Phenotypic spectrum of ALPK3-related cardiomyopathy

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Cardiomyopathies are a major cause of cardiovascular disease.
• Alpha-kinase 3 (ALPK3) gene variants are newly identified causes of early-onset pediatric cardiomyopathy.
• Previous reports documented eight patients with biallelic ALPK3 pathogenic variants.

Purpose of the Study:

• To characterize the molecular and clinical phenotype of familial cardiomyopathy caused by ALPK3 variants.
• To expand the understanding of ALPK3-associated cardiomyopathy beyond early childhood onset.
• To investigate the genotype-phenotype correlation in a family with six affected individuals.

Main Methods:

• Genetic sequencing to identify ALPK3 variants.
• Clinical evaluation of affected individuals.
• Phenotypic characterization including echocardiography and medical history.

Main Results:

• Identified homozygosity for a deleterious ALPK3 sequence variant (NM_020778.4:c.639G>A:p.Trp213*) in six family members.
• Observed phenotypes including dilated cardiomyopathy progressing to hypertrophic cardiomyopathy (HCM) and HCM with left ventricular noncompaction.
• Demonstrated presentation from infancy to the fourth decade, with decreasing severity correlating with age.

Conclusions:

• Biallelic ALPK3 loss-of-function variants cause a spectrum of cardiomyopathies with variable age of onset.
• The phenotypic presentation of ALPK3-associated cardiomyopathy is broader than previously recognized.
• ALPK3 variants represent a significant genetic cause of familial cardiomyopathy across a wide age range.