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

Hideki Mutai, Naohiro Suzuki, Atsushi Shimizu, Chiharu Torii, Kazunori Namba, Noriko Morimoto, Jun Kudo, Kimitaka Kaga, Kenjiro Kosaki, Tatsuo Matsunaga

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number172
JournalOrphanet Journal of Rare Diseases
Volume8
Issue number1
DOIs
Publication statusPublished - 2013

Fingerprint

Deafness
Hearing Loss
Genes
Mutation
DNA
Vestibular Neuronitis
Usher Syndromes
Genetic Testing
Medical Records
Exons
Technology

Keywords

  • Deafness gene
  • Hereditary hearing loss
  • Heterogeneity
  • Target gene capture

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients : A cross-sectional, multi-center next-generation sequencing study. / Mutai, Hideki; Suzuki, Naohiro; Shimizu, Atsushi; Torii, Chiharu; Namba, Kazunori; Morimoto, Noriko; Kudo, Jun; Kaga, Kimitaka; Kosaki, Kenjiro; Matsunaga, Tatsuo.

In: Orphanet Journal of Rare Diseases, Vol. 8, No. 1, 172, 2013.

Research output: Contribution to journalArticle

Mutai, Hideki ; Suzuki, Naohiro ; Shimizu, Atsushi ; Torii, Chiharu ; Namba, Kazunori ; Morimoto, Noriko ; Kudo, Jun ; Kaga, Kimitaka ; Kosaki, Kenjiro ; Matsunaga, Tatsuo. / Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients : A cross-sectional, multi-center next-generation sequencing study. In: Orphanet Journal of Rare Diseases. 2013 ; Vol. 8, No. 1.
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T1 - Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients

T2 - A cross-sectional, multi-center next-generation sequencing study

AU - Mutai, Hideki

AU - Suzuki, Naohiro

AU - Shimizu, Atsushi

AU - Torii, Chiharu

AU - Namba, Kazunori

AU - Morimoto, Noriko

AU - Kudo, Jun

AU - Kaga, Kimitaka

AU - Kosaki, Kenjiro

AU - Matsunaga, Tatsuo

PY - 2013

Y1 - 2013

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AB - 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.

KW - Deafness gene

KW - Hereditary hearing loss

KW - Heterogeneity

KW - Target gene capture

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