Founder variants in sarcomere protein genes account for a significant proportion of disease-causing variants in patients with hypertrophic cardiomyopathy (HCM). However, information on founder variants in non-sarcomeric protein genes, such as FHOD3, which have only recently been associated with HCM, remains scarce. In this study, we conducted a retrospective analysis of exome sequencing data of 134 probands with HCM for recurrent pathogenic variants. We discovered a novel likely pathogenic variant c.1646+2T>C in FHOD3 in heterozygous state in eight probands with HCM and confirmed its presence in seven additional relatives. Individuals with this variant had a wide range of ages at onset of the disease (4–63 years). No adverse cardiac events were observed. Haplotype analysis revealed that the individuals with this variant shared a genomic region of approximately 5 Mbp surrounding the variant, confirming the founder effect of the variant. FHOD3 c.1646+2T>C is estimated to have arisen 58 generations ago (95% CI: 45–81) in a common ancestor living on the Balkans. A founder FHOD3 c.1646+2T>C variant is the second most common genetic variant in our cohort of patients with HCM, occurring in 16% of probands with a known genetic cause of HCM, which represents a substantially higher proportion than the currently estimated 0.5–2% for causal FHOD3 variants. Our study broadens the understanding of the genetic causes of HCM and may improve the diagnosis of this condition, particularly in patients from the Balkans.

Hypertrophic cardiomyopathy is often caused by pathogenic MYBPC3 variants. The study of Italian patients with HCM and MYBPC3(NM_000256.3):c.913_914del showed a higher disease penetrance in males and a higher frequency of arrhythmias compared to patients with other likely pathogenic and pathogenic (LP/P) MYBPC3 variants. We investigated the clinical outcomes of Slovenian probands with MYBPC3 LP/P variants, estimated the variant penetrance and compared the results with an Italian study. We identified 31 haplotype-matched individuals with MYBPC3:c.913_914del and 34 individuals with other LP/P MYBPC3 variants. We observed some significant differences in clinical and echocardiographic characteristics and frequency of adverse cardiac events between Slovenian and Italian probands with MYBPC3:c913_914del. We were unable to replicate previous findings for MYBPC3:c.913_914del, highlighting the complexity of genotype–phenotype associations. Graphical Abstract

Background: Cardiomyopathies (CMs) present phenotypically on a spectrum and in a proportion of patients the initial presentation is sudden cardiac arrest (SCA). Studies performing genetic screening of SCA survivors have identified (likely) pathogenic (LP/P) variants in 2–50% of probands, with mean cohort ages ranging from 28 to 64 years. Due to inconsistent data in the literature, our study aimed to genetically characterise Slovenian SCA survivors with clinically confirmed/suspected cardiomyopathy (CM). The present study included 29 probands (17 women, 59%) with clinically confirmed/suspected CM who survived SCA and were referred to the Clinical Institute of Genomic Medicine for genetic testing between January 2010 and July 2024. The majority of probands (23; 79%) underwent whole exome sequencing, and the remainder either clinical exome (5; 17%) or panel sequencing (1; 4%). Genetic data were analysed following ACMG/AMP guidelines and ACGS recommendations. Results: Probands survived SCA at a mean age of 49 ± 17 years (range 15–71), and 12 (41%) were < 50 years old. The majority had clinically confirmed/suspected arrhythmogenic (10; 34.5%) or dilated (9; 31.0%) CM, while the remainder had clinically undefined (5; 17.2%), hypertrophic (4; 13.8%), or non-compaction (1; 3.4%) CM. Seven LP/P variants in CM-related genes were identified in eight (28.6%) probands. In addition, 16 variants of uncertain significance (VUS) were identified in 12 (41.3%) probands. Probands’ age at SCA did not significantly affect the yield, as LP/P variants were identified in four probands < 50 years at SCA and in four > 50 years (p = 0.56), nor did the positive family history of heart disease (p = 0.55) or sudden cardiac death (p = 0.43). There were also no significant differences in probands' age and test outcome, as the mean age of patients with LP/P variants was 46 ± 21 years, those with the VUS(s) were 45 ± 15 years, and those without candidate variant(s) were 55 ± 12 years (p = 0.41). Conclusions: LP/P variants were identified in almost one-third of Slovenian SCA survivors with clinically confirmed/suspected CM. Genetic testing of SCA survivors with structural clinical findings provides additional confirmation of the clinical diagnosis and a basis for identifying relatives at risk of heart disease, allowing for better management.