Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

PLoS One. 2017 Jan 11;12(1):e0170038. doi: 10.1371/journal.pone.0170038. eCollection 2017.

Abstract

Purpose: Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition.

Methods: Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations.

Results: Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5-30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%).

Conclusions: Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations.

MeSH terms

  • Adult
  • Aged
  • Belgium
  • Cohort Studies
  • DNA Mutational Analysis
  • Eye Proteins / genetics
  • Family
  • Female
  • Gene Frequency
  • Genes, Dominant
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • RNA Splicing Factors / genetics*
  • Retinitis Pigmentosa / genetics

Substances

  • Eye Proteins
  • RNA Splicing Factors

Grant support

This study was supported by Belspo (IAP project P7/43 Belgian Medical Genomics Initiative) to EDB, by the Ghent University Special Research Fund (BOF15/GOA/011) to EDB, by the Research Foundation Flanders (FWO) (EYE-splice, G0C6715N) to EDB and FC, by the Research in Ophthalmology (FRO) to CVC. FC is recipient of postdoctoral fellowship of the FWO, EDB and BPL are Senior Clinical Investigators of the FWO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.