Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Koji M. Nishiguchi, Richard G. Tearle, Yangfan P. Liu, Edwin C. Oh, Noriko Miyake, Paola Benaglio, Shyana Harper, Hanna Koskiniemi-Kuendig, Giulia Venturini, Dror Sharon, Robert K. Koenekoop, Makoto Nakamura, Mineo Kondo, Shinji Ueno, Tetsuhiro R. Yasuma, Jacques S. Beckmann, Shiro Ikegawa, Naomichi Matsumoto, Hiroko Terasaki, Eliot L. BersonNicholas Katsanis, Carlo Rivolta

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)


We performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. We detected homozygous or compound heterozygous mutations in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of ∼446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonineprotein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome.

Original languageEnglish
Pages (from-to)16139-16144
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number40
Publication statusPublished - 2013 Oct 1
Externally publishedYes


  • Ciliopathy
  • Medical genetics
  • Ophthalmology
  • Retinal blindness

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene'. Together they form a unique fingerprint.

Cite this