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

Sara Nagy^{1

2}, Alistair T Pagnamenta³, Elisa Cali¹, Hilde M H Braakman⁴, Juerd Wijntjes⁵, Benno Kusters⁶, Marc Gotkine⁷, Orly Elpeleg⁸, Vardiella Meiner⁸, Jerica Lenberg⁹, Kristen Wigby^{9

10

11}, Jennifer Friedman¹¹, Luke D Perry^{12

13

14}, Alexander M Rossor¹, Anna Uhrova Meszarosova¹⁵, Dana Thomasova¹⁵, Saiju Jacob^{16

17}, Mary O'Driscoll¹⁸, Lenika De Simone^{19

20}, Dorothy K Grange²¹, Richard Sommerville²¹, Zahra Firoozfar²², Shahryar Alavi²², Mahta Mazaheri^{23

24}, Jevin M Parmar^{25

26}, Phillipa J Lamont²⁷, Veronica Pini¹², Anna Sarkozy^{12

14}, Francesco Muntoni^{12

13}, Gianina Ravenscroft^{25

26}, Eppie Jones²⁸, Declan O'Rourke²⁹, Melissa Nel^{30

31}, Jeannine M Heckmann³², Michelle Kvalsund^{33

34}, Musambo M Kapapa³⁵, Somwe Wa Somwe³⁶, David R Bearden^{33

37}, Arman Çakar^{1

38}, Anne-Marie Childs³⁹, Rita Horvath⁴⁰, Mary M Reilly¹, Henry Houlden¹, Reza Maroofian¹

Affiliations

¹ Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
² Department of Neurology, University Hospital Basel, University of Basel, Basel 4031, Switzerland.
³ NIHR Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford OX3 9DU, UK.
⁴ Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center & Donders Institute for Brain, Cognition and Behavior, Nijmegen 6525 GA, The Netherlands.
⁵ Department of Neurology and Clinical Neurophysiology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen 6525 GD, The Netherlands.
⁶ Department of Pathology, Radboudumc, Nijmegen 6525 GA, The Netherlands.
⁷ Department of Neurology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
⁸ Department of Genetics, Hadassah Medical Center, Hebrew University Medical Center, Jerusalem 9574869, Israel.
⁹ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
¹⁰ Rady Children's Hospital, San Diego, CA 92123, USA.
¹¹ Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
¹² The Dubowitz Neuromuscular Centre, UCL Great Ormond Street, Great Ormond Street Hospital, London WC1N 1EH, UK.
¹³ NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
¹⁴ MRC International Centre for Genomic Medicine in Neuromuscular Diseases, London WC1N 3BG, UK.
¹⁵ Neurogenetic Laboratory, Department of Paediatric Neurology, and Institute of Biology and Medical Genetics, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague 150 06, Czech Republic.
¹⁶ Department of Neurology, University Hospitals Birmingham, Birmingham B15 2TT, UK.
¹⁷ Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
¹⁸ West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham B15 2TG, UK.
¹⁹ Division of Genetics, Genomics, and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
²⁰ Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
²¹ Department of Neurology at Washington University, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63108, USA.
²² Palindrome, Isfahan 83714, Iran.
²³ Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd 97514, Iran.
²⁴ Dr. Mazaheri's Medical Genetics Lab, Yazd 97514, Iran.
²⁵ Rare Disease Genetics and Functional Genomics Group, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia.
²⁶ Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia.
²⁷ Royal Perth Hospital, Perth, WA 6000, Australia.
²⁸ Genomics Medicine Ireland, Dublin D18 K7W4, Ireland.
²⁹ Children's Health Ireland at Temple Street, Dublin, Dublin D01 XD99, Ireland.
³⁰ Neurogenomics Lab, Neuroscience Institute, University of Cape Town, Cape Town 7935, South Africa.
³¹ Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7935, South Africa.
³² Neurology Research Group, Neuroscience Institute, University of Cape Town, Cape Town 7935, South Africa.
³³ Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, USA.
³⁴ Department of Internal Medicine, University of Zambia School of Medicine, Ridgeway, Lusaka, Zambia.
³⁵ Department of Physiotherapy, University of Zambia School of Health Sciences, Lusaka, Zambia.
³⁶ Department of Paediatrics and Child Health, School of Medicine and Health Sciences, University of Lusaka, Lusaka, Zambia.
³⁷ Department of Educational Psychology, University of Zambia, Lusaka, Zambia.
³⁸ Neuromuscular Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey.
³⁹ Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK.
⁴⁰ Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, UK.

PMID: 39502942
PMCID: PMC11535570
DOI: 10.1093/braincomms/fcae377

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

Sara Nagy et al. Brain Commun. 2024.

. 2024 Oct 28;6(6):fcae377.

doi: 10.1093/braincomms/fcae377. eCollection 2024.

Authors

Affiliations

¹ Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
² Department of Neurology, University Hospital Basel, University of Basel, Basel 4031, Switzerland.
³ NIHR Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford OX3 9DU, UK.
⁴ Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center & Donders Institute for Brain, Cognition and Behavior, Nijmegen 6525 GA, The Netherlands.
⁵ Department of Neurology and Clinical Neurophysiology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen 6525 GD, The Netherlands.
⁶ Department of Pathology, Radboudumc, Nijmegen 6525 GA, The Netherlands.
⁷ Department of Neurology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
⁸ Department of Genetics, Hadassah Medical Center, Hebrew University Medical Center, Jerusalem 9574869, Israel.
⁹ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
¹⁰ Rady Children's Hospital, San Diego, CA 92123, USA.
¹¹ Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
¹² The Dubowitz Neuromuscular Centre, UCL Great Ormond Street, Great Ormond Street Hospital, London WC1N 1EH, UK.
¹³ NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
¹⁴ MRC International Centre for Genomic Medicine in Neuromuscular Diseases, London WC1N 3BG, UK.
¹⁵ Neurogenetic Laboratory, Department of Paediatric Neurology, and Institute of Biology and Medical Genetics, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague 150 06, Czech Republic.
¹⁶ Department of Neurology, University Hospitals Birmingham, Birmingham B15 2TT, UK.
¹⁷ Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
¹⁸ West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham B15 2TG, UK.
¹⁹ Division of Genetics, Genomics, and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
²⁰ Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
²¹ Department of Neurology at Washington University, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63108, USA.
²² Palindrome, Isfahan 83714, Iran.
²³ Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd 97514, Iran.
²⁴ Dr. Mazaheri's Medical Genetics Lab, Yazd 97514, Iran.
²⁵ Rare Disease Genetics and Functional Genomics Group, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia.
²⁶ Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia.
²⁷ Royal Perth Hospital, Perth, WA 6000, Australia.
²⁸ Genomics Medicine Ireland, Dublin D18 K7W4, Ireland.
²⁹ Children's Health Ireland at Temple Street, Dublin, Dublin D01 XD99, Ireland.
³⁰ Neurogenomics Lab, Neuroscience Institute, University of Cape Town, Cape Town 7935, South Africa.
³¹ Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7935, South Africa.
³² Neurology Research Group, Neuroscience Institute, University of Cape Town, Cape Town 7935, South Africa.
³³ Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, USA.
³⁴ Department of Internal Medicine, University of Zambia School of Medicine, Ridgeway, Lusaka, Zambia.
³⁵ Department of Physiotherapy, University of Zambia School of Health Sciences, Lusaka, Zambia.
³⁶ Department of Paediatrics and Child Health, School of Medicine and Health Sciences, University of Lusaka, Lusaka, Zambia.
³⁷ Department of Educational Psychology, University of Zambia, Lusaka, Zambia.
³⁸ Neuromuscular Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey.
³⁹ Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK.
⁴⁰ Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, UK.

PMID: 39502942
PMCID: PMC11535570
DOI: 10.1093/braincomms/fcae377

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.

Keywords: VWA1; neuromuscular disorders; neuromyopathy; recessive disorders.

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Conflict of interest statement

The authors report no competing interests.

Figures

**Figure 1**
**Clinical and imaging features of affected individuals with VWA1 disease.** Images of affected individuals from Patients 1 (**A and B**), 3 (**C–E**), 8 (F) and 13 (G) showing moderate lower distal limb atrophy (**A and D**) with pes planus (**B and C**), overlying second toe (B), upgoing toes (B), dolichocephaly and frontal bossing (E), scapula alata (F) and pes excavatum (G). (H) Muscle biopsy of the vastus lateralis muscle of Patient 8 shows extensive neurogenic abnormalities with many areas of fibre type grouping seen by ATPase (pH 4.6) staining. Light brown fibres correspond to Type 2B or 2C, while dark brown-stained fibres are Type 1 and red fibres Type 2A. Scale bar: 1 mm. (I) Muscle ultrasound of the left tibialis anterior from the same patient shows a moth-eaten pattern consisting of round, dark areas with remaining viable motor units, surrounded by tissue with increased greyscale level reflecting permanently denervated and fibrosed muscle tissue.

**Figure 2**
**Pedigrees of 15 families described in the study.** Filled symbols with arrow indicate phenotypic features consistent with VWA1-related disease. Grey shading in Family 5 indicates an individual with walking problems. In Family 6, sibling of the affected patient showed a similar phenotype but had no disease-causing variants in *VWA1*. Note that the grandmother of the affected individual in Family 7 corresponds to the described case in Family 7 in Pagnamenta *et al.* NA, not available; UK, unknown; WT, wild type.

**Figure 3**
**Genomic position of *VWA1* variants.** Of the 13 *VWA1* variants (NM_022834.5 and NP_073745.2 correspond to *VWA1* mRNA and protein reference sequence accession numbers, respectively) described in the study, only the founder variants p.Gly25ArgfsTer74, p.Leu71Pro and p.Arg293SerfsTer58 have been described in the literature to be associated with disease.

**Figure 4**
**Major features in individuals with VWA1 disease.** (A) The frequency of selected clinical symptoms. (B) The frequency of diagnostic signs in percentage (%). Results are based on data from 54 patients (n = 20 from presented cohort and n = 34 from previous publications).^,, CK, creatine kinase; EMG, electromyography; LL, lower limb; NCS, nerve conduction studies; UL, upper limb.

See this image and copyright information in PMC

References

1. Pagnamenta AT, Kaiyrzhanov R, Zou Y, et al. An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy. Brain. 2021;144(2):584–600. - PMC - PubMed
1. 100,000 Genomes Project Pilot Investigators; Smedley D, Smith KR, et al. 100,000 genomes pilot on rare-disease diagnosis in health care—Preliminary report. N Engl J Med. 2021;385(20):1868–1880. - PMC - PubMed
1. Deschauer M, Hengel H, Rupprich K, et al. Bi-allelic truncating mutations in VWA1 cause neuromyopathy. Brain. 2021;144(2):574–583. - PubMed
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1. van Baalen A, Stephani U. Muscle fibre type grouping in high resolution ultrasound. Arch Dis Child. 2005;90(11):1189. - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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