The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes

Abstract

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.

Hypertrophic Cardiomyopathy in Underrepresented Populations: Clinical and Genetic Landscape Based on a Russian Single-Center Cohort Study

“…All carriers of the p.Q1233* variant were from the Central (Moscow) District of Russia and of Slavic origin. The MYBPC3 p.Q1233* variant has also been found to be very common in some Eastern European countries, such as Belarus and Hungary [44], where its founder effect has been confirmed. In Western countries, the prevalence of the p.Q1233* variant is less than 1% [24,26,34].…”

“…There were no homozygous or compound heterozygous patients with two truncating variants (Figure 1). Compared to patients with a single P/LP/VUS-LP variant (n = 70), patients with two rare variants (n = 10) had a significantly higher SCD risk score (5.9 [3.5-7.3] vs. 2.9 [1.9-4.0], p = 0.011), larger left atrium (52 [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] vs. 43 [39][40][41][42][43][44][45][46][47][48][49][50] mm, p = 0.017), more frequent high systolic pulmonary artery pressure (63 vs. 14%, p = 0.004), and a trend toward more frequent severe NYHA class III/IV (38 vs. 11%, p = 0.07). The clinical course of HCM was highly variable, ranging from mild symptoms to severe HF progression and SCD in middle age.…”

A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study

“…FHOD3 was only recently added to the list of intrinsic genes implicated in HCM in 2022 [2]. Therefore, it has not been included in earlier studies using panel sequencing to elucidate the genetic background of patients with HCM [29][30][31]. With the inclusion of the FHOD3 in cardiomyopathy gene panels, the prevalence of FHOD3-associated HCM could be significantly higher than currently estimated, particularly among patients with HCM with Balkan ancestry.…”

ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy

“…No excess TTN variants were noted in cases compared to controls in two studies. 34,35 There is one report of a frameshift located in the A-band (percent spliced-in; PSI 100%), 36 and one termination in the I-band (PSI 100%) 37 in individuals with HCM. One study reported a missense variant in an immunoglobulin domain near the M-line A-band transition zone of TTN in a medaka mutagenesis fish model with diastolic dysfunction, highlighting this as an important region.…”