Poison exon annotations improve the yield of clinically relevant variants in genomic diagnostic testing.

ABSTRACT:

Purpose

Neurodevelopmental disorders (NDDs) often result from rare genetic variation, but genomic testing yield for NDDs remains around 50%, suggesting some clinically relevant rare variants may be missed by standard analyses. Here we analyze "poison exons" (PEs) which, while often absent from standard gene annotations, are alternative exons whose inclusion results in a premature termination codon. Variants that alter PE inclusion can lead to loss-of-function and may be highly penetrant contributors to disease.

Methods

We curated published RNA-seq data from developing mouse cortex to define 1,937 PE regions conserved between humans and mice and potentially relevant to NDDs. We then analyzed variants found by genome sequencing in multiple NDD cohorts.

Results

Across 2,

SUBMITTER: Felker SA 

PROVIDER: S-EPMC9882217 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature