes in Japanese subjects and underscores implications for efficient genetic testing.

【 授权许可】

   
2013 Mutai et al.; licensee BioMed Central Ltd.

【 图 表 】

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