Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations.

IF 4.1 Q1 CLINICAL NEUROLOGY Brain communications Pub Date : 2024-10-28 eCollection Date: 2024-01-01 DOI:10.1093/braincomms/fcae377
Sara Nagy, Alistair T Pagnamenta, Elisa Cali, Hilde M H Braakman, Juerd Wijntjes, Benno Kusters, Marc Gotkine, Orly Elpeleg, Vardiella Meiner, Jerica Lenberg, Kristen Wigby, Jennifer Friedman, Luke D Perry, Alexander M Rossor, Anna Uhrova Meszarosova, Dana Thomasova, Saiju Jacob, Mary O'Driscoll, Lenika De Simone, Dorothy K Grange, Richard Sommerville, Zahra Firoozfar, Shahryar Alavi, Mahta Mazaheri, Jevin M Parmar, Phillipa J Lamont, Veronica Pini, Anna Sarkozy, Francesco Muntoni, Gianina Ravenscroft, Eppie Jones, Declan O'Rourke, Melissa Nel, Jeannine M Heckmann, Michelle Kvalsund, Musambo M Kapapa, Somwe Wa Somwe, David R Bearden, Arman Çakar, Anne-Marie Childs, Rita Horvath, Mary M Reilly, Henry Houlden, Reza Maroofian
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Abstract

A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain-containing 1 (VWA1). This study further delineates the disease characteristics in a cohort of 20 individuals diagnosed through genome or exome sequencing, incorporating neurophysiological, laboratory and imaging data, along with data from previously reported cases across three different studies. Newly reported clinical features include hypermobility/hyperlaxity, axial weakness, dysmorphic signs, asymmetric presentation, dystonic features and, notably, upper motor neuron signs. Foot drop, foot deformities and distal leg weakness followed by early proximal leg weakness are confirmed to be initial manifestations. Additionally, this study identified 11 novel VWA1 variants, reaffirming the 10 bp insertion-induced p.Gly25ArgfsTer74 as the most prevalent disease-causing allele, with a carrier frequency of ∼1 in 441 in the UK and Western European population. Importantly, VWA1-related pathology may mimic various neuromuscular conditions, advocating for its inclusion in diverse gene panels spanning hereditary neuropathies to muscular dystrophies. The study highlights the potential of lower quality control filters in exome analysis to enhance diagnostic yield of VWA1 disease that may account for up to 1% of unexplained hereditary neuropathies.

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常染色体隐性 VWA1 相关疾病:表型变异和基因突变的综合分析。
在一组 34 人的队列中发现了一种新发现的遗传性轴索运动神经病变亚型,其特征是早期近端肢体受累,这些人体内含有含冯-威廉因子 A 结构域 1(VWA1)的双偶变异。本研究通过基因组或外显子组测序,结合神经生理学、实验室和影像学数据,以及之前在三项不同研究中报告的病例数据,进一步描述了通过基因组或外显子组测序确诊的 20 人队列中的疾病特征。新报告的临床特征包括过度活动/过度松弛、轴性乏力、畸形体征、不对称表现、肌张力障碍特征,尤其是上运动神经元体征。足下垂、足部畸形和腿远端无力以及随后出现的早期腿近端无力被证实是最初的表现。此外,这项研究还发现了 11 个新型 VWA1 变异,再次确认了 10 bp 插入诱导的 p.Gly25ArgfsTer74 是最常见的致病等位基因,在英国和西欧人群中的携带率为 441 分之 1。重要的是,与 VWA1 相关的病理学可能会模拟各种神经肌肉疾病,因此应将其纳入从遗传性神经病到肌肉萎缩症的各种基因组中。这项研究强调了在外显子组分析中使用较低质量控制过滤器的潜力,以提高VWA1疾病的诊断率,这种疾病可能占不明原因遗传性神经病的1%。
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