P72New variant in CMYA5 gene is associated with early-onset restrictive cardiomyopathy and autism-spectrum disorder

Abstract

Background: Among various types of cardiomyopathies, restrictive cardiomyopathy (RCM), especially in combination with neuromuscular phenotype, is one of the least studied. Where only several genes expressed in cardiac and skeletal muscle were linked to this type of cardiopmyopathy (DES, BAG3, FLNC). In the present study, we applied an exome sequencing strategy in order to search a genetic background of early-onset RCM, associated with myopathy and mood disorder. Materials and Methods. Whole exome sequencing was performed on seven probands with a combination of RCM and signs of neuromuscular disorder using SureSelect Human All Exon target enrichment kit. Variant calling was performed according to GATK BestPractice recommendation. Variant annotation was performed using Annovar. Results: 7 patients with RCM and neuromuscular phenotype were included into the study. In all patients, cardiac manifestation of the disorder preceded the diagnosis of neuromuscular disorder. In 6 patients, the mutation in earlier described cardiomyopathy and myopathy-associated genes such as DES, BAG3 and FLNC were identified. In one patient, a new variant in CMYA5 gene (E683G , Chr5: 79026636:A>GNM-153610) was identified. The patient presented with RCM and muscle weakness at 2 years of age. Myopathic pattern was confirmed by electromyography. At the age of 3 years the mood disorder (autism-spectrum disorder) was suspected. By the age of 5 years the patient was discussed as a potential candidate for cardiac transplantation due to severe congestive heart failure. However, due to neurological and mood condition the cardiac transplantation was not performed. The familial screening revealed that newly described CMYA5 variant was inherited from the father who has very moderate cardiac structural abnormalities (left atrial dilation) and no clinical signs of myopathy or psychiatry disorder. In addition, his family history was remarkable due to sudden cardiac death in mother at 40 years of age and early cardiac related infant death. According to ACMG guidelines, the variant was classified as VUS (variant of unknown significance). However, available reports regarding the role of CMYA5 gene is development of schizophrenia and bipolar disorders as well as data obtained on animal model regarding CMYA5-associated cardiomyopathy allow to pay attention to this VUS as a possible causative-gene candidate. Conclusion. In the present study, we described a new variant of unknown significance in CMYA5 gene, detected in a patient with early-onset RCM, myopathy and mood disorder. Taking into account the potential role of CMYA5 gene in pathogenesis of schizophrenia, bipolar disorder and cardiomyopathy in animal models, this variant can represent a potential disease -causative variant leading to RCM with neuromuscular phenotype with incomplete penetrance. More detailed functional and morphological studies are needed to evolve the role of CMYA5 in cardiomyopathy development.