263 GENETIC CAUSES OF CARDIOMYOPATHIES IN CHILDREN

Abstract

Abstract Background The genetic background of paediatric cardiomyopathies is only partially resolved, because of their rarity and heterogeneity. However, the assessment of aetiology is of paramount importance in order to define prognosis and therapeutic choices. Moreover, the recognition of genetic causes is the basis for cascade screening in the family. Aims This study aimed to identify the genetic causes of cardiomyopathies in children evaluated and followed at our paediatric hospital. Methods A validated Next Generation Sequencing (NGS) target panel was performed in a cohort of 76 paediatric patients: 36 Hypertrophic Cardiomyopathy, (HCM), 24 Dilated Cardiomyopathy (DCM), 3 Restrictive Cardiomyopathy (RCM), 2 Left Ventricular Non Compaction (LVNC), 10 Arrhythmogenic Cardiomyopathy (AC) and one with a cardiac arrest. Genetic counselling was offered to parents. Furthermore, 9 patients with negative genes panel were selected for Whole Exome Sequencing (WES). Results By target genes panel analysis we identified a pathogenic or likely pathogenic variant in 32/76 patients (42%). Most genotyped patients had a sarcomeric aetiology and MYH7 (11/32, 34%), MYBPC3 (7/32, 22%) and thin-filaments genes (9/32, 28%) resulted the most mutated genes. 11/32 (34%) patients had a complex genotype. In one patient we found the rare coexistence of two independent monogenic diseases (Osteogenesis Imperfecta and HCM) due respectively to COL1A1 and MYH7 variants. Moreover, we identified five syndromic cases (5/32, 16%): three patients with Noonan Syndrome (one with SOS1 variant and two with PTPN11 variants), one boy with Danon Disease (with LAMP2 variant) and a newborn with Alström Syndrome (due to ALMS1 variants). By WES we identified a de novo variant in FLNC gene in a 7 years old child RCM, a Noonan Syndrome due to biallelic LZTR1 variants in a 9 years old child, two PLEC1 variants in a newborn with DCM and Epidermolysis bullosa, and a de novo NKX2-5 variant in a child with RCM. Conclusions A definitive molecular diagnosis could be obtained in a substantial proportion of children (42%). The genetic test results had direct implications for clinical management, to suggest therapeutic interventions. Moreover, predictive genetic testing in family members resulted very important for clinical follow-up and to establish the recurrence risk for subsequent pregnancies.