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An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy

journal contribution
submitted on 2024-05-22, 09:01 and posted on 2024-05-22, 09:02 authored by Alistair T Pagnamenta, Rauan Kaiyrzhanov, Yaqun Zou, Sahar I Da'as, Reza Maroofian, Sandra Donkervoort, Natalia Dominik, Marlen Lauffer, Matteo P Ferla, Andrea Orioli, Adam Giess, Arianna Tucci, Christian Beetz, Maryam Sedghi, Behnaz Ansari, Rita Barresi, Keivan Basiri, Andrea Cortese, Greg Elgar, Miguel A Fernandez-Garcia, Janice Yip, A Reghan Foley, Nicholas Gutowski, Heinz Jungbluth, Saskia Lassche, Tim Lavin, Carlo Marcelis, Peter Marks, Chiara Marini-Bettolo, Livija Medne, Ali-Reza Moslemi, Anna Sarkozy, Mary M Reilly, Francesco Muntoni, Francisca Millan, Colleen C Muraresku, Anna C Need, Andrea H Nemeth, Sarah B Neuhaus, Fiona Norwood, Marie O'Donnell, Mary O’Driscoll, Julia Rankin, Sabrina W Yum, Zarazuela Zolkipli-Cunningham, Isabell Brusius, Gilbert Wunderlich, John C Ambrose, Prabhu Arumugam, Emma L Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M Boissiere, Christopher R Boustred, Helen Brittain, Mark J Caulfield, Georgia C Chan, Clare E H Craig, Louise C Daugherty, Anna de Burca, Andrew Devereau, Rebecca E Foulger, Tom Fowler, Pedro Furió-Tarí, Joanne M Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E Holman, Tim J P Hubbard, Kristina ibáñez, Rob Jackson, Louise J Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Kay Lawson, Sarah E A Leigh, Ivonne U S Leong, Javier F Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Peter O’Donovan, Chris A Odhams, Christine Patch, Mariana Buongermino Pereira, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Mina Ryten, Kevin Savage, Kushmita Sawant, Richard H Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R Smith, Samuel C Smith, Alona Sosinsky, William Spooner, Helen E Stevens, Alexander Stuckey, Razvan Sultana, Mélanie Tanguy, Ellen R A Thomas, Simon R Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A Watters, Matthew J Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M Wood, Magdalena Zarowiecki, Mert Karakaya, Brunhilde Wirth, Khalid A Fakhro, Homa Tajsharghi, Carsten G Bönnemann, Jenny C Taylor, Henry Houlden, Genomics England Research Consortium

The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6–83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.

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Published in: Brain
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Open Access funding provided by the Qatar National Library.



  • English


Oxford University Press

Publication Year

  • 2021

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This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Sidra Medicine
  • Weill Cornell Medicine - Qatar
  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU

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