Abstract 15640: A Digenic Etiology Implicates Alpk3 and Myl2 Variants as Likely Causal Mutations in Familial Hypertrophic Cardiomyopathy
Introduction: Familial Hypertrophic Cardiomyopathy (FHCM) is an autosomal dominant single gene disorder, commonly caused by mutations in genes encoding sarcomere proteins. Despite genetic testing by whole exome sequencing (WES), the causal genes in approximately 40% of the FHCM remain unknown.
Hypothesis: A subset of FHCM is digenic in etiology and hence, the affected individual do not share a single causal variant.
Methods: WES of FHCM trios, rare variant analysis and sequencing of additional family members.
Results: We identified 6 FHCM trios in whom WES did not identify a shared causal variant in the known FHCM genes. The WES data were filtered for the heterozygous Loss of Function (LoF), defined as stop gain/loss, splice and frameshift, variants and rare pathogenic missense (MAF<0.01) variants, followed by analysis of expression in the heart. Dozens of LoF variants and pathogenic variants were shared among the affected members of each trio. Notably, a rare pathogenic (p.T81M) variant in the ALPK3 gene, implicated in cardiomyopathies, was shared among the affected trios (mother and two offspring). The offspring but not the mother also shared a pathogenic variant (p.A13T) in the MYL2 gene, a known gene for FHCM. The p.A13T variant was inherited from siblings father, who had cardiac hypertrophy and aortic stenosis. Siblings digenic for the p.A13T and p.T81M variants had severe FHCM, heart failure, and severe left ventricular outflow tract obstruction (mean gradient >100 mmHg). In contrast, family members with the ALPK3 variant had no or mild cardiac hypertrophy and were asymptomatic. The trio also shared other rare LoF and pathogenic variants, including a p.E2272X variant in COL6A5 and p.L1228I variant in PPRC1, which are expressed at low levels in the heart and were less likely to cause cardiac pathology.
Conclusions: Rare variant analysis of the WES data in the affected FHCM trios with no shared pathogenic variants in the known FHCM genes led to identification of pathogenic variants in ALKP3 and MYL2 as the likely causal variants. The findings suggest that a subset of FHCM might be digenic in etiology. Thus, the “missing causal genes” in the conventionally considered single gene disorders might be in part due to a digenic etiology.
Author Disclosures: L. Li: None. Y. Tan: None. J.T. Willerson: None. A.J. Marian: None.
- © 2016 by American Heart Association, Inc.