Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies-Reference-Cited by-全球学者库

Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies

Published:2022-09-09 Issue:4 Volume:32 Page:595-607
ISSN:0964-6906
Container-title:Human Molecular Genetics
language:en
Short-container-title:

Author:

Daich Varela Malena¹²^ORCID,Bellingham James¹,Motta Fabiana¹³,Jurkute Neringa¹²,Ellingford Jamie M⁴⁵,Quinodoz Mathieu⁶⁷⁸,Oprych Kathryn¹,Niblock Michael¹,Janeschitz-Kriegl Lucas⁶⁷,Kaminska Karolina⁶⁷,Cancellieri Francesca⁶⁷,Scholl Hendrik P N⁶⁷,Lenassi Eva⁴⁵,Schiff Elena²,Knight Hannah²,Black Graeme⁴⁵,Rivolta Carlo⁶⁷⁸,Cheetham Michael E¹^ORCID,Michaelides Michel¹²,Mahroo Omar A¹²^ORCID,Moore Anthony T¹²⁹,Webster Andrew R¹²,Arno Gavin¹²¹⁰

Affiliation:

1. UCL Institute of Ophthalmology , London EC1V 9EL , UK

2. Moorfields Eye Hospital , London EC1V 2PD , UK

3. Department of Ophthalmology, Universidade Federal de Sao Paulo , Sao Paulo 04021001 , Brazil

4. North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, St Mary’s Hospital , Manchester M13 9WL , UK

5. Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester , Manchester M13 9PL , UK

6. Institute of Molecular and Clinical Ophthalmology Basel , Basel 4031 , Switzerland

7. Department of Ophthalmology, University of Basel , Basel 4031 , Switzerland

8. Department of Genetics and Genome Biology, University of Leicester , Leicester LE1 7RH , UK

9. University of California , San Francisco, CA 94607 , USA

10. North Thames Genomic Laboratory Hub, Great Ormond Street Hospital For Children , London WC1N 3JH , UK

Abstract

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.

Funder

Moorfields Eye Charity

Stephen and Elizabeth Archer in memory of Marion Woods

National Eye Research Centre

National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology

Fight For Sight UK Early Career Investigator Award

National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital Institute for Child Health

National Institute for Health Research and NHS England

Medical Research Council

Swiss National Science Foundation

Publisher

Oxford University Press (OUP)