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Mutations in splicing factor genes are a major cause of autosomal dominant retinitis pigmentosa in Belgian families

(2017) PLOS ONE. 12(1).
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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.
Keywords
ROD-CONE DYSTROPHY, RHODOPSIN GENE, RNA HELICASE, MISSENSE MUTATIONS, CLINICAL-FEATURES, MACULAR DYSTROPHY, PROM1 MUTATION, TRI-SNRNP, PROTEIN, RP1

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Chicago
Van Cauwenbergh, Caroline, Frauke Coppieters, Dimitri Roels, Sarah De Jaegere, Helena Flipts, Julie De Zaeytijd, SOPHIE WALRAEDT, et al. 2017. “Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families.” Plos One 12 (1).
APA
Van Cauwenbergh, C., Coppieters, F., Roels, D., De Jaegere, S., Flipts, H., De Zaeytijd, J., WALRAEDT, S., et al. (2017). Mutations in splicing factor genes are a major cause of autosomal dominant retinitis pigmentosa in Belgian families. PLOS ONE, 12(1).
Vancouver
1.
Van Cauwenbergh C, Coppieters F, Roels D, De Jaegere S, Flipts H, De Zaeytijd J, et al. Mutations in splicing factor genes are a major cause of autosomal dominant retinitis pigmentosa in Belgian families. PLOS ONE. 2017;12(1).
MLA
Van Cauwenbergh, Caroline, Frauke Coppieters, Dimitri Roels, et al. “Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families.” PLOS ONE 12.1 (2017): n. pag. Print.
@article{8509887,
  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.},
  articleno    = {e0170038},
  author       = {Van Cauwenbergh, Caroline and Coppieters, Frauke and Roels, Dimitri and De Jaegere, Sarah and Flipts, Helena and De Zaeytijd, Julie and WALRAEDT, SOPHIE and Claes, Charlotte and Fransen, Erik and Van Camp, Guy and Depasse, Fanny and Casteels, Ingele and de Ravel, Thomy and Leroy, Bart and De Baere, Elfride},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  keyword      = {ROD-CONE DYSTROPHY,RHODOPSIN GENE,RNA HELICASE,MISSENSE MUTATIONS,CLINICAL-FEATURES,MACULAR DYSTROPHY,PROM1 MUTATION,TRI-SNRNP,PROTEIN,RP1},
  language     = {eng},
  number       = {1},
  pages        = {18},
  title        = {Mutations in splicing factor genes are a major cause of autosomal dominant retinitis pigmentosa in Belgian families},
  url          = {http://dx.doi.org/10.1371/journal.pone.0170038},
  volume       = {12},
  year         = {2017},
}

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