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

Autor:	Qian X; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, United States.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States., Wang J; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States., Wang M; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States., Igelman AD; Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, United States., Jones KD; Retina Foundation of the Southwest and Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, United States., Li Y; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States., Wang K; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States., Goetz KE; Office of the Director, National Eye Institute/National Institutes of Health, Bethesda, MD, United States., Birch DG; Retina Foundation of the Southwest and Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, United States., Yang P; Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, United States., Pennesi ME; Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, United States., Chen R; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in genetics [Front Genet] 2021 Mar 02; Vol. 12, pp. 647400. Date of Electronic Publication: 2021 Mar 02 (Print Publication: 2021).
DOI:	10.3389/fgene.2021.647400
Abstrakt:	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 in vitro minigene system was applied to further validate the effect of these variants on the splicing pattern of the associated genes. The prediction scores assigned to splice-site disruption positively correlated with the impact of mutations on splicing, as those with lower prediction scores demonstrated partial splicing. Through this study, we estimated the contribution of deep-intronic splice mutations to unassigned IRD patients and leveraged in silico and in vitro methods to establish a framework for prioritizing deep intronic variant candidates for mechanistic and functional analyses. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Qian, Wang, Wang, Igelman, Jones, Li, Wang, Goetz, Birch, Yang, Pennesi and Chen.)
Databáze:	MEDLINE
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