Genetic cause of heterogeneous inherited myopathies in a cohort of Greek patients

Abstract

Inherited muscle disorders are caused by pathogenic changes in numerous genes. Herein, we aimed to investigate the etiology of muscle disease in 24 consecutive Greek patients with myopathy suspected to be genetic in origin, based on clinical presentation and laboratory and electrophysiological findings and absence of known acquired causes of myopathy. Of these, 16 patients (8 females, median 24 years-old, range 7 to 67 years-old) were diagnosed by Whole Exome Sequencing as suffering from a specific type of inherited muscle disorder. Specifically, we have identified causative variants in 6 limb-girdle muscular dystrophy genes (6 patients; ANO5, CAPN3, DYSF, ISPD, LAMA2, SGCA), 3 metabolic myopathy genes (4 patients; CPT2, ETFDH, GAA), 1 congenital myotonia gene (1 patient; CLCN1), 1 mitochondrial myopathy gene (1 patient; MT-TE) and 3 other myopathy-associated genes (4 patients; CAV3, LMNA, MYOT). In 6 additional family members affected by myopathy, we reached genetic diagnosis following identification of a causative variant in an index patient. In our patients, genetic diagnosis ended a lengthy diagnostic process and, in the case of Multiple acyl-CoA dehydrogenase deficiency and Pompe's disease, it enabled specific treatment to be initiated. These results further expand the genotypic and phenotypic spectrum of inherited myopathies.

Keywords: Genetic diagnosis; Genetics; Inherited myopathy; Limb-girdle muscular dystrophy; Whole exome sequencing.

Fig. 1

Photos of the upper extremities of patient #2, showing marked atrophy of the proximal muscles and scapular winging. This patient and his similarly affected brother were found to harbor both the p.Tyr537* change and the deletion of exons 2 to 8 in the CAPN3 gene in compound heterozygosity.

Fig. 2

Family pedigree of patient #13, harboring a heterozygous novel splice site variant (c.1608+2T>C) in the LMNA gene. The proband is indicated by an arrowhead (III-2) and subjects possibly affected by laminopathy are colored in grey. Subjects II-5, III-1 and III-2 suffered from second degree atrioventricular block and dilated cardiomyopathy and underwent either a permanent pacemaker or an implantable cardioverter-defibrillator insertion. The symbol for deceased subjects is marked with a diagonal bar and age of death is placed in the upper right corner.

Fig. 3

Photos of the patient #15 showing muscle atrophy in the shoulder girdle and the lower half of the facial musculature. WES testing identified the p.Thr57fs*2 (c.170delC) change in the MYOT gene, suggesting the diagnosis of myotilinopathy.