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Cardiac phenotype characterization at magnetic resonance imaging in alpha-protein kinase 3-associated hypertrophic
Insights
Alpha-protein kinase 3 (ALPK3) gene variants are linked to distinct hypertrophic cardiomyopathy (HCM) phenotypes, primarily apical hypertrophy with less fibrosis. This study clarifies ALPK3 variant carrier characteristics in HCM patients.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Cardiomyopathies
Background:
- Alpha-protein kinase 3 (ALPK3) is a recently identified candidate gene for hypertrophic cardiomyopathy (HCM).
- Limited clinical data exists for individuals carrying ALPK3 variants.
- Understanding ALPK3's role is crucial for diagnosing and managing HCM.
Purpose of the Study:
- To determine the prevalence of heterozygous ALPK3 variants in adult HCM patients using whole-exome sequencing.
- To characterize the clinical and cardiac magnetic resonance imaging (CMR) phenotypes of individuals with ALPK3 variants.
- To compare ALPK3 variant carriers with sarcomere gene variant carriers.
Main Methods:
- Whole-exome sequencing and 3 Tesla cardiac magnetic resonance imaging (CMR) were performed on 575 consecutive HCM patients.
- Patients with rare missense (MAF < 0.0005) or truncating ALPK3 variants were classified as genotype-positive.
- Phenotypic data, including hypertrophy patterns and left ventricular (LV) fibrosis, were analyzed.
Main Results:
- Heterozygous ALPK3 variants were found in 6.43% (37/575) of HCM patients.
- ALPK3 carriers exhibited a higher prevalence of apical hypertrophy (59.5%) and reduced LV fibrosis compared to sarcomere variant carriers.
- Single ALPK3 variants were associated with apical HCM (ApHCM) and lower late gadolinium enhancement (LGE) extent.
Conclusions:
- Heterozygous ALPK3 variants are associated with a distinct HCM phenotype characterized by apical hypertrophy, particularly mixed ApHCM.
- ALPK3 variant carriers demonstrate a lower burden of myocardial fibrosis.
- These findings highlight ALPK3 as a significant gene in HCM, with specific phenotypic implications.
Background:
Alpha-protein kinase 3 (ALPK3) was recently identified as a candidate gene associated with hypertrophic cardiomyopathy (HCM). However, clinical data regarding carriers of ALPK3 variants are limited. Therefore, this study amied to evaluate the prevalence of heterozygous ALPK3 variants in adult patients with HCM and to elucidate the phenotypes of individuals harboring these variants.
Methods:
575 consecutive patients diagnosed with HCM who underwent 3T cardiovascular magnetic resonance (CMR) imaging and whole-exome sequencing genetic testing were recruited. Patients harboring ALPK3 rare missense variants (minor allele frequency < 0.0005) or truncating variants were considered genotype-positive.
Results:
Among the 575 included patients (65.0% [374/575] male; median age: 50 [40-61] years), 37 (6.43%) showed heterozygous ALPK3 variants. In comparison with sarcomere variant carriers, ALPK3 heterozygotes showed a higher prevalence of apical hypertrophy (59.5% [22/37] vs 20.2% [66/326], P < 0.001) and a lower fibrosis burden, with a two-fold reduction in the incidence of extensive fibrosis (≥15% left ventricle [LV] mass: 8.1% [3/37] vs 14.7% [48/326], P < 0.001). Patients with single ALPK3 variants were more likely to present with apical HCM (ApHCM; 80.0% [16/20]vs 35.3% [6/17], P, 0.006) and show a lower extent of late gadolinium enhancement (LGE; 1.26 [0.00-5.77] % vs 6.00 [3.63-8.50] %, P, 0.011) than those with both ALPK3 and sarcomere variants. CMR characteristics showed no significant differences between carriers with truncating and missense ALPK3 variants. Moreover, among patients with ApHCM, those with single ALPK3 variants were more likely to present with mixed ApHCM (87.5% [14/16] vs 55.2% [16/29] vs 14.3% [1/7], P < 0.05), a lower extent of LGE (0.67 [0-5.77] % vs 6.32 [2.39-10.90] % vs 3.32 [0.00-4.68] %, P < 0.05), and greater free-wall and apex LGE involvement (85.7% [6/7] vs 41.6% [10/24] vs 50% [2/4]) than those with myosin-binding protein C or β-myosin heavy chain variants.
Conclusion:
The clinical phenotype of individuals harboring heterozygous ALPK3 variants showed distinct characteristics, characterized by apical hypertrophy, especially mixed apical hypertrophy, and a lower extent of fibrosis.
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