• Carolin Anna Maria Koriath, Fernando Guntoro, Penelope Norsworthy, Egor Dolzhenko, Michael Eberle, Hensman MossDavina JDJSt George's University of London, London, UK.Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK., Michael Flower, Holger Hummerich, Anne Elizabeth Rosser, Sarah J Tabrizi, Simon Mead, and Edward J Wild.
• LMU University Hospital, Department of Psychiatry and Psychotherapie, Ludwig Maximilian University of Munich, Munchen, Bayern, Germany.
• J. Neurol. Neurosurg. Psychiatr. 2024 Oct 23.

BackgroundGenetic testing for Huntington's disease (HD) was initially usually positive but more recently the negative rate has increased: patients with negative HD tests are described as having HD phenocopy syndromes (HDPC). This study examines their clinical characteristics and investigates the genetic causes of HDPC.MethodsClinical data from neurogenetics clinics and HDPC gene-panel data were analysed. Additionally, a subset of 50 patients with HDPC underwent whole-genome sequencing (WGS) analysed via Expansion Hunter and Ingenuity Variant Analysis.ResultsHDPC prevalence was estimated at 2.3-2.9 per 100 000. No clinical discriminators between patients with HD and HDPC could be identified. In the gene-panel data, deleterious variants and potentially deleterious variants were over-represented in cases versus controls. WGS analysis identified one ATXN1 expansion in a patient with HDPC.ConclusionsThe HDPC phenotype is consistent with HD, but the genotype is distinct. Both established deleterious variants and novel potentially deleterious variants in genes related to neurodegeneration contribute to HDPC.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.

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