The frequency and clinical impact of synonymous HTT loss-of-interruption and duplication-of-interruption variants in a diverse HD cohort.

Autor:	Dawson J; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada., Kay C; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada., Black HF; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada., Bortnick S; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada., Javier K; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada., Xia Q; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada., Sandhu A; Research Informatics, BC Children's Hospital Research Institute, Vancouver, Canada., Buchanan C; Auckland City Hospital, Health New Zealand, Auckland, New Zealand., Hogg V; Auckland City Hospital, Health New Zealand, Auckland, New Zealand., Chang FCF; Huntington Disease Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia; Sydney Medical School, Westmead Campus, University of Sydney, Sydney, Australia., Goto J; Department of Neurology, International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan., Arning L; Department of Human Genetics, Medical Faculty, Ruhr University of Bochum, Bochum, Germany., Saft C; Department of Neurology, Huntington Center North Rhine-Westphalia, St. Josef-Hospital Bochum, Ruhr University Bochum, Bochum, Germany., Bijlsma EK; Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands., Nguyen HP; Department of Human Genetics, Medical Faculty, Ruhr University of Bochum, Bochum, Germany., Roxburgh R; Auckland City Hospital, Health New Zealand, Auckland, New Zealand; Department of Medicine and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand., Hayden MR; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada. Electronic address: mrh@cmmt.ubc.ca.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 Nov; Vol. 26 (11), pp. 101239. Date of Electronic Publication: 2024 Aug 10.
DOI:	10.1016/j.gim.2024.101239
Abstrakt:	Purpose: To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD). Methods: We screened symptomatic HD participants from the UBC HD Biobank and 5 research sites for sequence variants. After variant identification, we examined the clinical impact and frequency in the reduced penetrance range. Results: Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of Total Motor Score by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of 2 symptomatic HD participants with diagnostic repeats below the pathogenetic range. Conclusion: Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cutoff ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD. Competing Interests: Conflict of Interest Michael R. Hayden is the CEO of Prilenia Therapeutics, a private company, and serves on the public boards of Ionis Pharmaceuticals, AbCellera and 89bio. All other authors declare no conflicts of interest. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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