Partial microduplication in the histone acetyltransferase complex member KANSL1 is associated with congenital heart defects in 22q11.2 microdeletion syndrome patients.
Partial microduplication in the histone acetyltransferase complex member KANSL1 is associated with congenital heart defects in 22q11.2 microdeletion syndrome patients.
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DOI：
10.1038/s41598-017-01896-w
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发表时间：
2017-05-11
影响因子：
4.6
通讯作者：
Repetto GM
中科院分区：
文献类型：
--
作者：
León LE;Benavides F;Espinoza K;Vial C;Alvarez P;Palomares M;Lay-Son G;Miranda M;Repetto GM
22q11.2微缺失综合征（22q11.2 ds）是人类最常见的微缺失疾病，其发病率为1/4000活产婴儿。它是由染色体22q11.2区1.5 - 3mb的杂合缺失引起的。缺失的患者表现为神经精神问题、颅面异常和心血管畸形。然而，表型是高度可变的，与临床异质性相关的因素尚不完全清楚。约65%的22q11.2DS患者有先天性心脏缺陷（CHD）。本研究的主要目的是确定22q11.2DS患者中可能与冠心病不完全外显相关的常见CNVs。利用阵列技术对253例22q11.2DS患者的基因组DNA进行分析，发现位于17q21.31区的微重复与冠心病存在相关性（p值= 0.023,OR = 2.75, 95% CI = 1.17-7.03）。该区域包括KANSL1基因的前三个外显子。生物信息学分析表明，在一个miRNA-mRNA网络中，KANSL1和CRKL（一个位于22q11.2DS常缺失区域的基因）是同一个调控模块的一部分。这些结果表明，KANSL1微重复结合22q11.2缺失与这些患者冠心病风险增加相关，提示KANSL1在22q11.2 ds患者中起修饰基因的作用。
22q11.2 microdeletion syndrome (22q11.2DS) is the most common microdeletion disorder in humans, with an incidence of 1/4000 live births. It is caused by a heterozygous deletion of 1.5–3 Mb on chromosome region 22q11.2. Patients with the deletion present features that include neuropsychiatric problems, craniofacial abnormalities and cardiovascular malformations. However, the phenotype is highly variable and the factors related to the clinical heterogeneity are not fully understood. About 65% of patients with 22q11.2DS have congenital heart defects (CHD). The main goal of this study was to identify common CNVs in 22q11.2DS patients that could be associated with the incomplete penetrance of CHD. Analysis of genomic DNA from 253 patients with 22q11.2DS using array technology showed an association between a microduplication located in region 17q21.31 and CHD (p-value = 0.023, OR = 2.75, 95% CI = 1.17–7.03). This region includes the first three exons of KANSL1 gene. Bioinformatic analysis showed that KANSL1 and CRKL, a gene in the commonly deleted region of 22q11.2DS, are part of the same regulatory module in a miRNA-mRNA network. These results show that a KANSL1 microduplication, in combination with the 22q11.2 deletion, is associated with increased risk of CHD in these patients, suggesting that KANSL1 plays a role as a modifier gene in 22q11.2DS patients.