Novel compound heterozygous ALPK3 mutations (c.4234C>T and c.3491G>A), causing hypertrophic cardiomyopathy treated...

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant cardiovascular disease characterised by myocardial hypertrophy with a prevalence of approximately 0.2%-0.5%. Recently, in addition to mutations in genes encoding sarcomeric proteins, which have traditionally been implicated in the development of HCM, mutations in genes encoding non-sarcomeric proteins have also been found to be associated with the development of HCM.This report details the first documented case in China of severe HCM caused by compound heterozygous mutations in the non-sarcomeric proteins Alpha-kinase 3 (ALPK3) gene.

This article reports the case of an 18-year-old female patient with HCM, who presented to hospital with sudden transient loss of consciousness while hiking,and the diagnosis was confirmed by echocardiography and genetic testing. Whole exome sequencing revealed a novel compound heterozygous variant in the ALPK3 gene (c.4234C > T nonsense mutation and c.3491G > A missense mutation) in the proband, which was reported for the first time in China. The patient presented with severe myocardial hypertrophy, biventricular involvement, occult biventricular obstruction, simian crease, history of syncope and high risk of sudden death. After ineffective conservative pharmacological treatment, the patient underwent the first international percutaneous intramyocardial septal radiofrequency ablation (PIMSRA, Liwen procedure), which resulted in complete remission of clinical symptoms 6 months after the procedure. It strongly supports the consideration of the Liwen procedure as an effective therapeutic strategy for similar patients harboring pathogenic ALPK3 variants.

This case suggests that compound heterozygosity for nonsense mutations combined with missense mutations in the ALPK3 gene can lead to early-onset severe HCM, enriches the mutation spectrum of the ALPK3 gene, reveals high frequency mutation sites in exons 4 and 10 specific to East Asian populations, suggesting potential racial genetic heterogeneity, and that the Liwen procedure is a safe and effective treatment for HCM.