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

Jessica Dawson; Chris Kay; Hailey Findlay Black; Stephanie Bortnick; Kyla Javier; Qingwen Xia; Akshdeep Sandhu; Christina Buchanan; Virginia Hogg; Florence C F Chang; Jun Goto; Larissa Arning; Carsten Saft; Emilia K Bijlsma; Huu P Nguyen; Richard Roxburgh; Michael R Hayden

doi:10.1016/j.gim.2024.101239

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

Genet Med. 2024 Aug 10;26(11):101239. doi: 10.1016/j.gim.2024.101239. Online ahead of print.

Authors

Jessica Dawson¹, Chris Kay¹, Hailey Findlay Black¹, Stephanie Bortnick¹, Kyla Javier¹, Qingwen Xia¹, Akshdeep Sandhu², Christina Buchanan³, Virginia Hogg³, Florence C F Chang⁴, Jun Goto⁵, Larissa Arning⁶, Carsten Saft⁷, Emilia K Bijlsma⁸, Huu P Nguyen⁶, Richard Roxburgh⁹, Michael R Hayden¹⁰

Affiliations

¹ Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
² Research Informatics, BC Children's Hospital Research Institute, Vancouver, Canada.
³ Auckland City Hospital, Health New Zealand, Auckland, New Zealand.
⁴ Huntington Disease Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia; Sydney Medical School, Westmead Campus, University of Sydney, Sydney, Australia.
⁵ Department of Neurology, International University of Health and Welfare, Ichikawa Hospital, Chiba, Japan.
⁶ Department of Human Genetics, Medical Faculty, Ruhr University of Bochum, Bochum, Germany.
⁷ Department of Neurology, Huntington Center North Rhine-Westphalia, St. Josef-Hospital Bochum, Ruhr University Bochum, Bochum, Germany.
⁸ Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
⁹ 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.
¹⁰ Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada. Electronic address: mrh@cmmt.ubc.ca.

PMID: 39140258
DOI: 10.1016/j.gim.2024.101239

Abstract

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.

Keywords: Clinical impact; Diverse cohort; Genetic modifiers; Huntington disease; Loss of interruption.