Identification of Deep-Intronic Splice Mutations in a Large Cohort of Patients With Inherited Retinal Diseases

Authors

Xinye Qian
Jun Wang
Meng Wang
Austin D Igelman
Kaylie D Jones
Yumei Li
Keqing Wang
Kerry E Goetz
David G Birch
Paul Yang
Mark E Pennesi
Rui Chen

Publication Date

1-1-2021

Journal

Frontiers in Genetics

DOI

10.3389/fgene.2021.647400

PMID

33737949

PMCID

PMC7960924

PubMedCentral® Posted Date

3-2-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

inherited retinal dystrophies, whole-genome sequencing, splicing, deep-intronic mutations, minigenes

Abstract

High throughput sequencing technologies have revolutionized the identification of mutations responsible for a diverse set of Mendelian disorders, including inherited retinal disorders (IRDs). However, the causal mutations remain elusive for a significant proportion of patients. This may be partially due to pathogenic mutations located in non-coding regions, which are largely missed by capture sequencing targeting the coding regions. The advent of whole-genome sequencing (WGS) allows us to systematically detect non-coding variations. However, the interpretation of these variations remains a significant bottleneck. In this study, we investigated the contribution of deep-intronic splice variants to IRDs. WGS was performed for a cohort of 571 IRD patients who lack a confident molecular diagnosis, and potential deep intronic variants that affect proper splicing were identified using SpliceAI. A total of six deleterious deep intronic variants were identified in eight patients. An

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