Abstract
Mutations in the genes of the RAS/MAPK pathway form a large group of clinically and genetically overlapping syndromes, which include diseases of the cardiovascular system. The spectrum of cardiovascular abnormalities includes different congenital heart diseases (CHD), cardiomyopathies (CM) mostly with a hypertrophic phenotype, and heart rhythm disorders. About 20% of all cases in children with hypertrophic CM are due to RASopathies, 42% of which are detected in children during their first year of life.
Objective – the research aims to determine the molecular genetic causes and clinical outcomes of hypertrophic CM in children with RASopathies.
Material and methods. 64 children, aged from 1 month to 17 years old, with different varieties of RASopathies were included into the research. All patients underwent examination and treatment from 2012 to 2021 in National Medical Research Center for Children's Health Federal state autonomous institution of the Russian Federation Ministry of Health.
Results. Hypertrophic CM as a part of RASopathy was diagnosed in 46 cases (72%). The disease was caused by nucleotide variants in the genes PTPN11 (n = 16), RAF1 (n = 13), RIT1 (n = 8), BRAF (n = 3), LZTR1 (n = 2), SOS1 (n = 2), SOS2 (n = 1) and SHOC2 (n = 1). The obstructive form of hypertrophic CM was detected in 32 children. The average age when hypertrophic CM was diagnosed is 13,5 months, and the average age when the gene syndrome was verified is 57,4 months. Six new nucleotide variants were identified in the genes of the RAS/MAPK pathway. The most common variant in patients with hypertrophic CM is c.770C>T, p.S257L missense mutation in exon 7 of the RAF1 gene. Septal myectomy was performed in 5 patients with variants in the PTPN11 gene, in 3 cases with RAF1 gene mutation, in 1 case with SOS1 gene mutation, and in 2 patients with biallelic mutations in the LZTR1 gene.
Conclusion. The presence of hypertrophic CM significantly affects the prognosis of this group of patients and often requires early surgical intervention due to the large number of obstructive CM forms and the high occurrence of concomitant CHD.
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About the authors
- Leila A. Gandaeva, Cand. Med. Sci., Senior Researcher, Pediatric Cardiologist; ORCID
- Valentina G. Kaverina, Junior Researcher, Pediatrician; ORCID
- Elena N. Basargina, Dr. Med. Sci., Professor, Chief Researcher, Head of Department; ORCID
- Aleksandr A. Pushkov, Cand. Med. Sci., Leading Researcher; ORCID
- Kirill V. Savostyanov, Dr. Biol. Sci., Head of the Medical Genetic Center and Laboratory of Medical Genomics; ORCID
