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Defective splicing of the RB1 transcript is the dominant cause of retinoblastomas.

ABSTRACT: Defective splicing is a common cause of genetic diseases. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations with most mapping to the critical GT or AG nucleotides within the 5' and 3' splice sites. However, splicing mutations are underreported and the fraction of splicing mutations that compose all disease alleles varies greatly across disease gene. For example, there is a great excess (46%; ~threefold) of hereditary disease alleles that map to splice sites in RB1 that cause retinoblastoma. Furthermore, mutations in the exons and deeper intronic position may also affect splicing. We recently developed a high-throughput method that assays reported disease mutations for their ability to disrupt pre-mRNA splicing. Surprisingly, 27% of RB1-coding mutations tested also disrupt splicing. High-throughput in vitro spliceosomal assembly assay reveals heterogeneity in which stage of spliceosomal assembly is affected by splicing mutations. 58% of exonic splicing mutations were primarily blocked at the A complex in transition to the B complex and 33% were blocked at the B complex. Several mutants appear to reduce more than one step in the assembly. As RB1 splicing mutants are enriched in retinoblastoma disease alleles, additional priority should be allocated to this class of allele while interpreting clinical sequencing experiments. Analysis of the spectrum of RB1 variants observed in 60,706 exomes identifies 197 variants that have enough potential to disrupt splicing to warrant further consideration.

SUBMITTER: Cygan KJ

PROVIDER: S-EPMC6699175 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Defective splicing of the RB1 transcript is the dominant cause of retinoblastomas.

Cygan Kamil J KJ Soemedi Rachel R Rhine Christy L CL Profeta Abraham A Murphy Eileen L EL Murray Michael F MF Fairbrother William G WG

Human genetics 20170805 9

Defective splicing is a common cause of genetic diseases. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations with most mapping to the critical GT or AG nucleotides within the 5' and 3' splice sites. However, splicing mutations are underreported and the fraction of splicing mutations that compose all disease alleles varies greatly across disease gene. For example, there is a great excess (46%; ~threefold) of hereditary disease alleles that map to splice sites ...[more]

PMID: 28780672

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Project description: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.

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Defective splicing of the RB1 transcript is the dominant cause of retinoblastomas.

Publications

Defective splicing of the RB1 transcript is the dominant cause of retinoblastomas.

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