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.

Mutation spectrum of hereditary myopathies in Turkish patients and novel variants

“…We observed a high heterogeneity of genetic etiology in our hereditary myopathy patient group, similar to previous reports (Sanga et al., 2020; Stehlíková et al., 2017; Zaganaset al., 2020). The alterations were observed in 16 genes related to hereditary myopathy.…”

“…Recently, hereditary myopathy‐related genes have been increasing with the spread of NGS. In this way, understanding the genotype–phenotype correlation and genetic subgroup classification makes rapid diagnosis, correct and effective genetic counseling, and better specific treatment more possible (Retterer et al., 2016; Zaganas et al., 2020). At present, variants in more than 100 different genes have been associated with hereditary myopathies (Evilä et al., 2016; Kaplan & Hamroun, 2014).…”

Pathogenic Mutations and Putative Phenotype-Affecting Variants in Polish Myofibrillar Myopathy Patients

“…Additionally, with the reporting of new cases, the reported clinical manifestations of mutations in a given gene are likely to expand. Recent large sequencing studies show that the genetic background of muscle diseases is more complex than previously appreciated [ 27 , 28 , 29 ]. In addition, our data suggest that mutations in more than one gene in a patient can result in a more severe phenotype.…”

ANO5-related muscle diseases: From clinics and genetics to pathology and research strategies

“…Since phenotypic appearance of ANO5 -related muscle diseases show a considerable variability and many “Anoctaminopathy features” are also characteristic for other muscular disorders, genetic testing is recommended for approaching the correct diagnosis. Molecular genetic testing can be performed by various approaches including direct Sanger sequencing, multigene panels, both should inquire the most common variations of the genetic mutational spectrum of the given area 32 or unbiased next generation sequencing (whole exome or whole genome). With the start of genetic research on Anoctaminopathies, a considerable number of pathogenic and putative pathogenic variants were detected.…”