@article {527, title = {Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 Jul}, pages = {e002038}, abstract = {

BACKGROUND: We have previously described 19 pedigrees with apparent lamin ()-related dilated cardiomyopathy (DCM) manifesting in affected family members across multiple generations. In 6 of 19 families, at least 1 individual with idiopathic DCM did not carry the family{\textquoteright}s 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 nonsegregating variants.

RESULTS: In 5 of 6 pedigrees, we identified at least 1 additional rare variant in a known DCM gene that could plausibly contribute to disease in the variant-negative individuals. Bilineal inheritance was clear or presumed to be present in 3 of 5 families and was possible in the remaining 2. At least 1 individual with a 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{\textquoteright}s nonsegregating 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.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.117.002038}, author = {Cowan, Jason R and Kinnamon, Daniel D and Morales, Ana and Salyer, Lorien and Nickerson, Deborah A and Hershberger, Ray E} }