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

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.

Mutated VWA8 Is Associated With Developmental Delay, Microcephaly, and Scoliosis and Plays a Novel Role in Early Development and Skeletal Morphogenesis in Zebrafish

“…Recently, biallelic variants in the VWA1 gene have been associated with recessive hereditary motor neuropathy (Deschauer et al, 2021;Pagnamenta et al, 2021). The family reported in the present study has several affected individuals with overlapping phenotypes as reported in the VWA1 mutated patients.…”

Methylome and Transcriptome-Based Integration Analysis Identified Molecular Signatures Associated With Meningitis Induced by Glaesserella parasuis

“…VWA1 encodes the von Willebrand factor A domain containing 1 protein, which is an extracellular matrix protein expressed in muscle and peripheral nerves but whose function is poorly understood (47,48). Lack of VWA1 is known to compromise peripheral nerve structure and function in a VWA1 knock-out mouse model (49). Exome sequencing identified bi-allelic loss of function variants in VWA1 as the molecular basis of neuromyopathy, a neuromuscular disorder (50).…”

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

“…STRs are highly polymorphic and exhibit pathogenicity through an array of different mechanisms. Much remains to be learned about the basic biology of STR expansion disorders and the distinction between a benign and pathogenic allele, particularly for recently described STR disease genes like RFC1 ( 9 ), GIPC1 ( 51 ), LRP12 ( 52 ), NOTCH2NLC ( 14 , 52 ), and VWA1 ( 10 ). By resolving the full diversity of STR sizes and motif conformations in clinically affected and nonaffected individuals, our targeted ONT sequencing assay may be applied to better define pathogenic boundaries and investigate the role of phenotypic modifiers, such as internal STR interruptions.…”