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

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

doi:10.1007/s00415-022-11307-4

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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

, Cynthia Sandor, Elliott Rees, Kathryn J. Peall

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

Swansea University Author: Grace Bailey

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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
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa66533

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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. 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spelling	2024-06-19T16:14:44.0246543 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
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container_start_page	6436
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doi_str_mv	10.1007/s00415-022-11307-4
publisher	Springer Science and Business Media LLC
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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	2022-12-01T20:31:11Z
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Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study

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