AUTHOR=Dai Jiaqi , Li Ke , Huang Man , Sun Yang , Liu Hao , Li Zongzhe , Chen Peng , Wang Hong , Wu Dongyang , Chen Yanghui , Xiao Lei , Wei Haoran , Li Rui , Peng Liyuan , Yu Ting , Wang Yan , Wang Dao Wen 

TITLE=The Involvement of ALPK3 in Hypertrophic Cardiomyopathy in East Asia

JOURNAL=Frontiers in Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.915649

DOI=10.3389/fmed.2022.915649

ISSN=2296-858X

ABSTRACT=<sec><title>Objective</title><p><italic>ALPK3</italic> is associated with a recessive form of pediatric cardiomyopathy accompanied by musculoskeletal and craniofacial abnormalities. Heterozygous truncating variants in this gene (<italic>ALPK3</italic>tv) have recently been confirmed as a cause of autosomal dominant hypertrophic cardiomyopathy (HCM). Whether <italic>ALPK3</italic> is also implicated in HCM in East Asia and the effect of missense variants in <italic>ALPK3</italic> on HCM remains unresolved.</p></sec><sec><title>Methods</title><p>We compared the frequency of rare deleterious variants in <italic>ALPK3</italic> in a study cohort comprised of 793 HCM cases of East Asian descent to that in the controls subset of Genome Aggregation Database (gnomAD). Gene burden test was used to assess this association. The involvement of these variants in HCM was further validated by independent cohort. The clinical characteristics and prognoses of these carriers were compared with sarcomere-positive and negative patients.</p></sec><sec><title>Results</title><p>Rare deleterious variants in <italic>ALPK3</italic> were significantly enriched in HCM compared with gnomAD controls (truncating: 4/793 vs. 4/4523, <italic>P</italic> = 0.02; missense: 25/793 vs. 46/4523, <italic>P</italic> = 2.56e-5). Replication in an independent cohort provided more supporting evidence. Further comparisons revealed that <italic>ALPK3</italic> carriers displayed more severe hypertrophy in interventricular septum (IVS) and apex, as well as greater maximal left ventricular wall thickness, relative to sarcomere negatives.</p></sec><sec><title>Conclusion</title><p>Heterozygous rare variants in <italic>ALPK3</italic>, both missense and truncating variants, are associated with HCM in East Asians.</p></sec>