A Potential Oligogenic Etiology of Hypertrophic Cardiomyopathy, A Classic Single Gene Disorder
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 about 40% of the HCM cases remain unknown, typically in small families and sporadic cases, wherein co-segregation could not be established.
Objective: To test the hypothesis that the "missing causal genes" in HCM is, in part, because of an oligogenic etiology, wherein the pathogenic variants do not co-segregate with the phenotype.
Methods and Results: A clinically affected trio with HCM underwent clinical evaluation, electrocardiography, echocardiography, magnetic resonance imaging, and whole exome sequencing (WES). Pathogenic variants in the WES data were identified using established algorithms. Family members were genotyped by Sanger sequencing and co-segregation was analyzed. The siblings had a severe course while the mother had a mild course. Variant analysis showed that the trio shared 145 heterozygous pathogenic variants in 139 genes, including two 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 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 co-segregate with the phenotype.
- Received December 31, 2016.
- Revision received February 16, 2017.
- Accepted February 21, 2017.