Abstract
RATIONALE: Hypertrophic cardiomyopathy (HCM) is a prototypic single-gene disease caused mainly by mutations in genes encoding sarcomere proteins. Despite the remarkable advances, the causal genes in ≈40% of the HCM cases remain unknown, typically in small families and sporadic cases, wherein cosegregation could not be established. OBJECTIVE: To test the hypothesis that the missing causal genes in HCM is, in part, because of an oligogenic cause, wherein the pathogenic variants do not cosegregate with the phenotype. METHODS AND RESULTS: A clinically affected trio with HCM underwent clinical evaluation, electrocardiography, echocardiography, magnetic resonance imaging, and whole exome sequencing. Pathogenic variants in the whole exome sequencing data were identified using established algorithms. Family members were genotyped by Sanger sequencing and cosegregation was analyzed. The siblings had a severe course, whereas the mother had a mild course. Variant analysis showed that the trio shared 145 heterozygous pathogenic variants in 139 genes, including 2 in cardiomyopathy genes TTN and ALPK3. The siblings also had the pathogenic variant p.Ala13Thr variant in MYL2, a known gene for HCM. The sibling's father also carried the p.Ala13Thr variant, in whom an unambiguous diagnosis of HCM could not be made because of concomitant severe aortic stenosis. The TTN variant segregated with HCM, except in a 7-year-old boy, who had a normal phenotype. The ALPK3 variant, shared by the affected trio, did not segregate with the phenotype. CONCLUSIONS: We posit that a subset of HCM might be oligogenic caused by multiple pathogenic variants that do not perfectly cosegregate with the phenotype.