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

Orphanet J Rare Dis. 2013 Oct 28;8:172. doi: 10.1186/1750-1172-8-172.


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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anion Transport Proteins / genetics
  • Asian Continental Ancestry Group / genetics
  • Cadherins / genetics
  • Connexins
  • Cross-Sectional Studies
  • Deafness / genetics*
  • Genetic Testing
  • Hearing Loss / genetics*
  • Hearing Loss, Sensorineural / genetics
  • High-Throughput Nucleotide Sequencing / methods*
  • Homeodomain Proteins / genetics
  • Humans
  • Myosin VIIa
  • Myosins / genetics
  • Sulfate Transporters
  • Transcription Factor Brn-3C / genetics
  • Usher Syndromes / genetics


  • Anion Transport Proteins
  • CDH23 protein, human
  • Cadherins
  • Connexins
  • GJB2 protein, human
  • Homeodomain Proteins
  • MYO7A protein, human
  • Myosin VIIa
  • PCDH15 protein, human
  • POU4F3 protein, human
  • SIX1 protein, human
  • SLC26A5 protein, human
  • Sulfate Transporters
  • Transcription Factor Brn-3C
  • Myosins

Supplementary concepts

  • Deafness, Autosomal Dominant 5
  • Usher syndrome, type 2A