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

Brain. 2021 Mar 3;144(2):584-600. doi: 10.1093/brain/awaa420.

Alistair T Pagnamenta ¹, Rauan Kaiyrzhanov ², Yaqun Zou ³, Sahar I Da'as ⁴, Reza Maroofian ², Sandra Donkervoort ³, Natalia Dominik ², Marlen Lauffer ⁵, Matteo P Ferla ¹, Andrea Orioli ⁶ ⁷, Adam Giess ⁶ ⁷, Arianna Tucci ⁶ ⁷, Christian Beetz ⁸, Maryam Sedghi ⁹, Behnaz Ansari ¹⁰, Rita Barresi ¹¹ ¹², Keivan Basiri ¹⁰, Andrea Cortese ², Greg Elgar ⁶ ⁷, Miguel A Fernandez-Garcia ¹³, Janice Yip ², A Reghan Foley ³, Nicholas Gutowski ¹⁴, Heinz Jungbluth ¹³ ¹⁵ ¹⁶, Saskia Lassche ¹⁷, Tim Lavin ¹⁸, Carlo Marcelis ¹⁹, Peter Marks ²⁰, Chiara Marini-Bettolo ¹¹ ¹², Livija Medne ²¹, Ali-Reza Moslemi ²², Anna Sarkozy ²³, Mary M Reilly ², Francesco Muntoni ²³, Francisca Millan ²⁴, Colleen C Muraresku ²⁵, Anna C Need ⁶ ⁷, Andrea H Nemeth ²⁶ ²⁷, Sarah B Neuhaus ³, Fiona Norwood ²⁸, Marie O'Donnell ²⁰, Mary O'Driscoll ²⁰, Julia Rankin ²⁹, Sabrina W Yum ³⁰, Zarazuela Zolkipli-Cunningham ²⁵ ³¹, Isabell Brusius ⁵, Gilbert Wunderlich ³², Genomics England Research Consortium, Mert Karakaya ⁵, Brunhilde Wirth ⁵, Khalid A Fakhro ⁴ ³³ ³⁴, Homa Tajsharghi ³⁵, Carsten G Bönnemann ³, Jenny C Taylor ¹, Henry Houlden ²

Affiliations

1 NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
2 Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK.
3 Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, Bethesda, MD, USA.
4 Department of Human Genetics, Sidra Medicine, Doha, Qatar.
5 Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), Institute of Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany.
6 William Harvey Research Institute, Queen Mary University of London, London, UK.
7 Genomics England, London, UK.
8 Centogene AG, Rostock, Germany.
9 Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
10 Department of Neurology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
11 The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
12 Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK.
13 Department of Paediatric Neurology - Neuromuscular Service, Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK.
14 Department of Neurology, Royal Devon and Exeter NHS Trust, Exeter, UK.
15 Randall Division of Cell and Molecular Biophysics Muscle Signalling Section, King's College London, London, UK.
16 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
17 Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
18 Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK.
19 Department of Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
20 West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.
21 Divisions of Neurology and Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
22 Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
23 The Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital Trust, London, UK.
24 GeneDx, Gaithersburg, 20877 MD, USA.
25 Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children's Hospital of Philadelphia, PA, USA.
26 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
27 Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
28 Department of Neurology, King's College Hospital, London, UK.
29 Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Trust, Exeter, UK.
30 Division of Pediatric Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
31 Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA, USA.
32 Department of Neurology, Center for Rare Diseases Cologne, University Hospital Cologne, Cologne, Germany.
33 College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
34 Department of Genetic Medicine, Weill Cornell Medical College, Doha, Qatar.
35 School of Health Science, Division Biomedicine and Translational Medicine, University of Skovde, Sweden.

PMID: 33559681 DOI: 10.1093/brain/awaa420

Abstract

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.

Keywords

EMG; genetics: neuropathy; hereditary motor and sensory neuropathies; nerve conduction studies; whole-genome sequencing.

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