Clinical and Genetic Characteristics of 114 Russian Children with a Monogenic Non-Sarcomeric Hypertrophic Cardiomyopathy Phenotype

Introduction. In children, cardiomyopathies with a morphofunctional phenotype similar to sarcomeric hypertrophic cardiomyopathies are associated with various syndromes and diseases in almost half of cases, and for some of these nosologies, etiopathogenetic therapy is currently possible.

Aim: to determine the clinical, laboratory-instrumental, and genetic characteristics of the most common monogenic orphan diseases accompanied by a hypertrophic cardiomyopathy phenotype in children.

Methods. The study included 335 patients diagnosed with hypertrophic cardiomyopathies who were regularly followed up at the cardiology department of the National Medical Research Center for Children’s Health, Ministry of Health of the Russian Federation, from 2014 to 2025. All patients underwent molecular genetic analysis of target genomic regions containing 420 genes, in which pathogenic variants have been described in patients with a hypertrophic cardiomyopathy phenotype, using high-throughput sequencing. According to the study design, a comparative analysis of the course of the hypertrophic cardiomyopathy phenotype in children was performed based on the etiological cause—within the framework of inherited metabolic disorders, due to mitochondrial pathology, and RAS-pathy syndromes (n=114).

Results. Molecular genetic examination of patients with a hypertrophic cardiomyopathy phenotype verified rare hereditary diseases, including mitochondrial disorders (causal variants in mitochondrial or nuclear DNA), Pompe disease, Danon disease, PRKAG2 syndrome, and various RAS-pathy syndromes. A comparative characterization was performed, showing a high frequency of the hypertrophic cardiomyopathy phenotype in children with early-onset RAS-pathy syndromes. Myocardial hypertrophy exceeding 30 mm was rarely recorded; a symmetric form of the disease was significantly more common in mitochondrial pathology, asymmetric in RAS-pathy syndromes, and biventricular in inherited metabolic disorders. In addition to myocardial hypertrophy, patients with inherited metabolic disorders and mitochondrial pathology exhibited left ventricular dilation and reduced contractility. Patients with RAS-pathy syndromes had more pronounced (grade II–III) mitral regurgitation and a high frequency of pulmonary valve insufficiency (30.8%). Wolff–Parkinson–White syndrome (WPW) phenomenon and nonsustained supraventricular tachycardia were recorded in inherited metabolic disorders. In mitochondrial pathology, an increase in creatine phosphokinase-MB (CK-MB) with normal CK levels was noted; in inherited metabolic disorders, high values of CK, lactate dehydrogenase, and transaminases were observed. No significant difference in the frequency of elevation or in NT-proBNP levels was found between patients. Surgical treatment in the form of septal myectomy was performed mainly in RAS-pathy syndromes (23; 20%) and in one case of PRKAG2 syndrome. During the follow-up period, 17 (14.7%) children died; heart transplantation and cardioverter defibrillator implantation were performed in patients with Danon disease and PRKAG2 syndrome.

Conclusion. Myocardial hypertrophy in children may be the first symptom of numerous non-sarcomeric monogenic diseases with varying etiologies, prognoses, and treatments. Understanding the features of the hypertrophic cardiomyopathy phenotype course allows for differential diagnosis before molecular genetic results are available and enables timely treatment adjustments. The introduction of high-throughput sequencing into clinical practice allows simultaneous analysis of a large number of genes causing the hypertrophic cardiomyopathy phenotype, opening new possibilities for early diagnosis of rare diseases in children and providing a better evidence base for further research.

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