Oligogenic Inheritance in Dilated Cardiomyopathy is Illustrated in Non-segregating Lamin A/C (LMNA) Pedigrees

Introduction: We and others have proposed that, unlike many Mendelian diseases of monogenic cause, 20-30% of dilated cardiomyopathy (DCM) may be attributed to an oligogenic model wherein disease risk is modified by rare variants in multiple genes. Next to titin ( TTN ) truncating variants, variants in lamin A/C ( LMNA ) are the largest single genetic contributor to DCM, accounting for ~5-10% of familial and ~2-5% of non-familial cases. We have previously described 19 multiplex families with LMNA -related DCM. In six of these families (32%) at least one individual with idiopathic DCM (IDC) did not carry the causal LMNA variant (termed a non-segregating pedigree) even though nuclear imaging of lamin localization supported a pathogenic effect. Hypothesis: We hypothesized that additional causative genetic factors in these families may underlie DCM observed in LMNA mutation-negative individuals. Methods: Affected family members underwent exome sequencing to identify additional genetic causes of DCM. Results: In five of six pedigrees, we identified a second rare variant plausibly accounting for disease in the LMNA mutation-negative individuals. These rare variants were identified in BAG3 , NEXN , PLN , RBM20 , and TTN , all of which have been previously identified as genes relevant for DCM. Bilineal inheritance was observed or inferred from pedigree structure in three of the six families. At least one individual with a LMNA variant also carried a variant in the second identified gene in each of the multi-gene families. Double carrier status in all affected patients resulted in advanced disease involving DCM-related mortality or advanced therapies such as heart transplant. While clinical impact on single-variant carriers varied more widely by both family and individual, pedigree structures supported an oligogenic disease model. Conclusions: Our data support DCM as a genetically heterogeneous disease where disease risk may be modified simultaneously by multiple genes at a frequency higher than previously anticipated.