G.P.261: Whole exome sequencing in patients with congenital myopathies

Abstract

Congenital myopathies (CM) are a group of disorders presenting at birth or early infancy, characterised by muscle weakness and specific changes in the muscle biopsy. During the recent decade a number of genes have been discovered, however, additional novel genes are yet to be identified as genetic diagnosis cannot be currently established in many CM patients. With the aim to identify the genetic defect in 33 CM patients, in whom mutations in suspected genes have been previously excluded, we carried out whole exome sequencing (WES). From the 33 patients, 19 have been resolved and 14 patients are still being investigated as the initial WES data analysis failed to identify possible candidate genes. Among the resolved cases, two patients with muscle biopsy suggestive of core myopathy and one with centronuclear myopathy, carried heterozygous truncating <i>TTN</i> mutations supporting the emerging data that <i>TTN</i> mutations should be investigated as causative in patients with unresolved centronuclear and core myopathy. We also identified a homozygous missense mutation in <i>STAC3</i> gene in a patient with King-Denborough syndrome and core-like changes on muscle biopsy, indicating a causative role of <i>STAC3</i> mutations in King–Denborough syndrome. Recently, a homozygous missense mutation in <i>STAC3</i> gene was identified in patients with Native American myopathy. A patient with a severe phenotype and muscle biopsy changes suggestive of nemaline myopathy, carried a homozygous missense mutation in <i>KLHL40</i>. Mutations in <i>KLHL40</i> have been very recently identified as a frequent cause of severe autosomal-recessive nemaline myopathy. Ten of the resolved patients carried mutations in potentially causative genes which are currently under investigation.