Congenital myopathy

Gene: VWA1

I don't know

the phenotype associated with this gene is mostly characterized by childhood or adult onset, slowly progressive, non–length-dependent axonal hereditary motor neuropathy, with involvement of the proximal lower limbs as well. however, histological and neurophysiological findings reported in the study by Deschauer et al. were both neuropathic and myopathic leading to the definition of neuromyopathy. however, as indicated by Nagy et al, "the true myopathic nature of the disease remained controversial, with some proposing a primarily neurogenic pathology and a secondary myopathic process". overall there is not yet enough evidence to suggest that variants in this gene can cause a primary myopathy.

Created: 19 Sep 2025, 10:28 a.m. | Last Modified: 19 Sep 2025, 10:28 a.m.

Panel Version: 6.35

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• PMID:39502942
• PMID: 33459760

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Comment on list classification: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber.

Created: 19 Feb 2025, 12:49 p.m. | Last Modified: 19 Feb 2025, 12:49 p.m.

Panel Version: 5.13

The rating of this gene should remain amber on this panel based on recommendation by Anna Sarkozy. Her recommendation is based on evidence from new publications on this gene and associated phenotype, which is summarised in the review, PMID:39502942.

The recommendation from the NHS Genomic Medicine Service is as below:
The myopathic nature of the conditions associated with this gene remains controversial and currently there doesn't appear to be sufficient evidence to consider VWA1-related disorder as a myopathy. Therefore this gene-condition is out of scope of this Clinical Indication and at most should remain amber.

Created: 19 Feb 2025, 12:41 p.m. | Last Modified: 19 Feb 2025, 12:52 p.m.

Panel Version: 5.13

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 39502942

Comment on list classification: Promoting to amber, with a recommendation for consideration for a green rating following expert review as to whether the phenotype fits the scope of the congenital myopathy panel.

Created: 15 Feb 2024, 6:09 p.m. | Last Modified: 15 Feb 2024, 6:09 p.m.

Panel Version: 4.36

In PMID: 33459760 Deschauer et al 2021 report 15 affected individuals from six families of German, Arabic, and Roma descent with biallelic loss of function variants in VWA1 and a neuromuscular phenotype. In 3 of the families the onset of symptoms was in childhood (ages 2-18yr in F3, ages 2-3yr in F4, and at school age in F5). Muscle biopsies of 3 individuals (F1-II.2, F2-II.1, and F5-II.1) revealed myopathic changes. A 10-bp tandem repeat is duplicated in one variant (p.Gly25Argfs*74]) and deleted in another variant (p.Gly21Alafs*12]). The duplication was found in 3 German families, homozygous in one and compound heterozygous in the other two.

PMID: 33559681 Pagnamenta et al 2021 report 17 individuals from 15 families with an autosomal-recessive, hereditary motor neuropathy and rare biallelic variants in VWA1. The p.(G25Rfs*74) 10-bp repeat expansion was observed in 14/15 families and was homozygous in 10/15. The authors state that the mean age of symptom recognition was 2.0 ± 1.4 years with tip-toe walking, foot deformities, Achilles tendon contractures, and recurrent hip and patellar dislocations.

Given the young age of onset in some patients and myopathy seen in biopsys this gene may be a candidate for green rating on this panel, subject to expert review.
Sources: Literature

Created: 15 Feb 2024, 6:07 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neuronopathy, distal hereditary motor, autosomal recessive 7, OMIM:619216; neuronopathy, distal hereditary motor, autosomal recessive 7, MONDO:0030977

Publications

• 33459760