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.

Centre for Medical Research University of Western Australia Nedlands WA 6009 Australia

Centre for Neuromuscular Diseases Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology London WC1N 3BG UK

Children's Health Ireland at Temple Street Dublin Dublin D01 XD99 Ireland

Department of Clinical Neurosciences University of Cambridge Cambridge CB2 2PY UK

Department of Educational Psychology University of Zambia Lusaka Zambia

Department of Genetics Hadassah Medical Center Hebrew University Medical Center Jerusalem 9574869 Israel

Department of Internal Medicine University of Zambia School of Medicine Ridgeway Lusaka Zambia

Department of Medical Genetics School of Medicine Shahid Sadoughi University of Medical Sciences Yazd 97514 Iran

Department of Medicine Faculty of Health Sciences University of Cape Town Cape Town 7935 South Africa

Department of Neurology and Clinical Neurophysiology Donders Institute for Brain Cognition and Behavior Radboud University Medical Center Nijmegen 6525 GD The Netherlands

Department of Neurology at Washington University Washington University School of Medicine St Louis Children's Hospital St Louis MO 63108 USA

Department of Neurology Hadassah Medical Organization and Faculty of Medicine Hebrew University of Jerusalem Jerusalem 9112001 Israel

Department of Neurology University Hospital Basel University of Basel Basel 4031 Switzerland

Department of Neurology University Hospitals Birmingham Birmingham B15 2TT UK

Department of Neurology University of Rochester Medical Center Rochester NY 14618 USA

Department of Paediatric Neurology Leeds Teaching Hospitals NHS Trust Leeds LS1 3EX UK

Department of Paediatrics and Child Health School of Medicine and Health Sciences University of Lusaka Lusaka Zambia

Department of Pathology Radboudumc Nijmegen 6525 GA The Netherlands

Department of Pediatric Neurology Amalia Children's Hospital Radboud University Medical Center and Donders Institute for Brain Cognition and Behavior Nijmegen 6525 GA The Netherlands

Department of Pediatrics University of California San Diego La Jolla CA 92093 USA

Department of Physiotherapy University of Zambia School of Health Sciences Lusaka Zambia

Division of Genetics Genomics and Metabolism Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL 60611 USA

Division of Neurology Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL 60611 USA

Dr Mazaheri's Medical Genetics Lab Yazd 97514 Iran

Genomics Medicine Ireland Dublin D18 K7W4 Ireland

Institute of Immunology and Immunotherapy University of Birmingham Birmingham B15 2TT UK

MRC International Centre for Genomic Medicine in Neuromuscular Diseases London WC1N 3BG UK

Neurogenetic Laboratory Department of Paediatric Neurology and Institute of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and University Hospital Motol Prague 150 06 Czech Republic

Neurogenomics Lab Neuroscience Institute University of Cape Town Cape Town 7935 South Africa

Neurology Research Group Neuroscience Institute University of Cape Town Cape Town 7935 South Africa

Neuromuscular Unit Istanbul Faculty of Medicine Istanbul University Istanbul 34093 Turkey

NIHR Great Ormond Street Hospital Biomedical Research Centre UCL Great Ormond Street Institute of Child Health London WC1N 1EH UK

NIHR Oxford Biomedical Research Centre Centre for Human Genetics University of Oxford Oxford OX3 9DU UK

Palindrome Isfahan 83714 Iran

Rady Children's Hospital San Diego CA 92123 USA

Rady Children's Institute for Genomic Medicine San Diego CA 92123 USA

Rare Disease Genetics and Functional Genomics Group Harry Perkins Institute of Medical Research Nedlands WA 6009 Australia

Royal Perth Hospital Perth WA 6000 Australia

The Dubowitz Neuromuscular Centre UCL Great Ormond Street Great Ormond Street Hospital London WC1N 1EH UK

West Midlands Regional Clinical Genetics Service and Birmingham Health Partners Birmingham Women's and Children's Hospital NHS Foundation Trust Birmingham B15 2TG UK

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