1. Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families
- Author
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Fanny Depasse, Elfride De Baere, Bart P. Leroy, Charlotte Claes, Ingele Casteels, Erik Fransén, Caroline Van Cauwenbergh, Dimitri Roels, Thomy de Ravel, Frauke Coppieters, Julie De Zaeytijd, Sarah De Jaegere, Sophie Walraedt, Guy Van Camp, Helena Flipts, Clinical sciences, and Medical Genetics
- Subjects
MISSENSE MUTATIONS ,Pigments ,Male ,0301 basic medicine ,PRPF31 ,family ,Molecular biology ,DNA Mutational Analysis ,Psychologie appliquée ,Gene Identification and Analysis ,PROTEIN ,lcsh:Medicine ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Sequencing techniques ,0302 clinical medicine ,Belgium ,Gene Frequency ,Medicine and Health Sciences ,Missense mutation ,DNA sequencing ,Mutation frequency ,Frameshift Mutation ,lcsh:Science ,Exome sequencing ,Genes, Dominant ,Genetics ,Mutation ,Multidisciplinary ,Nonsense Mutation ,Genomics ,Sciences bio-médicales et agricoles ,Middle Aged ,RP1 ,Physical Sciences ,Cohort studies ,ROD-CONE DYSTROPHY ,Female ,RNA Splicing Factors ,Biologie ,Transcriptome Analysis ,Engineering sciences. Technology ,Retinitis Pigmentosa ,Research Article ,Next-Generation Sequencing ,Adult ,TRI-SNRNP ,Retinitis Pigmentosa/genetics ,Materials Science ,Nonsense mutation ,RHODOPSIN GENE ,Eye Proteins/genetics ,Biology ,Frameshift mutation ,MACULAR DYSTROPHY ,03 medical and health sciences ,Signs and Symptoms ,Diagnostic Medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Eye Proteins ,RNA Splicing Factors/genetics ,Mutation Detection ,Alleles ,Materials by Attribute ,Aged ,Genetic heterogeneity ,CLINICAL-FEATURES ,lcsh:R ,Biology and Life Sciences ,Computational Biology ,Genome Analysis ,PROM1 MUTATION ,eye diseases ,Research and analysis methods ,Molecular biology techniques ,030104 developmental biology ,Genetic Loci ,030221 ophthalmology & optometry ,lcsh:Q ,Atrophy ,mutation ,RNA HELICASE - 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, SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2017