|Title||Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Cowan, JR, Kinnamon, DD, Morales, A, Salyer, L, Nickerson, DA, Hershberger, RE|
|Journal||Circ Genom Precis Med|
|Date Published||2018 Jul|
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'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'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.
|Alternate Journal||Circ Genom Precis Med|
|PubMed Central ID||PMC6294440|
|Grant List||M01 RR000334 / RR / NCRR NIH HHS / United States |
R01 HL058626 / HL / NHLBI NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States