Abstract

The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being ‘pathogenic’ or ‘benign’ is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as ‘pathogenic’ or ‘likely pathogenic’; one in five of these cases could lead to new or refined diagnoses.

Details

Title
Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders
Author
Rowlands, Charlie 1 ; Thomas, Huw B 1 ; Lord, Jenny 2 ; Wai, Htoo A 2 ; Gavin, Arno 3 ; Beaman Glenda 1 ; Sergouniotis Panagiotis 1 ; Gomes-Silva, Beatriz 4 ; Campbell, Christopher 5 ; Gossan Nicole 5 ; Hardcastle, Claire 5 ; Webb, Kevin 6 ; O’Callaghan Christopher 7 ; Hirst, Robert A 8 ; Ramsden, Simon 5 ; Jones, Elizabeth 5 ; Clayton-Smith, Jill 1 ; Webster, Andrew R 9 ; Ambrose, J C 10 ; Arumugam, P 10 ; Bevers, R 10 ; Bleda, M 10 ; Boardman-Pretty, F 11 ; Boustred, C R 10 ; Brittain, H 10 ; Caulfield, M J 11 ; Chan, G C 10 ; Fowler, T 10 ; Giess, A 10 ; Hamblin, A 10 ; Henderson, S 11 ; Hubbard T J P 10 ; Jackson, R 10 ; Jones, L J 11 ; Kasperaviciute, D 11 ; Kayikci, M 10 ; Kousathanas, A 10 ; Lahnstein, L 10 ; Leigh S E A 10 ; Leong, I U, S 10 ; Lopez, F J 10 ; Maleady-Crowe, F 10 ; McEntagart, M 10 ; Minneci, F 10 ; Moutsianas, L 11 ; Mueller, M 11 ; Murugaesu, N 10 ; Need, A C 11 ; O’Donovan P 10 ; Odhams, C A 10 ; Patch, C 11 ; Perez-Gil, D 10 ; Pereira, M B 10 ; Pullinger, J 10 ; Rahim, T 10 ; Rendon, A 10 ; Rogers, T 10 ; Savage, K 10 ; Sawant, K 10 ; Scott, R H 10 ; Siddiq, A 10 ; Sieghart, A 10 ; Smith, S C 10 ; Sosinsky, A 11 ; Stuckey, A 10 ; Tanguy, M 10 ; Taylor Tavares A L 10 ; Thomas E R A 11 ; Thompson, S R 10 ; Tucci, A 11 ; Welland, M J 10 ; Williams, E 10 ; Witkowsa, K 11 ; Wood, S M 11 ; Douglas Andrew G L 12 ; O’Keefe Raymond T 4 ; Newman, William G 1 ; Baralle Diana 12 ; Black Graeme C M 1 ; Ellingford, Jamie M 1 

1  Manchester University Hospitals NHS Foundation Trust, St Mary’s Hospital, North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester, UK (GRID:grid.416523.7) (ISNI:0000 0004 0641 2620); University of Manchester, Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester, UK (GRID:grid.5379.8) (ISNI:0000000121662407) 
2  University of Southampton, Human Development and Health, Faculty of Medicine, Southampton, UK (GRID:grid.5491.9) (ISNI:0000 0004 1936 9297) 
3  UCL, Institute of Ophthalmology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Moorfields Eye Hospital NHS Foundation Trust, London, UK (GRID:grid.436474.6) (ISNI:0000 0000 9168 0080); Great Ormond Street Hospital NHS Foundation Trust, London, UK (GRID:grid.420468.c) 
4  University of Manchester, Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester, UK (GRID:grid.5379.8) (ISNI:0000000121662407) 
5  Manchester University Hospitals NHS Foundation Trust, St Mary’s Hospital, North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester, UK (GRID:grid.416523.7) (ISNI:0000 0004 0641 2620) 
6  Manchester University Hospitals NHS Foundation Trust, Manchester Adult Cystic Fibrosis Centre, Manchester, UK (GRID:grid.451052.7) (ISNI:0000 0004 0581 2008) 
7  UCL Great Ormond Street Institute of Child Health & Great Ormond Street Children’s Hospital & NIHR Great Ormond Street Hospital Biomedical Research Centre, Respiratory, Critical Care and Anaesthesia, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); University of Leicester, Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, Leicester, UK (GRID:grid.9918.9) (ISNI:0000 0004 1936 8411) 
8  University of Leicester, Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RKCSB, Leicester, UK (GRID:grid.9918.9) (ISNI:0000 0004 1936 8411) 
9  UCL, Institute of Ophthalmology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Moorfields Eye Hospital NHS Foundation Trust, London, UK (GRID:grid.436474.6) (ISNI:0000 0000 9168 0080) 
10  Genomics England, London, UK (GRID:grid.498322.6) 
11  Genomics England, London, UK (GRID:grid.498322.6); Queen Mary University of London, William Harvey Research Institute, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
12  University of Southampton, Human Development and Health, Faculty of Medicine, Southampton, UK (GRID:grid.5491.9) (ISNI:0000 0004 1936 9297); University Hospital Southampton NHS Foundation Trust, Wessex Clinical Genetics Service, Southampton, UK (GRID:grid.430506.4) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-021-99747-2
ProQuest document ID
2582895099
Copyright
© The Author(s) 2021. 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.