Targeted next-generation sequencing detects novel gene–phenotype associations and expands the mutational spectrum in cardiomyopathies

Abstract

Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity and mortality. These diseases are genetically diverse and associated with rare mutations in a large number of genes, many of which overlap among the phenotypes. To better investigate the genetic overlap between these three phenotypes and to identify new genotype–phenotype correlations, we designed a custom gene panel consisting of 115 genes known to be associated with cardiomyopathic phenotypes and channelopathies. A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC, was recruited for the study on the basis of more severe phenotypes and family history of cardiomyopathy and/or sudden death. We detected a total of 142 rare variants in 40 genes, and all patients were found to be carriers of at least one rare variant. Twenty-eight of the 142 rare variants were also predicted as potentially pathogenic variants and found in 26 patients. In 23 out of 38 patients, we found at least one novel potential gene–phenotype association. In particular, we detected three variants in OBSCN gene in ARVC patients, four variants in ANK2 gene and two variants in DLG1, TRPM4, and AKAP9 genes in DCM patients, two variants in PSEN2 gene and four variants in AKAP9 gene in HCM patients. Overall, our results confirmed that cardiomyopathic patients could carry multiple rare gene variants; in addition, our investigation of the genetic overlap among cardiomyopathies revealed new gene–phenotype associations. Furthermore, as our study confirms, data obtained using targeted next-generation sequencing could provide a remarkable contribution to the molecular diagnosis of cardiomyopathies, early identification of patients at risk for arrhythmia development, and better clinical management of cardiomyopathic patients.

Intracellular calcium current disorder and disease phenotype in OBSCN mutant iPSC-based cardiomyocytes in arrhythmogenic right ventricular cardiomyopathy

“…The patient in our study, a Chinese national clinically diagnosed with ARVC according to the criteria set by the Task Force 24 , developed this novel heterozygous mutation in OBSCN that might be of relevance to the pathogenesis of ARVC (whole genome sequencing did not detect other genes known to be associated with ARVC). The T-wave inversion and epsilon waves clinically manifested in the electrocardiogram and the right ventricular abnormality on the echocardiography observed in our patient were similar to the Italian-based clinical characteristics portrayed in patients with ARVC also carrying mutations in OBSCN 21 , 23 . We also determined that the OBSCN mutation was related to the decrease of protein expression level of obscurin, pointing to haploinsufficiency as a possible disease-causing mechanism.…”

“…In a study of 30 index patients with end-stage heart failure, mutations in OBSCN were identified in 5 subjects (17%) 21 . similarly, heterozygous mutations in OBSCN were identified in 6 of 74 unrelated individuals with hypertrophic cardiomyopathy, and in 3 of 10 patients with left ventricular densification 23 .…”

Overlapping Phenotypes and Degree of Ventricular Dilatation Are Associated with Severity of Systolic Impairment and Late Gadolinium Enhancement in Non-Ischemic Cardiomyopathies

“…Although this report found no connections of coexisting trabeculations that fit within NC/C ratio criteria in DCM with clinical points, it only could be partially compared to the present study and our previous study due to using triple criteria of thinning of the compact myocardium, NC/C ratio, and sufficient share of non-compact myocardium in total mass of the left ventricle [ 27 ]. The second most common combination, DCM/HCM, was found in nearly one-third of our overlapping patients, but this combination could be even more powerfully connected with undesirable prognosis due to partially shared gene basics [ 28 , 29 ]. The least frequent combination in our settings was the DCM/HCM/LVNC, with only a single case in the monitored period, which was also previously described in a large registry with clinical endpoints, which reported a greater incidence of cardiovascular adverse events [ 30 ].…”

Morphomechanic phenotypic variability of sarcomeric cardiomyopathies: A multifactorial polygenic perspective

“…47,50–52 Recent research encompassing other genes having sporadic PMs identified several rare variants underlying both HCM and DCM. 53 Seeing how pleiotropic PMs of sarcomeric genes can elicit such strikingly contrasting (Figures 2–4) phenotypes as HCM and DCM has spurred sarcomere-biology research, 54 and the sarcomere’s chemomechanical cross-bridge kinetics/dynamics cycle clarified how cardiomyopathic PMs perturb force-production. 55 Briefly, myosins consist of a head motor-domain (MD), which generates movement, and a neck (lever-arm) transitioning into the tail domain and associated with several regulatory light-chain subunits (cf.…”