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

Abstract

PurposeAutosomal 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.MethodsMutation 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.ResultsMolecular 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%).ConclusionsOverall, 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.

Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease

“…Previous functional studies have demonstrated that p.Ala615Thr variant is a benign polymorphism, and by itself only slightly affects the enzymatic activity of HGSNAT (Feldhammer, Durand, & Pshezhetsky, ). This change, however, has been linked to the phenotype of retinitis pigmentosa when present in homozygosity or heterozygosity (either in cis or trans ) with other HGSNAT mutations (Comander et al, ; Haer‐Wigman et al, ; Van Cauwenbergh et al, ). p.Ala615Thr shows the highest allele frequency (0.01462 in gnomAD) in the Ashkenazi Jewish population (Table S6B).…”

Proper splicing contributes to visual function in the aging Drosophila eye

“…Despite this correlation between splicing factor levels and splicing outcomes during aging, it is not clear whether the decreased expression of splicing factors causes the observed age‐associated changes in splicing. As several splicing factors are mutated in age‐related eye disease, understanding the link between individual splicing regulators and age‐associated changes in splicing could have important implications for human health (Daiger, Sullivan, & Bowne, 2013; Sullivan et al, 2006; Van Cauwenbergh et al, 2017). …”

Genotype–Phenotype Analysis of a Novel Recessive and a Recurrent Dominant SNRNP200 Variant Causing Retinitis Pigmentosa

“…Pan et al 19 suggested that patients harboring the mutation c.3260C>T may be associated with a more severe phenotype than patients with the mutation c.2042G>A. We therefore compared the reported symptoms and age at onset, as well the phenotype, of all mutations published to date [4][5][6][7][8][9][10][11][12]19,[27][28][29][30][31][32][33][34][35][36] in Table 5. Reduced vision and night blindness, less often visual field changes, are the most commonly reported symptoms.…”