Massively parallel DNA sequencing facilitates diagnosis of patients with Usher syndrome type 1

PLoS One. 2014 Mar 11;9(3):e90688. doi: 10.1371/journal.pone.0090688. eCollection 2014.


Usher syndrome is an autosomal recessive disorder manifesting hearing loss, retinitis pigmentosa and vestibular dysfunction, and having three clinical subtypes. Usher syndrome type 1 is the most severe subtype due to its profound hearing loss, lack of vestibular responses, and retinitis pigmentosa that appears in prepuberty. Six of the corresponding genes have been identified, making early diagnosis through DNA testing possible, with many immediate and several long-term advantages for patients and their families. However, the conventional genetic techniques, such as direct sequence analysis, are both time-consuming and expensive. Targeted exon sequencing of selected genes using the massively parallel DNA sequencing technology will potentially enable us to systematically tackle previously intractable monogenic disorders and improve molecular diagnosis. Using this technique combined with direct sequence analysis, we screened 17 unrelated Usher syndrome type 1 patients and detected probable pathogenic variants in the 16 of them (94.1%) who carried at least one mutation. Seven patients had the MYO7A mutation (41.2%), which is the most common type in Japanese. Most of the mutations were detected by only the massively parallel DNA sequencing. We report here four patients, who had probable pathogenic mutations in two different Usher syndrome type 1 genes, and one case of MYO7A/PCDH15 digenic inheritance. This is the first report of Usher syndrome mutation analysis using massively parallel DNA sequencing and the frequency of Usher syndrome type 1 genes in Japanese. Mutation screening using this technique has the power to quickly identify mutations of many causative genes while maintaining cost-benefit performance. In addition, the simultaneous mutation analysis of large numbers of genes is useful for detecting mutations in different genes that are possibly disease modifiers or of digenic inheritance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Alleles
  • Amino Acid Substitution
  • Child
  • DNA Mutational Analysis
  • Exons
  • Female
  • Genetic Association Studies
  • Genetic Testing*
  • Genotype
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Phenotype
  • Usher Syndromes / diagnosis*
  • Usher Syndromes / genetics*
  • Young Adult

Associated data

  • RefSeq/NM_000260
  • RefSeq/NM_001195263
  • RefSeq/NM_015404
  • RefSeq/NM_022124
  • RefSeq/NM_032119
  • RefSeq/NM_033056
  • RefSeq/NM_153676
  • RefSeq/NM_173477
  • RefSeq/NM_174878
  • RefSeq/NM_206933

Grants and funding

This study was supported by a Health and Labour Sciences Research Grant for Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labour and Welfare of Japan (S.U.), and by a Grant-in-Aid for Scientific Research from the (then) Ministry of Education, Science and Culture of Japan ( (S.U.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.