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Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study

Megan E. Wadon, Eilidh Fenner, Kimberley M. Kendall, Grace Bailey Orcid Logo, Cynthia Sandor, Elliott Rees, Kathryn J. Peall Orcid Logo

Journal of Neurology, Volume: 269, Issue: 12, Pages: 6436 - 6451

Swansea University Author: Grace Bailey Orcid Logo

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DOI (Published version): 10.1007/s00415-022-11307-4

Abstract

The spectrum of non-motor symptoms in dystonia remains unclear. Using UK Biobank data, we analysed clinical phenotypic and genetic information in the largest dystonia cohort reported to date. Case–control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatr...

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Published in: Journal of Neurology
ISSN: 0340-5354 1432-1459
Published: Springer Science and Business Media LLC 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa66533
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Case–control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatric, pain, sleep and cognition) of increased symptom burden in dystonia. Whole exome data were used to determine the rate and likely pathogenicity of variants in Mendelian inherited dystonia causing genes and linked to clinical data. Within the dystonia cohort, phenotypic and genetic single-nucleotide polymorphism (SNP) data were combined in a mixed model analysis to derive genetically informed phenotypic axes. A total of 1572 individuals with dystonia were identified, including cervical dystonia (n = 775), blepharospasm (n = 131), tremor (n = 488) and dystonia, unspecified (n = 154) groups. Phenotypic patterns highlighted a predominance of psychiatric symptoms (anxiety and depression), excess pain and sleep disturbance. Cognitive impairment was limited to prospective memory and fluid intelligence. Whole exome sequencing identified 798 loss of function variants in dystonia-linked genes, 67 missense variants (MPC &gt; 3) and 305 other forms of non-synonymous variants (including inframe deletion, inframe insertion, stop loss and start loss variants). A single loss of function variant (ANO3) was identified in the dystonia cohort. Combined SNP and clinical data identified multiple genetically informed phenotypic axes with predominance of psychiatric, pain and sleep non-motor domains. An excess of psychiatric, pain and sleep symptoms were evident across all forms of dystonia. 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spelling v2 66533 2024-05-29 Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study 1e09a407fca9e8047e7738b18d381130 0000-0003-4646-3134 Grace Bailey Grace Bailey true false 2024-05-29 MEDS The spectrum of non-motor symptoms in dystonia remains unclear. Using UK Biobank data, we analysed clinical phenotypic and genetic information in the largest dystonia cohort reported to date. Case–control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatric, pain, sleep and cognition) of increased symptom burden in dystonia. Whole exome data were used to determine the rate and likely pathogenicity of variants in Mendelian inherited dystonia causing genes and linked to clinical data. Within the dystonia cohort, phenotypic and genetic single-nucleotide polymorphism (SNP) data were combined in a mixed model analysis to derive genetically informed phenotypic axes. A total of 1572 individuals with dystonia were identified, including cervical dystonia (n = 775), blepharospasm (n = 131), tremor (n = 488) and dystonia, unspecified (n = 154) groups. Phenotypic patterns highlighted a predominance of psychiatric symptoms (anxiety and depression), excess pain and sleep disturbance. Cognitive impairment was limited to prospective memory and fluid intelligence. Whole exome sequencing identified 798 loss of function variants in dystonia-linked genes, 67 missense variants (MPC > 3) and 305 other forms of non-synonymous variants (including inframe deletion, inframe insertion, stop loss and start loss variants). A single loss of function variant (ANO3) was identified in the dystonia cohort. Combined SNP and clinical data identified multiple genetically informed phenotypic axes with predominance of psychiatric, pain and sleep non-motor domains. An excess of psychiatric, pain and sleep symptoms were evident across all forms of dystonia. Combination with genetic data highlights phenotypic subgroups consistent with the heterogeneity observed in clinical practice. Journal Article Journal of Neurology 269 12 6436 6451 Springer Science and Business Media LLC 0340-5354 1432-1459 Dystonia; Psychiatric; Pain; Sleep; Cognition 1 12 2022 2022-12-01 10.1007/s00415-022-11307-4 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee MEW is funded by the Jacques and Gloria Gossweiler Foundation, KJP is funded by an MRC Clinician-Scientist Fellowship (MR/P008593/1), and GAB is funded by a KESS2, European Social Fund and Cardiff University PhD Studentship. ER is funded by a UKRI Future Leaders Fellowship (MR/T018712/1). 2024-06-19T16:14:44.0246543 2024-05-29T20:04:55.3947733 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Health Data Science Megan E. Wadon 1 Eilidh Fenner 2 Kimberley M. Kendall 3 Grace Bailey 0000-0003-4646-3134 4 Cynthia Sandor 5 Elliott Rees 6 Kathryn J. Peall 0000-0003-4749-4944 7 66533__30684__3c076723581347498b90456e57d815a2.pdf 66533.VoR.pdf 2024-06-19T16:13:31.2263191 Output 1112906 application/pdf Version of Record true © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/
title Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study
spellingShingle Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study
Grace Bailey
title_short Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study
title_full Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study
title_fullStr Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study
title_full_unstemmed Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study
title_sort Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study
author_id_str_mv 1e09a407fca9e8047e7738b18d381130
author_id_fullname_str_mv 1e09a407fca9e8047e7738b18d381130_***_Grace Bailey
author Grace Bailey
author2 Megan E. Wadon
Eilidh Fenner
Kimberley M. Kendall
Grace Bailey
Cynthia Sandor
Elliott Rees
Kathryn J. Peall
format Journal article
container_title Journal of Neurology
container_volume 269
container_issue 12
container_start_page 6436
publishDate 2022
institution Swansea University
issn 0340-5354
1432-1459
doi_str_mv 10.1007/s00415-022-11307-4
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Health Data Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Health Data Science
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description The spectrum of non-motor symptoms in dystonia remains unclear. Using UK Biobank data, we analysed clinical phenotypic and genetic information in the largest dystonia cohort reported to date. Case–control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatric, pain, sleep and cognition) of increased symptom burden in dystonia. Whole exome data were used to determine the rate and likely pathogenicity of variants in Mendelian inherited dystonia causing genes and linked to clinical data. Within the dystonia cohort, phenotypic and genetic single-nucleotide polymorphism (SNP) data were combined in a mixed model analysis to derive genetically informed phenotypic axes. A total of 1572 individuals with dystonia were identified, including cervical dystonia (n = 775), blepharospasm (n = 131), tremor (n = 488) and dystonia, unspecified (n = 154) groups. Phenotypic patterns highlighted a predominance of psychiatric symptoms (anxiety and depression), excess pain and sleep disturbance. Cognitive impairment was limited to prospective memory and fluid intelligence. Whole exome sequencing identified 798 loss of function variants in dystonia-linked genes, 67 missense variants (MPC > 3) and 305 other forms of non-synonymous variants (including inframe deletion, inframe insertion, stop loss and start loss variants). A single loss of function variant (ANO3) was identified in the dystonia cohort. Combined SNP and clinical data identified multiple genetically informed phenotypic axes with predominance of psychiatric, pain and sleep non-motor domains. An excess of psychiatric, pain and sleep symptoms were evident across all forms of dystonia. Combination with genetic data highlights phenotypic subgroups consistent with the heterogeneity observed in clinical practice.
published_date 2022-12-01T16:14:42Z
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