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

Abstract

Background: Genetic 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.

Methods: Clinical 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.

Results: HDPC 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.

Conclusions: The 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.

Keywords: DEMENTIA; HUNTINGTON'S; MOVEMENT DISORDERS; NEUROGENETICS.

Figure 1. HD and HDPC display different patterns of concurrent symptoms: each symptom circle shows the percentage of patients in each group presenting with a given symptom; the circle is highlighted in red if the symptom differed significantly between the two groups (p≤0.05, logistical regression). Given the high number of included symptoms, none of the results withstood Bonferroni’s correction for multiple comparisons, but the results are interesting from an exploratory vantage point. The likelihood of a patient presenting with any given symptom pair was calculated using conditional probabilities, which express the likelihood that one symptom occurs given the presence of another in any given patient. If the likelihood is bilaterally equal or higher than 40%, a faint grey line connects the two symptoms, if it is equal or higher than 50%, the connecting line is emphasised in dark grey. All statistical analyses were done in R V.3.5.1 (https://www.rproject.org/) using the base package and custom written scripts. HD, Huntington’s disease; HDPC, HD phenocopy syndromes.