ALPK3 Truncating Variants Cause Autosomal Dominant Hypertrophic Cardiomyopathy

In hypertrophic cardiomyopathy, heart muscles are thicker, which can make it harder for the heart to receive and pump blood. While in most cases the condition will not affect daily life, it can cause heart failure and is frequently cited as the most common cause of sudden unexpected death in young people.

Hypertrophic cardiomyopathy (HCM) is a genetic condition caused by a change or mutation in one or more genes and is passed on through families. A child of someone with HCM has a 50% chance of inheriting the condition. Most people with HCM have no symptoms or feel stable throughout their life. However, others do have symptoms. Some people find that their symptoms worsen in later life. This may be because their heart muscle has slowly become stiffer, making it harder for the heart to pump.


A large team of international scientists led by those at the University College London (London, UK) analyzed the genomes of 2,817 people with hypertrophic cardiomyopathy referred from centers in Spain, the UK, Denmark, Russia, Latvia, Brazil, and Argentina. The discovery cohort comprised 770 consecutively evaluated unrelated patients with HCM. The aim of their study was to determine the frequency of heterozygous truncating alpha-protein kinase (ALPK3) variants (ALPK3tv) in patients with HCM and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.

From 2018 to 2020, ALPK3 was sequenced using next-generation sequencing in 4,904 consecutive unrelated probands with inherited cardiac conditions referred for molecular genetic diagnosis. Coding exons and intronic boundaries of 261 genes related to inherited cardiovascular diseases and sudden cardiac death (SCD) were captured using a custom probe library using the SureSelect Target Enrichment Kit for Illumina paired-end multiplexed sequencing method, (Agilent Technologies, Santa Clara, CA, USA), and sequenced using the HiSeq 1500 platform (Illumina, San Diego, CA, USA).

The investigators reported that in a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio (OR) 16.11) compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2,047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17). In comparison with a cohort of 1,679 genotyped patients with HCM with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%) and of a short PR interval (10%).

Luis R. Lopes, MD, PhD, a Consultant Cardiologist and the lead author of the study, said, “Hypertrophic cardiomyopathy is an extremely common genetic condition. Earlier, small-scale studies suggested that variants in the ALPK3 gene could be a cause of a rare pediatric form of cardiomyopathy, but only when two abnormal copies were inherited. We have now proved that just one abnormal copy is enough to cause hypertrophic cardiomyopathy in adults, looking at a large number of patients and families. This form of inheritance (autosomal dominant) is much more prevalent, as inheriting just one abnormal copy of a gene is more likely than inheriting two. Identifying a new genetic cause is important as it opens up new possibilities for potential treatment. It also helps families who have been affected by the condition, but who did not know why, to know that a cause has been found for their specific case.” The study was published on August 21 2021 in the European Heart Journal.

Related Links:
University College London
Agilent Technologies
Illumina