Genetic variant burden and adverse outcomes in pediatric cardiomyopathy.
Genetic variant burden and adverse outcomes in pediatric cardiomyopathy.
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DOI：
10.1038/s41390-020-1101-5
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发表时间：
2021-05
影响因子：
3.6
通讯作者：
Ahrens-Nicklas RC
中科院分区：
文献类型：
--
作者：
Burstein DS;Gaynor JW;Griffis H;Ritter A;Connor MJO;Rossano JW;Lin KY;Ahrens-Nicklas RC
以前在小儿心肌病（CM）的遗传学研究集中在诊断目的的致病性变异，有限的数据评估基因型结果的相关性。我们探讨了更大的遗传变异负担（致病性或未知意义的变异，VUS）是否与更差的结局相关。纳入了2010年至2018年期间接受多基因检测的扩张型CM [DCM]和肥厚型CM [HCM]儿童。复合终点为无主要不良心脏事件（MACE）。纳入了338例受试者[49% DCM，中位年龄5.7（IQR 0.2-13.4）岁，51% HCM，中位年龄3.0（IQR 0.1-12.5）岁]。在任一队列中，单独的致病性变体与MACE无关（DCM p=0.44; HCM p=0.46）。在DCM中，单独VUS（OR 4.0，95% CI 1.9-8.3）和除致病性变体（OR 5.2，95% CI 1.7-15.9）外的VUS与MACE相关。单独存在VUS或VUS与致病性变异的存在与HCM的MACE无关（分别为p=0.22和p=0.33）。遗传变异负担（致病性和VUS）增加与扩张型心肌病（DCM）的临床结局较差相关，但与肥厚型心肌病（HCM）无关。影响DCM发作的基因组变异可能与驱动疾病进展的基因组变异不同，这突出了通用基因检测对改善风险分层的潜在价值。
Previous genetic research in pediatric cardiomyopathy (CM) has focused on pathogenic variants for diagnostic purposes, with limited data evaluating genotype-outcome correlations. We explored whether greater genetic variant burden (pathogenic or variants of unknown significance, VUS) correlates with worse outcomes. Children with dilated CM [DCM] and hypertrophic CM [HCM] who underwent multigene testing between 2010 and 2018 were included. Composite endpoint was freedom from major adverse cardiac event (MACE). 338 subjects were included [49% DCM, median age 5.7 (IQR 0.2–13.4) yrs, 51% HCM, median age 3.0 (IQR 0.1–12.5) yrs]. Pathogenic variants alone were not associated with MACE in either cohort (DCM p=0.44; HCM p=0.46). In DCM, VUS alone (OR 4.0, 95% CI 1.9–8.3) and in addition to pathogenic variants (OR 5.2, 95% CI 1.7–15.9) was associated with MACE. Presence of VUS alone or in addition to pathogenic variants were not associated with MACE in HCM (p=0.22 and p=0.33, respectively). Increased genetic variant burden (pathogenic and VUS) is associated with worse clinical outcomes in DCM but not HCM. Genomic variants that influence DCM onset may be distinct from those driving disease progression, highlighting the potential value of universal genetic testing to improve risk stratification.
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DOI：
10.1016/j.jtcvs.2015.09.136
发表时间：
2016-04
期刊：
The Journal of thoracic and cardiovascular surgery
影响因子：
--
作者：
Kim DS;Kim JH;Burt AA;Crosslin DR;Burnham N;Kim CE;McDonald-McGinn DM;Zackai EH;Nicolson SC;Spray TL;Stanaway IB;Nickerson DA;Heagerty PJ;Hakonarson H;Gaynor JW;Jarvik GP
通讯作者：
Jarvik GP
影响因子：
8.9
作者：
Cuenca, Sofia;Ruiz-Cano, Maria J.;Garcia-Pavia, Pablo
通讯作者：
Garcia-Pavia, Pablo
影响因子：
4.8
作者：
Blue, Gillian M.;Ip, Eddie;Winlaw, David S.
通讯作者：
Winlaw, David S.
影响因子：
4.6
作者：
Kim, Daniel Seung;Kim, Jerry H.;Jarvik, Gail P.
通讯作者：
Jarvik, Gail P.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G