Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees

Abstract

Background: We have previously described 19 pedigrees with apparent lamin (LMNA)-related dilated cardiomyopathy (DCM) manifesting in affected family members across multiple generations. In 6 of 19 families, at least one individual with idiopathic DCM did not carry the family’s LMNA variant. We hypothesized that additional genetic cause may underlie DCM in these families. Methods: Affected family members underwent exome sequencing to identify additional genetic cause of DCM in the 6 families with non-segregating LMNA variants. Results: In 5 of 6 pedigrees, we identified at least one additional rare variant in a known DCM gene that could plausibly contribute to disease in the LMNA variant-negative individuals. Bilineal inheritance was clear or presumed to be present in 3 of 5 families and was possible in the remaining two. At least one individual with a LMNA variant also carried a variant in an additional identified DCM gene in each family. Using a multivariate linear mixed model for quantitative traits, we demonstrated that the presence of these additional variants was associated with a more severe phenotype after adjusting for sex, age, and the presence/absence of the family’s non-segregating LMNA variant. Conclusions: Our data support DCM as a genetically heterogeneous disease with, at times, multigene causation. Although the frequency of DCM resulting from multigenic cause is uncertain, our data suggest it may be higher than previously anticipated.

Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young

“…In the same context, Gifford et al (2018) showed that a human congenital heart defect, the left ventricular non-compaction cardiomyopathy, can be caused by a combination of rare, inherited heterozygous missense variants (Gifford et al 2018). Most recently, Cowan et al (2018) demonstrated that additional genetic variants underlie dilated cardiomyopathy in 6 families with non-segregating LMNA pedigrees and support multigenic and bilineal inheritance in these families (Cowan et al 2018). In the light of all these studies and the thorough genetic analysis of the present family, our results provide further evidence of oligogenic pattern of inheritance in complex cardiac disorder such as sudden cardiac death.…”

A rare cause of familial atrioventricular block with a novel LMNA mutation (p. Ala502Val)

“…Dilated cardiomyopathy is one of the most common causes of heart failure and sudden cardiac death in young people [3]. LMNA is one of the most common causal genes of CCD and DCM [4,5].…”

Familial dilated cardiomyopathy with a novel LMNA mutation (p.R429C): a case report

“…Dilated cardiomyopathy is one of the most common causes of heart failure and sudden cardiac death in adolescents. 3 Different genetic mutations may result in different onset ages and severity of dilated cardiomyopathy. Lamins A and C, encoded by LMNA gene, are nuclear intermediate filament proteins that form one of the major structural components of the lamina network, which underlies and mechanically supports the nuclear envelope.…”