Novel compound heterozygous ALPK3 mutations (c.4234C>T and c.3491G>A),causing hypertrophic cardiomyopathy treated with the Liwen procedure:case report

Liu Wen Jing¹Yang Hua^2,3Jiao feng hui⁴Hu Hai ying⁵Xu wen juan⁶Wang Ya nan⁷Duan Li ping⁸Zhao Xiu feng⁹Zhang Ren jie¹⁰Chao Chang^11,2*

• ¹19033008716, Hebei, China
• ²Handan First Hospital, Handan, China
• ³15133070861, Hebei, China
• ⁴15132023175, Hebei, China
• ⁵15383204557, Hebei, China
• ⁶15231029024, Hebei, China
• ⁷15232089196, Hebei, China
• ⁸13303205226, Hebei, China
• ⁹13931042570, Hebei, China
• ¹⁰15232068088, Hebei, China
• ¹¹15832092155, hebei, China

Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant 14 cardiovascular disease characterised by myocardial hypertrophy with a prevalence of 15 approximately 0.2-0.5%. Recently, in addition to mutations in genes encoding 16 sarcomeric proteins, which have traditionally been implicated in the development of 17 HCM, mutations in genes encoding non-sarcomeric proteins have also been found to 18 be associated with the development of HCM.This report details the first documented 19 case in China of severe HCM caused by compound heterozygous mutations in the 20 non-sarcomeric proteins Alpha-kinase 3 (ALPK3) gene. 21 Case presentation: This article reports the case of an 18-year-old female patient with 22 HCM, who presented to hospital with sudden transient loss of consciousness while 23 hiking,and the diagnosis was confirmed by echocardiography and genetic testing. 24 Whole exome sequencing revealed a novel compound heterozygous variant in the 25 ALPK3 gene (c.4234C>T nonsense mutation and c.3491G>A missense mutation) in 26 the proband, which was reported for the first time in China. The patient presented 27 with severe myocardial hypertrophy, biventricular involvement, occult biventricular 28 obstruction, simian crease, history of syncope and high risk of sudden death. After 29 ineffective conservative pharmacological treatment, the patient underwent the first 30 international percutaneous intramyocardial septal radiofrequency ablation 31 (PIMSRA,Liwen procedure), which resulted in complete remission of clinical 32 symptoms 6 months after the procedure. It strongly supports the consideration of the 33 Liwen procedure as an effective therapeutic strategy for similar patients harboring 34 pathogenic ALPK3 variants. 35 Conclusions This case suggests that compound heterozygosity for nonsense 36 mutations combined with missense mutations in the ALPK3 gene can lead to 37 early-onset severe HCM, enriches the mutation spectrum of the ALPK3 gene, reveals 38 high frequency mutation sites in exons 4 and 10 specific to East Asian populations, 39 suggesting potential racial genetic heterogeneity, and that the Liwen procedure is a 40 safe and effective treatment for HCM.