Clinical and Genetic Characteristics of Hypertrophic Cardiomyopathy in 206 Russian Children: A Single-Center Study.

Background. Hypertrophic cardiomyopathy (HCM) is one of the most common forms of cardiomyopathy in children, characterized by a variable age of onset and variyng severity of clinical manifestations. In most cases, the causative variants of HCM are unique substitutions and are located in the genes encoding the proteins of the thick and thin myofilaments of the sarcomere. In Russia, publications on the characteristics of HCM are limited to the preschool age, small cohorts, and are primarily focused on syndromic forms of HCM, such as hereditary metabolic diseases and RASopathies. Aim: to describe the clinical and molecular genetic characteristics of Russian pediatric patients with hypertrophic cardiomyopathy. Methods. The case histories of 206 children with HCM were analyzed. Molecular genetic testing was performed by high-throughput sequencing, with subsequent validation of the results by bidirectional Sanger sequencing. All patients underwent determination of NTproBNP levels and an instrumental examination that included echocardiography, electrocardiography, and daily Holter monitoring, in some cases, cardiac MRI with intravenous contrast was also performed. Results. In 71% of patients, the cause of the disease was identified as nucleotide variants in the genes encoding the thick and thin filaments of the sarcomere, with a predominance of variants in the MYH7 gene (54%). Pathogenic variants in sarcomere-associated and other genes of monogenic HCM were found in 9% of patients, while in 11% of cases, no definitive genetic cause for myocardial hypertrophy could be identified. The obstructive form of the disease was diagnosed in 66 (32%) patients, half of which were caused by nucleotide variants in the MYH7 gene (p < 0.001). In contrast, the highest intraventricular obstruction gradient (>50 mm Hg) was identified in patients with variants in the TPM1, MYL3, and CACNA1C genes (p < 0.025). This study defines the clinical and genetic characteristics of a cohort with HCM (n=206), from which cases of hereditary metabolic diseases and RASopathies were excluded. Conclusion. Genetic verification of HCM is of fundamental importance for understanding the pathogenesis in each clinical case, determining treatment strategy, assessing disease prognosis, and enabling the development and implementation of targeted therapy. The study demonstrates differences in disease progression depending on the causative gene, most clearly manifested in patients with MYH7-HCM and MYBPC3-HCM, as well as the necessity of genetic testing for children with myocardial hypertrophy born to mothers with gestational diabetes. Given the relatively high percentage of “negative” results of the genetic test, the presence of causative variants in non-coding genomic regions, as well as a multifactorial disease etiology, can’t be ruled out. This necessitates continued research into the genetic background of HCM in various regions of the country.

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