Overlapping Phenotype of Adult-Onset ALPK3-Cardiomyopathy in the Setting of Two Novel Variants

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Inherited cardiomyopathies (CMPs) are significant causes of morbidity and mortality, often presenting with overlapping phenotypes that challenge morphological diagnosis.
• Genetic testing is crucial for accurate CMP diagnosis, family screening, prognosis, and personalized treatment strategies.
• Understanding genotype-phenotype correlations, especially for rare genes, is key to deciphering molecular mechanisms and developing targeted therapies.

Observation:

• This study details an adult-onset case with complex cardiomyopathy features, including asymmetric left ventricle hypertrophy, severe systolic dysfunction, hypertrabeculation, and restrictive physiology.
• Next-generation sequencing revealed two novel variants (c.1958C>G:p.Ser653* and c.3491G>A:p.Arg1164Gln) in the alpha-protein kinase 3 (ALPK3) gene.
• The trans-position of these ALPK3 variants was confirmed using plasmid cloning.

Findings:

• Two novel, likely pathogenic, biallelic variants in the ALPK3 gene were identified in a patient with a complex inherited cardiomyopathy phenotype.
• This case adds to the limited clinical data on ALPK3 variant carriers, particularly in adult-onset presentations.
• The identified variants expand the known mutational spectrum of ALPK3 in cardiomyopathies.

Implications:

• This finding contributes to the growing understanding of ALPK3's role in inherited cardiomyopathies.
• Further research into ALPK3 variants can refine diagnostic approaches and inform personalized medicine for affected individuals.
• Expanding the genotype-phenotype correlation for ALPK3 may facilitate the development of targeted therapeutic strategies for this specific form of cardiomyopathy.