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De novo variants in exomes of congenital heart disease patients identify risk genes and pathways

先天性心脏病患者外泌体的新生变异识别风险基因和通路

  • 影响因子:8.02
  • DOI:10.1186/s13073-019-0709-8
  • 作者列表:"Cigdem Sevim Bayrak","Peng Zhang","Martin Tristani-Firouzi","Bruce D. Gelb","Yuval Itan
  • 发表时间:2020-01-19
Abstract

Abstract Background Congenital heart disease (CHD) affects ~ 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently. De novo variants are estimated to contribute to approximately 8% of sporadic CHD. Methods CHD is genetically heterogeneous, making pathway enrichment analysis an effective approach to explore and statistically validate CHD-associated genes. In this study, we performed novel gene and pathway enrichment analyses of high-impact de novo variants in the recently published whole-exome sequencing (WES) data generated from a cohort of CHD 2645 parent-offspring trios to identify new CHD-causing candidate genes and mutations. We performed rigorous variant- and gene-level filtrations to identify potentially damaging variants, followed by enrichment analyses and gene prioritization. Results Our analyses revealed 23 novel genes that are likely to cause CHD, including HSP90AA1, ROCK2, IQGAP1, and CHD4, and sharing biological functions, pathways, molecular interactions, and properties with known CHD-causing genes. Conclusions Ultimately, these findings suggest novel genes that are likely to be contributing to CHD pathogenesis.

摘要

【摘要】背景先天性心脏病 (CHD) 影响了约 1% 的活产婴儿,是最常见的出生缺陷。虽然遗传因素对 CHD 的贡献一直被怀疑,但直到最近才被很好地确立。De novo 变异估计导致约 8% 的散发性 CHD。方法 CHD 具有遗传异质性,使通路富集分析成为探索和统计验证 CHD 相关基因的有效方法。在这项研究中,我们在最近发表的全外显子组测序 (WES) 中对高影响的从头变异体进行了新的基因和通路富集分析从 CHD 2645 亲代三联体队列中产生的数据,以确定新的导致 CHD 的候选基因和突变。我们进行了严格的变异和基因水平过滤,以确定潜在的破坏性变异,然后进行富集分析和基因优先排序。结果我们的分析揭示了 23 个可能导致 CHD 的新基因,包括 HSP90AA1 、 ROCK2 、 IQGAP1 和 CHD4,并共享生物学功能、通路、分子相互作用, 和已知 CHD 致病基因的特性。结论最终,这些发现提示可能有助于 CHD 发病的新基因。

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影响因子:1.65
发表时间:2020-01-13
来源期刊:Nursing research
DOI:10.1097/NNR.0000000000000415
作者列表:["Rodriguez J","Adams-Chapman I","Affuso O","Azuero A","Downs CA","Turner-Henson A","Rice M"]

METHODS:BACKGROUND:Preterm birth is a risk factor for elevated blood pressure in childhood and the development of hypertension and cardiometabolic disease in adulthood; however, mechanisms for the development of both are poorly understood. Rapid weight gain early in childhood may serve as a driver directly and indirectly through cortisol levels found to be elevated in early childhood in individuals born preterm. OBJECTIVES:The objective of this pilot study was to examine the effect sizes of the relationships between weight gain and blood pressure in toddlers born very preterm. A secondary aim was to note any mediating effect of cortisol on the relationships between weight gain and blood pressure. METHODS:A cross-sectional design with a convenience sample of 36 toddlers who were born very preterm was used to examine the relationships between postnatal weight gain, cortisol, and blood pressure at follow-up. RESULTS:Many of the participants experienced rapid weight gain in the first 12 months of life. Mean systolic and diastolic readings were 94 and 56.6, respectively. Diastolic blood pressure readings were obtained from 23 participants and the majority were elevated. Weight gain was associated with diastolic blood pressure with a medium effect size. A mediating role with cortisol was not supported.Although findings need to be validated in a larger sample, the blood pressure elevations in this sample were alarming. If readings continue to amplify as these children age, the fact that elevations are already present during the toddler period could indicate more significant cardiovascular disease in adulthood for this population. Rapid weight gain in early life may be a driver for elevated blood pressure even during early childhood in individuals born preterm.

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影响因子:2.3490
发表时间:2020-01-21
DOI:10.3389/fped.2019.00567
作者列表:["Camilla Sandrini","Claudio Lombardi","Andrew I. U. Shearn","Maria Victoria Ordonez","Massimo Caputo","Francesca Presti","Giovanni Battista Luciani","Lucia Rossetti","Giovanni Biglino","Giovanni Biglino"]

METHODS:This article presents a case series of n = 21 models of fetal cardiovascular anatomies obtained from post mortem microfocus computed tomography (micro-CT) data. The case series includes a broad range of diagnoses (e.g., tetralogy of Fallot, hypoplastic left heart syndrome, dextrocardia, double outlet right ventricle, atrio-ventricular septal defect) and cases also had a range of associated extra-cardiac malformations (e.g., VACTERL syndrome, central nervous system anomalies, renal anomalies). All cases were successfully reconstructed from the microfocus computed tomography data, demonstrating the feasibility of the technique and of the protocols, including in-house printing with a desktop 3D printer (Form2, Formlabs). All models were printed in 1:1 scale as well as with the 5-fold magnification, to provide insight into the intra-cardiac structures. Possible uses of the models include education and training.

影响因子:8.02
发表时间:2020-01-19
来源期刊:Genome Medicine
DOI:10.1186/s13073-019-0709-8
作者列表:["Cigdem Sevim Bayrak","Peng Zhang","Martin Tristani-Firouzi","Bruce D. Gelb","Yuval Itan"]

METHODS:Abstract Background Congenital heart disease (CHD) affects ~ 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently. De novo variants are estimated to contribute to approximately 8% of sporadic CHD. Methods CHD is genetically heterogeneous, making pathway enrichment analysis an effective approach to explore and statistically validate CHD-associated genes. In this study, we performed novel gene and pathway enrichment analyses of high-impact de novo variants in the recently published whole-exome sequencing (WES) data generated from a cohort of CHD 2645 parent-offspring trios to identify new CHD-causing candidate genes and mutations. We performed rigorous variant- and gene-level filtrations to identify potentially damaging variants, followed by enrichment analyses and gene prioritization. Results Our analyses revealed 23 novel genes that are likely to cause CHD, including HSP90AA1, ROCK2, IQGAP1, and CHD4, and sharing biological functions, pathways, molecular interactions, and properties with known CHD-causing genes. Conclusions Ultimately, these findings suggest novel genes that are likely to be contributing to CHD pathogenesis.

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