Bi-allelic truncating mutations in <i>VWA1</i> cause neuromyopathy
Marcus Deschauer, Holger Hengel, Katrin Rupprich, Martina Kreiß, Beate Schlotter‐Weigel, Mona Grimmel, Jakob Admard, Ilka Schneider, Bader Alhaddad, Anastasia Gazou, Marc Sturm, Matthias Vorgerd, Ghassan Balousha, Osama Balousha, Mohammed Falna, Jan S. Kirschke, Cornelia Kornblum, Berit Jordan, Torsten Kraya, Tim M. Strom, Joachim Weis, Lüdger Schöls, Ulrike Schara, Stephan Zierz, Olaf Rieß, Thomas Meitinger, Tobias B. Haack
Abstract
The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.