LAUSR

End-stage hypertrophic cardiomyopathy (esHCM) indicates the most progressive form of HCM with progression to left ventricle remodeling and systolic dysfunction and is common indication to heart transplant. It affects 2.4–15.7% of HCM cases and is associated with a poor prognosis (mortality in this group of patients reaches 11%). In this study patients with esHCM were investigated using next generation sequencing in order to examine the genetic causes of the most severe course of the disease. Despite huge amount of data from many studies, a clear genotype-phenotype correlation is still lacking and predictive value of genetic testing is sometimes undermined. However, there is an ongoing need for a prediction factors in HCM patients. Fifty seven patients (21 male, 36.8%) with esHCM were genetically investigated with next generation sequencing of a TruSight Cardio panel by Illumina that provides coverage of 174 genes with known associations to cardiac conditions including cardiomyopathies (n=52) or custom panel of 35 cardiomyopathies genes (n=5). Disease-causing variants where found in 47 probands (82.5%). Thirty-two probands (77.2%) had a single pathogenic or potentially pathogenic mutation in one of the sarcomeric genes: MYBPC3 (13, 22.8%), MYH7 (11, 19.3%), TNNT2 (3, 5.3%), TNNI3 (3, 5.3%), MYL3 (1, 1.8), TPM1 (1, 1.8%). In 13 (22.8%) probands we found a double mutation: in 7 (12.3) both variants sarcomeric (MYBPC3 and TNNT2 with MYH7, MYBPC3 and ACTA1) and in 5 (8.8%) one sarcomeric and the second non-sarcomeric cardiomyopathy variant (BAG3, ILK, PRKAG2, RBM20, SCN5A). In 3 (5.3%) probands we identified mutations or potentially disease-causing variants in genes associated Danon disease (LAMP2), glycogen storage disease of heart (PRKAG2) and double mutation FHL1 + PTPN11 (myopathy/Emery-Dreifuss muscular dystrophy and Noonan syndrome). In 10 (17.5%) patients, genetic examination did not reveal a candidate for disease-causing mutation. Surprisingly, a half of them had documented familial history of the disease. The majority of mutations in MYBPC3 were truncating variants (14/18, 78%). Thirty-three probands (57.9%) had a heart transplant or qualification to the procedure. Despite a similar background of typical HCM and esHCM and still ambiguous genotype-phenotype correlation, results may indicate that certain mutations (and not genes) may determine a more severe course of the disease. The majority of truncating variants in MYBPC3 gene may suggest their very strong impact on the course of the disease. Also, 3 neighboring variants in TNNT2 gene indicate a hot spot region for esHCM in our population. As expected, in single cases esHCM was related to specific non-sarcomeric genes (LAMP2, PRKAG2, FHL1). 17.5% of unsolved cases suggests that in such cases whole exome/genome sequencing might be needed to recognize the disease-causing mutation, especially when disease is familial. This work was supported by a grant 2.7/II/17 from the Institute of Cardiology, Warsaw, Poland.