Hypertrophic cardiomyopathy (HCM) is a primary disease of the myocardium most commonly
caused by mutations in sarcomeric genes. We aimed to perform a nationwide large-scale
genetic analysis of a previously unreported, representative HCM cohort in Hungary.
A total of 242 consecutive HCM index patients (127 men, 44 ± 11 years) were studied
with next generation sequencing using a custom-designed gene-panel comprising 98 cardiomyopathy-related
genes. A total of 90 patients (37%) carried pathogenic/likely pathogenic (P/LP) variants.
The percentage of patients with P/LP variants in genes with definitive evidence for
HCM association was 93%. Most of the patients with P/LP variants had mutations in
MYBPC3 (55 pts, 61%) and in MYH7 (21 pts, 23%). Double P/LP variants were present
in four patients (1.7%). P/LP variants in other genes could be detected in ≤3% of
patients. Of the patients without P/LP variants, 46 patients (19%) carried a variant
of unknown significance. Non-HCM P/LP variants were identified in six patients (2.5%),
with two in RAF1 (p.Leu633Val, p.Ser257Leu) and one in DES (p.Arg406Trp), FHL1 (p.Glu96Ter),
TTN (p.Lys23480fs), and in the mitochondrial genome (m.3243A>G). Frameshift, nonsense,
and splice-variants made up 82% of all P/LP MYBPC3 variants. In all the other genes,
missense mutations were the dominant form of variants. The MYBPC3 p.Gln1233Ter, the
MYBPC3 p.Pro955ArgfsTer95, and the MYBPC3 p.Ser593ProfsTer11 variants were identified
in 12, 7, and 13 patients, respectively. These three variants made up 36% of all patients
with identified P/LP variants, raising the possibility of a possible founder effect
for these mutations. Similar to other HCM populations, the MYBPC3 and the MYH7 genes
seemed to be the most frequently affected genes in Hungarian HCM patients. The high
prevalence of three MYBPC3 mutations raises the possibility of a founder effect in
our HCM cohort.
