Materials and methods.
Cohort of patients. From 2009-2015 150 probands with hypertrophic cardiomyopathy (HCM) and 60 probands with LVNC had underwent genetic screening.
Genetic analysis. Study was performed in accordance with the Helsinki declaration and the local ethics committee. Genetic screening of the targeted 10 genes (MYBPC3, TAZ, TPM1, LDB3, MYL2, ACTC1, MYL3, MYH7, TNNI3, and TNNT2) was performed by next generation sequencing followed by Sanger re-sequencing. Cascade familial screening was performed when available. De novo mutational status was counted only if genetic testing reveal absence of the genetic variant in both parents.
"Damaging" or "probably damaging" genetic variants were found in 39 HCM index cases (26%) what is less than expected. The vast majority of mutations were found in the MYH7 and MyBPC3 gene what fits with worldwide mutation rates. De novo origin was confirmed for 4 mutations (10% of all genotype-positive cases, and 2.6% in the whole HCM cohort). Three mutations had raised de novo in the MYH7 gene, and 1 probably damaging de novo variant was found in the TPM1 gene. Single de novo genetic variant in the MYH7 gene was found in the patient with familial HCM in addition to the known mutation in the MyBPC3 gene inherited from the affected mother. This patient had severe clinical phenotype and underwent reconstructive extended myectomy and ICD implantation at the age of 15 y.o.
"Damaging" or "probably damaging" genetic variants were found in 14 LVNC index cases (23%). Mutations in the MYH7 gene were also the most common finding. De novo status was confirmed for 4 mutations in the MYH7 gene (29% of all genotype-positive cases, and 6.6% in the whole LVNC cohort).
All carriers of de novo mutations had significantly younger age of clinical manifestation within own group.
Totally 18 mutations in the MYH7 gene were detected in this study in the whole cohort of patients (HCM and LVNC), and five of them had raised de novo.
Conclusion. Mutations de novo are responsible for a significant portion of the LVNC, and are less common but not negligible in HCM patients. Severe clinical phenotype within "mildly" affected family might be explained by additional de novo mutation (at least in some families). The MYH7 gene is an important source of de novo mutations maintaining the high prevalence of HCM and LVNC in population.
We were unable to track mutation origin in half of the cases because of incomplete data from the families. So the real prevalence of de novo mutations might be underestimated.