Cardiac Phenotype Characterization at MRI in ALPK3 Associated Hypertrophic Cardiomyopathy

Lutong Pu; Jie Wang; Mengdi Yu; Yuanwei Xu; Ke Wan; Jiajun Guo; Yangjie Li; Yuchi Han; Yucheng Chen

doi:10.1016/j.jocmr.2025.101930

Cardiac Phenotype Characterization at MRI in ALPK3 Associated Hypertrophic Cardiomyopathy

J Cardiovasc Magn Reson. 2025 Jun 26:101930. doi: 10.1016/j.jocmr.2025.101930. Online ahead of print.

Authors

Lutong Pu¹, Jie Wang², Mengdi Yu¹, Yuanwei Xu³, Ke Wan⁴, Jiajun Guo³, Yangjie Li¹, Yuchi Han⁵, Yucheng Chen⁶

Affiliations

¹ Department of Cardiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
² Department of Cardiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, B15 2TT, UK; Cardiac Imaging and Target Therapy Lab, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
³ Department of Cardiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Cardiac Imaging and Target Therapy Lab, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
⁴ Department of Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
⁵ Cardiovascular Division, Wexner Medical Center, The Ohio State University, USA.
⁶ Department of Cardiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Cardiac Imaging and Target Therapy Lab, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: chenyucheng2003@163.com.

PMID: 40581189
DOI: 10.1016/j.jocmr.2025.101930

Abstract

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.

Objectives: To evaluate the prevalence of heterozygous ALPK3 variants in adult patients with HCM through whole-exome sequencing, and to elucidate the phenotypes of individuals harboring these variants.

Methods: Consecutive 575 patients diagnosed with HCM who underwent 3 Tesla cardiac magnetic resonance imaging (CMR) 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% 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% vs. 20.2%, P < 0.001) and a lower fibrosis burden, with a 2-fold reduction in the incidence of extensive fibrosis (≥15% left ventricle [LV] mass: 8.1% vs. 14.7%, P < 0.001). Patients with single ALPK3 variants were more likely to present with apical HCM (ApHCM; 80.0% vs. 35.3%, 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% vs. 55.2% vs. 14.3%, 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% [six/7] vs. 41.6% [ten/24] vs. 50% [two/4]) than those with MYBPC3 or MYH7 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.

Keywords: ALPK3; Genetics; Heterozygote variant; Hypertrophic Cardiomyopathy.