An Excess of Deleterious Variants in VEGF-A Pathway Genes in Down-Syndrome-Associated Atrioventricular Septal Defects
An Excess of Deleterious Variants in VEGF-A Pathway Genes in Down-Syndrome-Associated Atrioventricular Septal Defects
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DOI：
10.1016/j.ajhg.2012.08.017
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发表时间：
2012-10-05
影响因子：
9.8
通讯作者：
Maslen, Cheryl L.
中科院分区：
文献类型：
--
作者：
Ackerman, Christine;Locke, Adam E.;Maslen, Cheryl L.
大约一半的21三体患者患有先天性心脏缺陷（CHD），而其余的人具有结构正常的心脏，这表明21三体是一个重要的风险因素，但不是心脏发育异常的原因。房室间隔缺损（AVSD）是唐氏综合征（DS）最常见的心脏缺陷，约65%的AVSD与DS有关。我们在DS和完全AVSD（病例= 141）和DS无CHD（对照= 141）的个体中使用候选基因方法，以确定是否涉及房室瓣间隔形态发生的基因中的罕见遗传变异导致该致敏人群中的AVSD。我们发现，与对照组相比，病例中预测为有害的变体显著过量（p < 0.0001）。在最严格的过滤水平下，我们在近20%的病例中发现了潜在的破坏性变异，但在对照组中不到3%。仅在病例中具有最高损害概率的变体存在于六个基因中：COL 6A 1，COL 6A 2，CRELD 1，FBLN 2，FRZB和GATA 5。一些病例特异性变异在无关个体中反复出现，在所研究的病例中有10%发生。在对照组中没有发现具有相同损害概率的变异，表明与AVSD具有高度特异性相关性。值得注意的是，所有这些基因都在VEGF-A途径中，尽管本研究中分析的候选基因代表了许多生化和发育途径，表明VEGF-A途径中的罕见变异可能有助于人类AVSD的遗传基础。
About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and similar to 65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans.