Biallelic variants in coenzyme Q10 biosynthesis pathway genes cause a retinitis pigmentosa phenotype

Neringa Jurkute; Francesca Cancellieri; Lisa Pohl; Catherina H Z Li; Robert A Heaton; Janine Reurink; James Bellingham; Mathieu Quinodoz; Georgia Yioti; Maria Stefaniotou; Marianna Weener; Theresia Zuleger; Tobias B Haack; Katarina Stingl; Genomics England Research Consortium; Carel B Hoyng; Omar A Mahroo; Iain Hargreaves; F Lucy Raymond; Michel Michaelides; Carlo Rivolta; Susanne Kohl; Susanne Roosing; Andrew R Webster; Gavin Arno

doi:10.1038/s41525-022-00330-z

Biallelic variants in coenzyme Q10 biosynthesis pathway genes cause a retinitis pigmentosa phenotype

NPJ Genom Med. 2022 Oct 20;7(1):60. doi: 10.1038/s41525-022-00330-z.

Authors

Neringa Jurkute^{1

2}, Francesca Cancellieri^{3

4}, Lisa Pohl⁵, Catherina H Z Li^{6

7}, Robert A Heaton⁸, Janine Reurink^{6

9}, James Bellingham¹⁰, Mathieu Quinodoz^{3

4

11}, Georgia Yioti¹², Maria Stefaniotou¹², Marianna Weener¹³, Theresia Zuleger¹⁴, Tobias B Haack^{14

15}, Katarina Stingl^{5

15}; Genomics England Research Consortium; Carel B Hoyng^{6

7}, Omar A Mahroo^{16

10}, Iain Hargreaves⁸, F Lucy Raymond^{17

18}, Michel Michaelides^{16

10}, Carlo Rivolta^{3

4

11}, Susanne Kohl¹⁹, Susanne Roosing^{6

9}, Andrew R Webster^{16

10}, Gavin Arno^{20

21

22}

Collaborators

Genomics England Research Consortium:
J C Ambrose, P Arumugam, R Bevers, M Bleda, F Boardman-Pretty, C R Boustred, H Brittain, M A Brown, M J Caulfield, G C Chan, A Giess, J N Griffin, A Hamblin, S Henderson, T J P Hubbard, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, A Kousathanas, L Lahnstein, A Lakey, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, M McEntagart, F Minneci, J Mitchell, L Moutsianas, M Mueller, N Murugaesu, A C Need, P O'Donovan, C A Odhams, C Patch, D Perez-Gil, M B Pereira, J Pullinger, T Rahim, A Rendon, T Rogers, K Savage, K Sawant, R H Scott, A Siddiq, A Sieghart, S C Smith, A Sosinsky, A Stuckey, M Tanguy, A L Taylor Tavares, E R A Thomas, S R Thompson, A Tucci, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki

Affiliations

¹ Moorfields Eye Hospital NHS Foundation Trust, London, UK. [email protected].
² Institute of Ophthalmology, University College London, London, UK. [email protected].
³ Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
⁴ Department of Ophthalmology, University of Basel, Basel, Switzerland.
⁵ University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany.
⁶ Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
⁸ School of Pharmacy and Biomolecular Sciences, Liverpool John Moores, Liverpool, UK.
⁹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰ Institute of Ophthalmology, University College London, London, UK.
¹¹ Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
¹² University of Ioannina Medical School, Ioannina, Greece.
¹³ Oftalmic Clinical Research Organization, Moscow, Russia.
¹⁴ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
¹⁵ Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.
¹⁶ Moorfields Eye Hospital NHS Foundation Trust, London, UK.
¹⁷ NIHR BioResource-Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
¹⁸ Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
¹⁹ Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
²⁰ Moorfields Eye Hospital NHS Foundation Trust, London, UK. [email protected].
²¹ Institute of Ophthalmology, University College London, London, UK. [email protected].
²² North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children, London, UK. [email protected].

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.

Abstract

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