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

IF 8.7 1区医学 Q1 CLINICAL NEUROLOGY Journal of Neurology, Neurosurgery, and Psychiatry Pub Date : 2024-10-23 DOI:10.1136/jnnp-2024-333602

Carolin Anna Maria Koriath, Fernando Guntoro, Penelope Norsworthy, Egor Dolzhenko, Michael Eberle, Davina J Hensman Moss, Michael Flower, Holger Hummerich, Anne Elizabeth Rosser, Sarah J Tabrizi, Simon Mead, Edward J Wild

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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.

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亨廷顿氏病表型综合征再探：临床比较与新一代测序探索。

背景：亨廷顿病（Huntington's disease，HD）基因检测最初通常呈阳性，但最近阴性率有所上升：HD检测呈阴性的患者被称为HD表型综合征（HD phenocopy syndromes，HDPC）。本研究探讨了这些患者的临床特征，并研究了 HDPC 的遗传原因：方法：分析了神经遗传学诊所的临床数据和 HDPC 基因组数据。此外，还对 50 名 HDPC 患者进行了全基因组测序（WGS），并通过 Expansion Hunter 和 Ingenuity 变异分析进行了分析：HDPC发病率估计为每10万人中有2.3-2.9人。HD患者和HDPC患者之间没有临床鉴别指标。在基因面板数据中，病例与对照组相比，有害变异和潜在有害变异的比例过高。WGS分析在一名HDPC患者中发现了一个ATXN1扩增：结论：HDPC 的表型与 HD 一致，但基因型不同。与神经变性相关的基因中既有的有害变异和新的潜在有害变异都是导致 HDPC 的原因。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Neurology, Neurosurgery, and Psychiatry 医学-精神病学

CiteScore

15.70

自引率

1.80%

发文量

888

审稿时长

6 months

期刊介绍： The Journal of Neurology, Neurosurgery & Psychiatry (JNNP) aspires to publish groundbreaking and cutting-edge research worldwide. Covering the entire spectrum of neurological sciences, the journal focuses on common disorders like stroke, multiple sclerosis, Parkinson’s disease, epilepsy, peripheral neuropathy, subarachnoid haemorrhage, and neuropsychiatry, while also addressing complex challenges such as ALS. With early online publication, regular podcasts, and an extensive archive collection boasting the longest half-life in clinical neuroscience journals, JNNP aims to be a trailblazer in the field.