The Urgency of Genetic Verification of Non-Compaction Cardiomyopathy in Children: Clinical Cases

Abstract

Background. Non-compaction cardiomyopathy is a group of genetically heterogeneous, poorly studied myocardial diseases with a variety of clinical manifestations (from asymptomatic course to progressive systolic dysfunction with symptoms of chronic heart failure, arrhythmias, and thromboembolic complications). Considering the variety of genetic disorders associated with the development of noncompaction cardiomyopathy, genetic verification of the diagnosis is important for determining the prognosis and conducting genetic counselling of families with cases of the disease.Description of the Clinical Case. The article presents two clinical observations of a severe course of non-compaction cardiomyopathy with remodeling of the heart cavities according to the dilated phenotype. In order to clarify the disease etiology, a molecular genetic study was conducted using the method of direct automatic sequencing with the analysis of targeted regions of 404 genes which mutations are described in hereditary diseases of the heart and blood vessels. After verifying the mutation (in the ACTC1 and MYBPC3 genes), we performed a search for the detected nucleotide substitution in the venous blood samples of parents and in one case — in the fetal DNA sample. The mode of inheritance has been determined; the probability of recurrence of the disease in siblings in subsequent pregnancies has been estimated.Conclusion. The description of clinical cases shows the importance of genetic verification of the diagnosis in patients with non-compaction cardiomyopathy for determining the disease prognosis and developing an algorithm for monitoring relatives of a proband.

Application of Long-Read Nanopore Sequencing to the Search for Mutations in Hypertrophic Cardiomyopathy

“…The nonsense variant p.Gln1233Ter of MYBPC3 , identified here, has already been described in other reports ( Figure 4 ) [ 15 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. HCM-causing MYBPC3 truncation variants, including p.Gln1233Ter, induce a reduction in the amount of cardiac myosin-binding protein C, which enhances maximal myofilament sliding velocities [ 40 ].…”

“…There is a tendency for earlier onset of the disease in males. The single published case of onset of left ventricular non-compaction in early childhood was a compound heterozygote with p.Gln1233Ter and another MYBPC3 pathogenic variant leading to p.Glu258Lys substitution [ 34 ]. We have previously found that there is accumulation of rare variants in genes associated with arrhythmogenic right ventricular cardiomyopathy in patients with HCM [ 41 ].…”

“… Clinical heterogeneity of HCM in carriers of p.Gln1233Ter of the MYBPC3 gene [ 15 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Legend.…”