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Pathogenicity and selective constraint on variation near splice sites
Jenny Lord1, Giuseppe Gallone1, Patrick J Short1
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
Genome Research
|December 28, 2018
Summary
Splicing mutations significantly contribute to developmental disorders (DDs). This study reveals critical splice site positions and estimates the impact of both canonical and noncanonical mutations on DDs.
Area of Science:
- Genetics
- Molecular Biology
- Human Disease
Background:
- Mutations affecting pre-mRNA splicing are key drivers of human diseases.
- Developmental disorders (DDs) can arise from genetic alterations impacting gene expression regulation.
Purpose of the Study:
- To investigate genetic selection patterns around splice sites.
- To quantify the contribution of splicing mutations to developmental disorders (DDs).
Main Methods:
- Exome sequencing data from 7833 probands with DDs and their parents were analyzed.
- Comparison with over 60,000 aggregated exomes from the Exome Aggregation Consortium was performed.
- Mutational burden analyses were conducted on proband-parent trios.
Main Results:
- Specific positions within and around splice sites were identified as functionally critical.
- Mutations at canonical dinucleotides accounted for 73% and flanking noncanonical positions for 27% of splicing mutations.
- 18 patients with de novo mutations in dominant DD-associated genes at noncanonical splice site positions were identified.
Conclusions:
- Splicing mutations are a substantial cause of developmental disorders.
- A significant portion (35%-40%) of pathogenic variants in noncanonical splice site positions may be underrepresented in current databases.
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