期刊
CIRCULATION-GENOMIC AND PRECISION MEDICINE
卷 11, 期 7, 页码 -出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGEN.117.002038
关键词
cardiomyopathy, dilated; exome sequencing; genetics; inheritance patterns; lamin type A; multifactorial inheritance; pedigree
资金
- National Institutes of Health [RO1 HL58626, 5 M01 RR000334]
- National Human Genome Research Institute
- National Heart, Lung and Blood Institute grant [HG006493]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL058626] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [UM1HG006493] Funding Source: NIH RePORTER
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 1 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 nonsegregating LMNA 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 LMNA 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 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 nonsegregating 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据