Case Presentation: A 41-year-old man with end-stage renal disease (ESRD), hypertension, hyperlipidemia, and hepatitis B-induced liver cirrhosis was evaluated after a computed tomography (CT) scan of his abdomen revealed an unexpected finding of cardiomegaly with moderate to large pericardial effusion. Subsequent transthoracic echocardiograms revealed moderate pericardial effusion without tamponade physiology but with increased interventricular septal and posterior wall thickness. The left ventricular outflow gradient was noted to be 41 mm, and the left ventricular ejection fraction was 55-60%. Further evaluation through cardiac magnetic resonance imaging confirmed a diagnosis of concentric hypertrophic cardiomyopathy (HCM), characterized by a maximum wall thickness of 2.0 cm in the septum. The left ventricular outflow tract systolic obstruction was attributed to a combination of systolic anterior motion and septal thickening. In subsequent outpatient cardiology follow-up, a genetic panel was ordered, and the patient was found to be heterozygous for two genetic variants: p.R3679Q (c.11036G>A) variant in the ALMS1 gene and p.T1643K (c.4928C>A) variant in the ALPK3 gene.
Discussion: While there are several known factors that can contribute to HCM, approximately 60% of cases in adolescents and adults are attributed to genetic factors. (1) We present a rare case of adult-onset hypertrophic cardiomyopathy associated with a heterozygous ALPK3 variant. Genetic testing is often considered upon the diagnosis of hypertrophic cardiomyopathy for purposes such as determining family members at risk, aiding in prenatal family planning, identifying associated syndromes like Fabry disease, and sometimes for confirmation of clinical diagnosis. (2) In contrast to well-studied genes like MYBPC3 and MYH7, which are commonly associated with HCM, ALPK3 is rare and understudied. Heterozygous ALPK3 variants are often classified as of unknown significance; nevertheless, recent studies have made substantial contributions on understanding the gene’s implications. A 2022 study by Dai et al. found that in 793 East Asian HCM cases, both missense and truncating heterozygous variants in ALPK3 were linked to HCM compared to controls. ALPK3 carriers displayed more severe hypertrophy in the interventricular septum, apex and greater maximal left ventricular wall thickness. (3) Herkert et al. found rare ALPK3 variants in 39 out of 1548 Dutch HCM patients and 15 out of 149 HCM U.S. patients. (4) Almomani et al. also emphasized the need for periodic screening in individuals with ALPK3 heterozygous mutations due to an increased risk of cardiomyopathy. (5)
Conclusions: The ALPK3 gene, which plays a significant role in cardiac function and pathologic remodeling, can be substantial in understanding the interplay of genetic factors in the pathology of hypertrophic cardiomyopathy. Given the rarity of ALPK3 mutations in HCM in the setting of limited research, further studies are crucial to establish causality and determine the need for screening and genetic counseling for both the patients and at-risk family members.