PUBLICATION

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

Authors
Nishiguchi, K.M., Tearle, R.G., Liu, Y.P., Oh, E.C., Miyake, N., Benaglio, P., Harper, S., Koskiniemi-Kuendig, H., Venturini, G., Sharon, D., Koenekoop, R.K., Nakamura, M., Kondo, M., Ueno, S., Yasuma, T.R., Beckmann, J.S., Ikegawa, S., Matsumoto, N., Terasaki, H., Berson, E.L., Katsanis, N., and Rivolta, C.
ID
ZDB-PUB-130927-22
Date
2013
Source
Proceedings of the National Academy of Sciences of the United States of America   110(40): 16139-16144 (Journal)
Registered Authors
Katsanis, Nicholas
Keywords
medical genetics, ophthalmology, ciliopathy, retinal blindness
MeSH Terms
  • Animals
  • Base Sequence
  • Frameshift Mutation/genetics
  • Gene Rearrangement/genetics*
  • Genetics, Medical
  • Genome, Human/genetics*
  • Genome-Wide Association Study
  • Humans
  • Japan
  • Molecular Sequence Data
  • Protein Serine-Threonine Kinases/genetics*
  • Retinitis Pigmentosa/genetics*
  • Sequence Analysis, DNA
  • United States
  • Zebrafish
PubMed
24043777 Full text @ Proc. Natl. Acad. Sci. USA
Abstract

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/threonine-protein 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.

Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes