Whole-exome sequencing identifies novel truncating ALPK3 variants in a compound heterozygous state associated with pediatric hypertrophic cardiomyopathy and phenotypic heterogeneity.

Background: Pathogenic biallelic variants in ALPK3 are associated with recessively inherited early-onset and severe cardiomyopathies in children, often accompanied by extracardiac manifestations such as facial deformities and skeletal malformations. However, the number of reported cases remains limited. In this study, we report two additional pediatric patients with hypertrophic cardiomyopathy (HCM) having (likely) pathogenic heterozygous ALPK3 variants in a compound heterozygous state, together with a comprehensive review of the literature.

Methods: Whole-exome sequencing (WES) was performed to identify potential genetic causes of cardiomyopathy in the patients. Candidate variants were confirmed by Sanger sequencing in the patients and their parents to determine segregation patterns. Clinical evaluations, including echocardiography and physical examinations, were conducted to assess both cardiac and extracardiac features.

Results: Patient 1, a 6-year-old girl, presented with HCM, short stature, webbed neck, joint contractures, pectus carinatum, and scoliosis. Patient 2, a 3-year-old boy, was diagnosed with HCM and exhibited reduced left ventricular systolic function and short stature. Genetic analysis identified novel (likely) pathogenic truncating variants in ALPK3 in a compound heterozygous state: c.109del, p.(R37Gfs*72) and c.2757dup, p.(T920Hfs*14) in patient 1; and c.3272del, p.(G1091Vfs*43) and c.3517A > T, p.(R1173*) in patient 2. Segregation analysis via Sanger sequencing confirmed that each pair of variants was inherited in trans from unaffected parents, consistent with a compound heterozygous configuration.

Conclusion: We report two pediatric HCM cases with novel ALPK3 variants, expanding the genetic and phenotypic spectrum of ALPK3-associated cardiomyopathies. These findings enhance our understanding of genotype-phenotype correlations and underscore the importance of genetic testing, comprehensive cardiac evaluation, and long-term follow-up for patients with ALPK3-related cardiomyopathy.