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Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations
S. Nagy, AT. Pagnamenta, E. Cali, HMH. Braakman, J. Wijntjes, B. Kusters, M. Gotkine, O. Elpeleg, V. Meiner, J. Lenberg, K. Wigby, J. Friedman, LD. Perry, AM. Rossor, A. Uhrova Meszarosova, D. Thomasova, S. Jacob, M. O'Driscoll, L. De Simone, DK....
Status not-indexed Language English Country England, Great Britain
Document type Journal Article
Grant support
Wellcome Trust - United Kingdom
MR/S005021/1
Medical Research Council - United Kingdom
UM1 HG008900
NHGRI NIH HHS - United States
NLK
Directory of Open Access Journals
from 2019
PubMed Central
from 2019
Oxford Journals Open Access Collection
from 2019-07-01
ROAD: Directory of Open Access Scholarly Resources
from 2019
- Publication type
- Journal Article MeSH
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
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 Internal Medicine University of Zambia School of Medicine Ridgeway Lusaka Zambia
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 Pathology Radboudumc 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 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
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
Rady Children's Hospital San Diego CA 92123 USA
Rady Children's Institute for Genomic Medicine San Diego CA 92123 USA
References provided by Crossref.org
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