Huntington's disease phenocopy syndromes revisited: a clinical comparison and next-generation sequencing exploration

When the genetic test for the Huntington's disease (HD) HTT expansion first became available almost 30 years ago, only 1% of patients tested negative. Since then, the test has become more accessible and the HD phenotype has expanded. More patients are being tested overall, and more negative tests are being received. These patients are deemed "HD phenocopy syndromes" (HDPC). In this study we established a current estimate for the prevalence of these patients. We also surveyed HD clinician experts on what would make them consider an HD test and compared both HD and HDPC patients to these expectations to decide whether they could be distinguished clinically; this proved impossible even when comparing symptom patterns. We re-analysed existing gene panel data for likely and potentially deleterious variants. Furthermore, we determined principles to prioritise patients for whole-genome sequencing (WGS). It was used to probe a 50 patient strong subcohort of HD phenocopy syndromes for known causes of HD-like and other neurodegenerative disease, identifying one ATXN1 expansion using ExpansionHunter®. This was a small genetic sub-study and therefore unsurprisingly no other known deleterious variants could be identified as in these cryptic understudied syndromes. Novel variants in known genes and variants in genes not yet linked to neurodegeneration may play an outsized role. ### Competing Interest Statement CK gratefully acknowledges the support of the Leonard Wolfson Foundation and the CHDI Foundation. S.J.T. received grant funding for her HD research from the Medical Research Council UK, the Wellcome Trust, the Rosetrees Trust, Takeda Pharmaceuticals, Cantervale Limited, the NIHR North Thames Local Clinical Research Network, the UK Dementia Research Institute, the Wolfson Foundation for Neurodegeneration and the CHDI Foundation. SM is supported by the Medical Research Council (UK), the NIHR Queen Square Dementia Biomedical Research Unit and the NIHR Biomedical Research Centre at University College Hospitals NHS Foundation Trust. EJW reports grants from Medical Research Council, CHDI Foundation, and F. Hoffmann‐La Roche Ltd; personal fees from Hoffman La Roche Ltd, Triplet Therapeutics, PTC Therapeutics, Takeda, Teitur Trophics and Vico Therapeutics. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. University College London Hospitals NHS Foundation Trust has received funds as compensation for conducting clinical trials for Ionis Pharmaceuticals, Pfizer and Teva Pharmaceuticals. DHM is funded through the University of London Chadburn Lectureship programme.