A novel compound heterozygous variant in ALPK3 induced hypertrophic cardiomyopathy: a case report

Abstract

Background: Malignant hypertrophic cardiomyopathy (HCM) phenotypes have potential risks of severe heart failure, fatal arrhythmia, and sudden cardiac death. Therefore, it is critical to predict the clinical outcomes of these patients. It was reported recently that the alpha kinase 3 (ALPK3) gene was involved in the occurrence of HCM. Herein we reported a girl with HCM, while whole-exome sequencing found novel compound heterozygous variants in ALPK3 gene, which identified a potential association.

Case presentation: We reported a 14-year-girl who suffered from clinical manifestations of cardiac failure, with sudden cardiac arrest before admission. The heartbeat recovered after cardiopulmonary resuscitation, though she remained unconscious without spontaneous breath. The patient stayed comatose when she was admitted. Physical examination indicated enlargement of the heart boundary. Laboratory results revealed a significant increment of myocardial markers, while imaging demonstrated hypertrophy of the left heart and interventricular septum. Whole-exome sequencing (WES) identified a compound heterozygous variant in ALPK3 gene consisting of c.3907_3922del and c.2200A>T, which was inherited from her parents. Both variants (p.G1303Lfs*28 and p.R734*) were disease-causing evaluated by MutationTaster (probability 1.000). The crystal structure of the complete amino acid sequence is predicted and evaluated by AlphaFold and SWISS-MODEL software (July, 2022), which revealed three domains. Moreover, both variants resulted in a wide protein-truncating variant and damaged protein function. Thus, a novel compound heterozygous variant in ALPK3 associated with HCM was diagnosed.

Conclusion: We described a young patient with ALPK3-associated HCM who experienced sudden cardiac arrest. Through WES, we identified a compound heterozygous variant in the ALPK3 gene, c.3907_3922del and c.2200A>T, which were inherited from the patient's parents and resulted in a truncated protein, indirectly causing the symptoms of HCM. In addition, WES provided clues in evaluating potential risks of gene variants on fatal clinical outcomes, and the nonsense and frameshift variants of ALPK3 were related to adverse clinical outcomes in HCM patients, which required implantable cardioverter defibrillator (ICD) timely.

Keywords: ALPK3; case report; hypertrophic cardiomyopathy; novel variant; whole-exome sequencing.

Figure 1

Radiology manifestation in the current proband. (A) Electrocardiographic examination demonstrated right axis deviation, enlargement of bi-ventricles and ventricular escape (arrow). (B) Cardiac magnetic resonance (CMR) demonstrated diffuse hypertrophy of ventricular myocardium, T2-weighting imaging revealed abnormal signal intensity of left ventricular subendocardial myocardium. (C) Transthoracic echocardiography (TTE) demonstrated significant hypertrophy of left ventricle and the interventricular septum.

Figure 2

The ALPK3 variants in this family. (A) Family pedigree revealed the maternal carrier of c.3907_3922del (p.G1303Lfs*28) and the paternal carrier of c.2200A>T (p.R734*). The current proband exhibited significant hypertrophic cardiomyopathy with compound heterozygous variants of ALPK3. circles represent females, squares represent males, and arrow indicates the proband. Black symbols indicate the clinical presentation of hypertrophic cardiomyopathy, grey symbols indicate carriers. (B) Sanger sequencing validation of the current proband and his parents. (C) The prevalence of ALPK3 variants of c.3907_3922del and c.2200A>T. (D) Summary of current reports on individual ALPK3 variants resulting in hypertrophic cardiomyopathy.

Figure 3

The effects of ALPK3 c.3907_3922delGGCCTCCTGGGGGCCT and c.2200A>T variants on the molecular structure of the protein. (A) AlphaFold protein structure database was used to predict the ALPK3 wild-type protein crystal structure. (B) Three domains of ALPK3 protein were labeled in red, green and orange individually. SWISS-MODEL presented the crystal structures of the variant's three domains, including two immunoglobulin-like (Ig-like) domains and an alpha-type protein kinase domain according to 6c6m.2.A, 3uto.2.A, and 1ia9.1.A model template. Ramachandran plots of three functional domains in wild-type sequences were displayed. (C,D) Truncating variant sites of p.G1303Lfs*28 and p.R734* caused by variants of c.3907_3922delGGCCTCCTGGGGGCCT and c.2200A>T was labelled in yellow.