Whole exome sequencing in patients with congenital myopathy

Introduction: Congenital myopathies (CM) are a heterogeneous group of muscle diseases presenting at birth or early infancy, characterised by muscle weakness and specific morphological changes in the muscle biopsy. During the recent decade a growing number of genes have been discovered, however, additional novel genes are yet to be identified as genetic diagnosis cannot be currently established in many patients with congenital myopathies. Methods: Eighteen patients with CM, where mutations in suspected genes have been previously excluded, were selected for whole exome sequencing (WES). WES was carried out by deCODE genetics and the data was analysed using deCODE Clinical Sequence Miner Tool. Results: Recently, a homozygous missense mutation in exon 10 of STAC3 gene was identified in patients with Native American myopathy. Analysis of WES data in our cases identified a homozygous STAC3 mutation in a patient with King-Denborough syndrome and core-like changes on muscle biopsy. STAC3 is a muscle specific gene involved in excitation–contraction coupling process. A second patient with a severe phenotype and muscle biopsy changes suggestive of nemaline myopathy, carried a homozygous missense mutation in KLHL40. Mutations in KLHL40 have been very recently identified as a frequent cause of severe autosomal-recessive nemaline myopathy. Two heterozygous truncating TTN mutations were detected in a patient with severe cardiomyopathy and muscle biopsy suggestive of a centronuclear myopathy (CNM) supporting the emerging data that TTN mutations should be investigated as causative in cases with unresolved CNM. Conclusions: By applying WES, we were able to reveal the molecular defect in 3 out of 18 patients in whom mutations in recently described genes causing CM were identified, showing that these genes should be considered in diagnostic testing. The remaining cases carried mutations in potentially novel genes which are under investigation.