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.
Original language | English |
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Article number | 97 |
Journal | npj Genomic Medicine |
Volume | 6 |
Issue number | 1 |
DOIs | |
Publication status | Published - 18 Nov 2021 |
Bibliographical note
Funding Information:We thank the affected individuals and their families for participating in this study and our funding bodies. We thank B. van Gestel for his expert bioinformatic input. The work of Z.F. is funded by the Foundation Fighting Blindness USA Project Program Award, grant no. PPA‐0517-0717‐RAD (to F.P.M.C., S.R., and C.B.H.). The research was supported by the European Union’s Horizon 2020 research and innovation program under the EJP RD COFUND-EJP No. 825575 (to F.P.M.C. and S.R.), the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Oogfonds, Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Stichting Blindenbelangen, Stichting Blindenhulp, Stichting tot Verbetering van het Lot der Blinden, and Stichting Blinden-Penning (to S.R. and F.P.M.C.). The work of L.W. and A.D. was supported by grant awards from Fighting Blindness Ireland (FB Irl; FB16FAR, FB18CRE, FB20DOC) (to F.P.M.C., S.R., and G.J.F.), The Health Research Board of Ireland (HRB; POR/2010/97) (to G.J.F.) in conjunction with Health Research Charities Ireland (HRCI; MRCG-2013-8, MRCG-2016-14) (to G.J.F.), the Irish Research Council (IRC; GOIPG/2017/ 1631) (to G.J.F.), and Science Foundation Ireland (SFI; 16/1A/4452) (to G.J.F.).
Publisher Copyright:
© 2021, The Author(s).