Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia
Author:
Chen Zhongbo123ORCID, Tucci Arianna4, Cipriani Valentina4, Gustavsson Emil K123ORCID, Ibañez Kristina45, Reynolds Regina H23ORCID, Zhang David23ORCID, Vestito Letizia346, García Alejandro Cisterna7ORCID, Sethi Siddharth18, Brenton Jonathan W23, García-Ruiz Sonia23, Fairbrother-Browne Aine239, Gil-Martinez Ana-Luisa123, Ambrose John C, Arumugam Prabhu, Bleda Marta, Boardman-Pretty Freya, Boissiere Jeanne M, Boustred Christopher R, Craig Clare E H, de Burca Anna, Devereau Andrew, Elgar Greg, Foulger Rebecca E, Furió-Tarí Pedro, Hackett Joanne, Halai Dina, Hamblin Angela, Henderson Shirley, Holman James, Hubbard Tim J P, Jackson Rob, Jones Louise J, Kayikci Melis, Lahnstein Lea, Lawson Kay, Leigh Sarah E A, Leong Ivonne U S, Lopez Javier F, Maleady-Crowe Fiona, Mason Joanne, Mueller Michael, Murugaesu Nirupa, Odhams Chris A, Perez-Gil Daniel, Polychronopoulos Dimitris, Pullinger John, Rahim Tahrima, Riesgo-Ferreiro Pablo, Rogers Tim, Ryten Mina, Savage Kevin, Sawant Kushmita, Siddiq Afshan, Sieghart Alexander, Smedley Damian, Sosinsky Alona, Spooner William, Stevens Helen E, Stuckey Alexander, Sultana Razvan, Thompson Simon R, Tregidgo Carolyn, Walsh Emma, Watters Sarah A, Welland Matthew J, Williams Eleanor, Witkowska Katarzyna, Wood Suzanne M, Zarowiecki Magdalena, Wood Nick10, Hardy John A111121314, Smedley Damian4ORCID, Houlden Henry15ORCID, Botía Juan17, Ryten Mina23ORCID,
Affiliation:
1. Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK 2. Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London , London WC1N 1EH , UK 3. NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London , London WC1N 1EH , UK 4. William Harvey Research Institute, Queen Mary University of London , London EC1M 6BQ , UK 5. Genomics England, Queen Mary University of London , London EC1M 6BQ , UK 6. Ear Institute, University College London , London WC1X 8EE , UK 7. Department of Information and Communications Engineering, University of Murcia , 30003 Murcia , Spain 8. Astex Pharmaceuticals , Cambridge Science Park, Cambridge , UK 9. Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King’s College London , London WC2R 2LS , UK 10. Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK 11. Reta Lila Weston Institute, Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK 12. UK Dementia Research Institute, University College London , London WC1E 6BT , UK 13. NIHR University College London Hospitals Biomedical Research Centre , London W1T 7DN , UK 14. Institute for Advanced Study, The Hong Kong University of Science and Technology , Hong Kong SAR , China 15. Department of Neuromuscular Disease, Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK
Abstract
Abstract
Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100 000 Genomes Project.
This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield.
To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene’s structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2182 individuals presenting with ataxia and 6658 non-neurological probands recruited in the 100 000 Genomes Project.
Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100 000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100 000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia.
Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci.
Funder
Leonard Wolfson Foundation UK Medical Research Council UK Dementia Research Institute Alzheimer’s Society Alzheimer’s Research UK Wellcome Trust Dolby Family Ventures National Institute for Health and Care Research Science and Technology Agency Fundación Séneca CARM
Publisher
Oxford University Press (OUP)
Subject
Neurology (clinical)
Cited by
7 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|