Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Etiology of Cardiomyopathies

Background:

• Hypertrophic cardiomyopathy (HCM) is a primary genetic heart muscle disease.
• The genetic underpinnings of HCM are complex, with numerous genes implicated.
• Identifying novel genetic contributors is crucial for understanding disease mechanisms and improving diagnostics.

Purpose of the Study:

• To investigate the frequency and pathogenicity of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with HCM.
• To confirm the role of ALPK3tv in HCM through burden testing and family co-segregation studies.
• To characterize the clinical phenotype associated with ALPK3tv in HCM patients.

Main Methods:

• Genomic analysis of discovery (n=770) and validation (n=2047) HCM cohorts to identify ALPK3tv.
• Comparison of ALPK3tv frequency against population controls (gnomAD).
• Family co-segregation analysis and comparison of ALPK3tv carriers with HCM patients stratified by sarcomere gene variant status (SP+ and SP-).

Main Results:

• Heterozygous ALPK3tv were identified in 1.56% of HCM patients in both discovery and validation cohorts, significantly higher than controls.
• ALPK3tv carriers exhibited a higher prevalence of apical/concentric hypertrophy patterns and short PR intervals.
• Long-term follow-up revealed that 9% of ALPK3tv patients experienced heart failure or cardiac transplantation, with evidence of myocardial fibrosis and myocyte vacuolation.

Conclusions:

• Heterozygous truncating ALPK3 variants (ALPK3tv) are pathogenic and represent a significant genetic cause of HCM.
• ALPK3tv are associated with a distinct HCM phenotype, including specific hypertrophy patterns and electrocardiographic findings.
• These findings underscore the importance of ALPK3 in cardiac development and function, and its role in HCM pathogenesis.