Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies
Year: 2022
Type: article
Study design: Observational Study
Abstract: The purpose of this paper is to identify likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes, using genome sequencing (GS). Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis, and plausible pathogenic variants and clinical phenotype evaluated by the multidisciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbor a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested by messenger RNA analysis, minigene or luciferase reporter assays. Previously unreported, likely pathogenic, non-coding variants in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10 and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1 and USH2A) or altered transcription levels (BBS10 and GUCY2D). MDT-led, phenotype-driven, non-coding variant re-analysis of GS is effective in identifying the missing causative alleles.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddac227
Authors: Malena Daich Varela, James Bellingham, Fabiana Motta, Neringa Jurkute, Jamie M Ellingford, Mathieu Quinodoz, Kathryn Oprych, Michael Niblock, Lucas Janeschitz-Kriegl, Karolina Kaminska, Francesca Cancellieri, Hendrik P N Scholl, Eva Lenassi, Elena Schiff, Hannah Knight, Graeme Black, Carlo Rivolta, Michael E Cheetham, Michel Michaelides, Omar A Mahroo, Anthony T Moore, Andrew R Webster, Gavin Arno
Institutions: Moorfields Eye Hospital, University College London, Universidade Federal de São Paulo, University of Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, University of Leicester, University of Basel, Institute of Molecular and Clinical Ophthalmology Basel, University of California, San Francisco, Great Ormond Street Hospital
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,181
Funders: National Science Foundation, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Sight Research UK, Fight for Sight UK, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Moorfields Eye Hospital NHS Foundation Trust, Moorfields Eye Charity, Medical Research Council
Awards: Genomics of inherited retinal diseases, G2274422225, G2381683370, G339059223, Non-Mendelian inheritance in retinal degenerations, G3847285604, Investigating mechanisms involved in retinal signalling in health and disease through detailed in vivo human electrophysiological investigation, G7156829537, Investigating mechanisms involved in retinal signalling in health and disease through detailed in vivo human electrophysiological investigation, G8524275990
OpenAlex ID: W4295227060