Abstract

The aim of this study was to investigate coenzyme Q10 (CoQ10) biosynthesis pathway defects in inherited retinal dystrophy. Individuals affected by inherited retinal dystrophy (IRD) underwent exome or genome sequencing for molecular diagnosis of their condition. Following negative IRD gene panel analysis, patients carrying biallelic variants in CoQ10 biosynthesis pathway genes were identified. Clinical data were collected from the medical records. Haplotypes harbouring the same missense variant were characterised from family genome sequencing (GS) data and direct Sanger sequencing. Candidate splice variants were characterised using Oxford Nanopore Technologies single molecule sequencing. The CoQ10 status of the human plasma was determined in some of the study patients. 13 individuals from 12 unrelated families harboured candidate pathogenic genotypes in the genes: PDSS1, COQ2, COQ4 and COQ5. The PDSS1 variant c.589 A > G was identified in three affected individuals from three unrelated families on a possible ancestral haplotype. Three variants (PDSS1 c.468-25 A > G, PDSS1 c.722-2 A > G, COQ5 c.682-7 T > G) were shown to lead to cryptic splicing. 6 affected individuals were diagnosed with non-syndromic retinitis pigmentosa and 7 had additional clinical findings. This study provides evidence of CoQ10 biosynthesis pathway gene defects leading to non-syndromic retinitis pigmentosa in some cases. Intronic variants outside of the canonical splice-sites represent an important cause of disease. RT-PCR nanopore sequencing is effective in characterising these splice defects.

Details

Title
Biallelic variants in coenzyme Q10 biosynthesis pathway genes cause a retinitis pigmentosa phenotype
Author
Jurkute, Neringa 1   VIAFID ORCID Logo  ; Cancellieri, Francesca 2   VIAFID ORCID Logo  ; Pohl, Lisa 3 ; Li, Catherina H. Z. 4 ; Heaton, Robert A. 5 ; Reurink, Janine 6   VIAFID ORCID Logo  ; Bellingham, James 7   VIAFID ORCID Logo  ; Quinodoz, Mathieu 8 ; Yioti, Georgia 9 ; Stefaniotou, Maria 9 ; Weener, Marianna 10   VIAFID ORCID Logo  ; Zuleger, Theresia 11 ; Haack, Tobias B. 12 ; Stingl, Katarina 13   VIAFID ORCID Logo  ; Ambrose, J. C. 14 ; Arumugam, P. 14 ; Bevers, R. 14 ; Bleda, M. 14 ; Boardman-Pretty, F. 15 ; Boustred, C. R. 14 ; Brittain, H. 14 ; Brown, M. A. 14 ; Caulfield, M. J. 15 ; Chan, G. C. 14 ; Giess, A. 14 ; Griffin, J. N. 14 ; Hamblin, A. 14 ; Henderson, S. 15 ; Hubbard, T. J. P. 14 ; Jackson, R. 14 ; Jones, L. J. 15 ; Kasperaviciute, D. 15 ; Kayikci, M. 14 ; Kousathanas, A. 14 ; Lahnstein, L. 14 ; Lakey, A. 14 ; Leigh, S. E. A. 14 ; Leong, I. U. S. 14 ; Lopez, F. J. 14 ; Maleady-Crowe, F. 14 ; McEntagart, M. 14 ; Minneci, F. 14 ; Mitchell, J. 14 ; Moutsianas, L. 15 ; Mueller, M. 15 ; Murugaesu, N. 14 ; Need, A. C. 15 ; O‘Donovan, P. 14 ; Odhams, C. A. 14 ; Patch, C. 15 ; Perez-Gil, D. 14 ; Pereira, M. B. 14 ; Pullinger, J. 14 ; Rahim, T. 14 ; Rendon, A. 14 ; Rogers, T. 14 ; Savage, K. 14 ; Sawant, K. 14 ; Scott, R. H. 14 ; Siddiq, A. 14 ; Sieghart, A. 14 ; Smith, S. C. 14 ; Sosinsky, A. 15 ; Stuckey, A. 14 ; Tanguy, M. 14 ; Taylor Tavares, A. L. 14 ; Thomas, E. R. A. 15 ; Thompson, S. R. 14 ; Tucci, A. 15 ; Welland, M. J. 14 ; Williams, E. 14 ; Witkowska, K. 15 ; Wood, S. M. 15 ; Zarowiecki, M. 14 ; Hoyng, Carel B. 4 ; Mahroo, Omar A. 1   VIAFID ORCID Logo  ; Hargreaves, Iain 5 ; Raymond, F. Lucy 16 ; Michaelides, Michel 1 ; Rivolta, Carlo 8   VIAFID ORCID Logo  ; Kohl, Susanne 17   VIAFID ORCID Logo  ; Roosing, Susanne 6   VIAFID ORCID Logo  ; Webster, Andrew R. 1 ; Arno, Gavin 18   VIAFID ORCID Logo 

 Moorfields Eye Hospital NHS Foundation Trust, London, UK (GRID:grid.436474.6) (ISNI:0000 0000 9168 0080); University College London, Institute of Ophthalmology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
 Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland (GRID:grid.508836.0); University of Basel, Department of Ophthalmology, Basel, Switzerland (GRID:grid.6612.3) (ISNI:0000 0004 1937 0642) 
 University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany (GRID:grid.411544.1) (ISNI:0000 0001 0196 8249) 
 Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Radboud University Medical Center, Department of Ophthalmology, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
 Liverpool John Moores, School of Pharmacy and Biomolecular Sciences, Liverpool, UK (GRID:grid.4425.7) (ISNI:0000 0004 0368 0654) 
 Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
 University College London, Institute of Ophthalmology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
 Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland (GRID:grid.508836.0); University of Basel, Department of Ophthalmology, Basel, Switzerland (GRID:grid.6612.3) (ISNI:0000 0004 1937 0642); University of Leicester, Department of Genetics and Genome Biology, Leicester, UK (GRID:grid.9918.9) (ISNI:0000 0004 1936 8411) 
 University of Ioannina Medical School, Ioannina, Greece (GRID:grid.9594.1) (ISNI:0000 0001 2108 7481) 
10  Oftalmic Clinical Research Organization, Moscow, Russia (GRID:grid.9594.1) 
11  University of Tübingen, Institute of Medical Genetics and Applied Genomics, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
12  University of Tübingen, Institute of Medical Genetics and Applied Genomics, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447); University of Tübingen, Centre for Rare Diseases, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
13  University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany (GRID:grid.411544.1) (ISNI:0000 0001 0196 8249); University of Tübingen, Centre for Rare Diseases, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
14  Genomics England, London, UK (GRID:grid.498322.6) 
15  Genomics England, London, UK (GRID:grid.498322.6); William Harvey Research Institute, Queen Mary University of London, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
16  Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, NIHR BioResource—Rare Diseases, Cambridge, UK (GRID:grid.24029.3d) (ISNI:0000 0004 0383 8386); University of Cambridge, Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
17  University of Tübingen, Institute for Ophthalmic Research, Centre for Ophthalmology, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
18  Moorfields Eye Hospital NHS Foundation Trust, London, UK (GRID:grid.436474.6) (ISNI:0000 0000 9168 0080); University College London, Institute of Ophthalmology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Great Ormond Street Hospital for Children, North Thames Genomic Laboratory Hub, London, UK (GRID:grid.420468.c) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20567944
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2726686218
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.