Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases
Citation:
Fadaie, Z. and Whelan, L. and Ben-Yosef, T. and Dockery, A. and Corradi, Z. and Gilissen, C. and Haer-Wigman, L. and Corominas, J. and Astuti, G.D.N. and de Rooij, L. and van den Born, L.I. and Klaver, C.C.W. and Hoyng, C.B. and Wynne, N. and Duignan, E.S. and Kenna, P.F. and Cremers, F.P.M. and Farrar, G.J. and Roosing, S., Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases, npj Genomic Medicine, 2021, 6, 1Download Item:
s41525-021-00261-1.pdf (Published (author's copy) - Peer Reviewed) 1.676Mb
Abstract:
Inherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by
pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic
testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was not found using whole-exome
sequencing or targeted capture sequencing. We performed whole-genome sequencing (WGS) to identify causative variants in 100
unresolved cases. After initial prioritization, we performed an in-depth interrogation of all noncoding and structural variants in
genes when one candidate variant was detected. In addition, functional analysis of putative splice-altering variants was performed
using in vitro splice assays. We identified the genetic cause of the disease in 24 patients. Causative coding variants were observed in
genes such as ATXN7, CEP78, EYS, FAM161A, and HGSNAT. Gene disrupting structural variants were also detected in ATXN7, PRPF31,
and RPGRIP1. In 14 monoallelic cases, we prioritized candidate noncanonical splice sites or deep-intronic variants that were
predicted to disrupt the splicing process based on in silico analyses. Of these, seven cases were resolved as they carried pathogenic
splice defects. WGS is a powerful tool to identify causative variants residing outside coding regions or heterozygous structural
variants. This approach was most efficient in cases with a distinct clinical diagnosis. In addition, in vitro splice assays provide
important evidence of the pathogenicity of rare variants.
Sponsor
Grant Number
Science Foundation Ireland (SFI)
16/1A/4452
Author's Homepage:
http://people.tcd.ie/gjfarrar
Author: Farrar, Gwyneth
Type of material:
Journal ArticleCollections:
Series/Report no:
npj Genomic Medicine;6;
1;
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http://dx.doi.org/10.1038/s41525-021-00261-1Licences: