Dataset Information

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

ABSTRACT:

Aims

The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.

Methods and results

In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.

Conclusions

Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

SUBMITTER: Lopes LR

PROVIDER: S-EPMC8380059 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

Lopes Luis R LR Garcia-Hernández Soledad S Lorenzini Massimiliano M Futema Marta M Chumakova Olga O Zateyshchikov Dmitry D Isidoro-Garcia Maria M Villacorta Eduardo E Escobar-Lopez Luis L Garcia-Pavia Pablo P Bilbao Raquel R Dobarro David D Sandin-Fuentes Maria M Catalli Claudio C Gener Querol Blanca B Mezcua Ainhoa A Garcia Pinilla Jose J Bloch Rasmussen Torsten T Ferreira-Aguar Ana A Revilla-Martí Pablo P Basurte Elorz Maria Teresa MT Bautista Paves Alicia A Ramon Gimeno Juan J Figueroa Ana Virginia AV Franco-Gutierrez Raul R Fuentes-Cañamero Maria Eugenia ME Martinez Moreno Marina M Ortiz-Genga Martin M Piqueras-Flores Jesus J Analia Ramos Karina K Rudzitis Ainars A Ruiz-Guerrero Luis L Stein Ricardo R Triguero-Bocharán Mayte M de la Higuera Luis L Ochoa Juan Pablo JP Abu-Bonsrah Dad D Kwok Cecilia Y T CYT Smith Jacob B JB Porrello Enzo R ER Akhtar Mohammed M MM Jager Joanna J Ashworth Michael M Syrris Petros P Elliott David A DA Monserrat Lorenzo L Elliott Perry M PM

European heart journal 20210801 32

<h4>Aims</h4>The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.<h4>Methods and results</h4>In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Geno ...[more]

PMID: 34263907

Similar Datasets

Project description:BackgroundMalignant 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 presentationWe 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.ConclusionWe 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.

Dataset Information

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

Aims

Methods and results

Conclusions

Publications

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

Similar Datasets

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