Novel ALPK3 variants cause infantile and late onset hypertrophic cardiomyopathy in a single family

Background/Objectives: Cardiomyopathies are clinically heterogeneous disorders that impair heart function and are the leading cause of cardiovascular morbidity and mortality in both children and adults. Of these, hypertrophic cardiomyopathy (HCM) characterized by increased left ventricular wall thickness and dilated cardiomyopathy (DCM) displaying ventricular dilatation, are most common. Alpha-protein kinase 3 (ALPK3) plays an essential role in sarcomere organization. Its mutations have been recently reported to be causative of the recessively inherited severe pediatric-onset DCM and HCM, accompanied by skeletal involvement and facial dysmorphism, as well as of the dominantly inherited adult-onset cardiomyopathy. We have ascertained kindred with multiple family members affected by infantile or late onset cardiomyopathy and aimed to elucidate the genetic basis of cardiomyopathy in the affected individuals.

Methods: The family members underwent clinical assessment and genotyping using whole-exome sequencing and Sanger sequencing.
Results: Compound heterozygosity for two novel variants in ALPK3 has been identified in two identical twin sisters, with severe infantile onset HCM and facial dysmorphism. Both their father and grandfather died by sudden death at young age, without specific diagnosis. Their uncle was diagnosed with adult-onset cardiomyopathy at the age of 56, and has been found to be heterozygous for the truncating ALPK3 variant, identified in both of his nephews.
Conclusion: We report two novel variants in ALPK3 in a kindred with individuals affected by both infantile onset and adult onset cardiomyopathy, and provide additional evidence for the reported phenotypic spectrum of ALPK3-related cardiac disease.