title: Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families.
abstract: OBJECTIVE
  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.
authors.affiliation: Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Caroline
authors.identifier: http://orcid.org/0000-0002-1948-9091
authors.initials: C
authors.lastname: Van Cauwenbergh
authors.affiliation: Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Frauke
authors.initials: F
authors.lastname: Coppieters
authors.affiliation: Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Roels
authors.affiliation: Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: De Jaegere
authors.affiliation: Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.|Center for Human Genetics, University Hospitals Leuven, Louvain, Belgium.
authors.forename: Helena
authors.initials: H
authors.lastname: Flipts
authors.affiliation: Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: De Zaeytijd
authors.affiliation: Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Walraedt
authors.affiliation: Center for Medical Genetics Antwerp, Antwerp University, Antwerp, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Claes
authors.affiliation: Center for Medical Genetics Antwerp, Antwerp University, Antwerp, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.affiliation: Center for Medical Genetics Antwerp, Antwerp University, Antwerp, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.affiliation: Department of Ophthalmology, Hôpital Erasme-ULB, Brussels, Belgium.
authors.forename: Fanny
authors.initials: F
authors.lastname: Depasse
authors.affiliation: Department of Ophthalmology, University Hospitals Leuven, Louvain, Belgium.
authors.forename: Ingele
authors.initials: I
authors.lastname: Casteels
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Louvain, Belgium.
authors.forename: Thomy
authors.initials: T
authors.lastname: de Ravel
authors.affiliation: Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.|Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.|Division of Ophthalmology & Center for Cellular & Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
mesh_terms: D000328:Adult; D000368:Aged; D001530:Belgium; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics; D005190:Family; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000072260:RNA Splicing Factors / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics
chemical_list: D005136:Eye Proteins; D000072260:RNA Splicing Factors