Background:

Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous cardiac disease associated with an increased risk of sudden cardiac death (SCD). Despite advances in genetic testing, many patients lack identified pathogenic variants, complicating risk assessment and management. This thesis explores the genetic and phenotypic landscape of HCM in southeastern Sweden through several studies aimed at expanding understanding of its causes and clinical variability.

Methods:

Five original studies integrated clinical, imaging, and genetic data from more than 300 HCM patients across a range of ages and disease presentations. Genetic testing methods included cardiomyopathy-specific gene panels, trio exome sequencing, and AI-assisted re-analysis of variants. Clinical data were retrospectively reviewed to compare genotype-positive (G+) and genotype-negative (G–) groups.

Results:

Paper I presented a rare case of a patient homozygous for a MYBPC3 missense variant, who progressed to end-stage heart failure and underwent heart transplantation. Heterozygous carriers in the family remained unaffected, suggesting a dose-dependent pathogenic effect.

Paper II demonstrated that in paediatric and early-onset HCM cases previously deemed "gene-negative," updated gene panels and trio exome sequencing uncovered pathogenic or likely pathogenic variants in 50% of cases and variants of uncertain significance in an additional 30%, underscoring the importance of revisiting negative results with expanded methods.

Paper III reported monozygotic twins with myocarditis and a novel likely pathogenic desmoplakin (DSP) variant, suggesting a potential overlap between myocarditis and arrhythmogenic cardiomyopathy. This highlighted the diagnostic relevance of genetic testing in cases of recurrent myocarditis with familial patterns.

Paper IV described a cohort of 225 adult HCM patients in southeastern Sweden. Of those tested, 38% were genotype positive, mainly for MYBPC3 and MYH7. G+ patients were younger, had more severe hypertrophy, higher rates of family history of HCM/SCD, and greater disease burden in first-degree relatives, supporting the utility of genetic testing in clinical risk stratification.

Paper V focused on 58 apical HCM (ApHCM) patients, a less genetically understood subtype. Only 14% carried pathogenic variants, suggesting a complex genetic basis. Despite this, patients had significant clinical issues, including atrial fibrillation (41.4%), ventricular arrhythmias (29.3%), and apical aneurysms (17.2%).

Conclusions:

This thesis reinforces the complex genetic architecture of HCM and the need for tailored genetic approaches. Homozygous or biallelic variants can cause severe phenotypes, and re-analysis of inconclusive cases with updated and expanded genetic methods improves diagnostic yield, especially in paediatric HCM. The discovery of desmosomal gene variants in myocarditis suggests overlap with arrhythmogenic cardiomyopathy and supports genetic testing in atypical cases. In adult HCM, genotype-positive status is associated with earlier onset, more severe disease, and familial clustering, though genotype-negative patients remain at risk. ApHCM appears genetically distinct, less often linked to known sarcomeric variants but with significant clinical complications. As the largest genetic HCM study in Sweden, this work provides valuable population-specific insights to enhance diagnosis, family screening, and risk stratification in inherited cardiomyopathies.