A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project.

ABSTRACT:

Background

Genomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data.

Methods

Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon-intron junctions and at putative

SUBMITTER: Blakes AJM 

PROVIDER: S-EPMC9327385 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature