Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects
Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects
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DOI：
10.1002/ajmg.a.35315
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发表时间：
2012-06-01
影响因子：
2
通讯作者：
Portman, Michael A.
中科院分区：
文献类型：
--
作者：
Priest, James R.;Girirajan, Santhosh;Portman, Michael A.
房室间隔缺损（AVSDs）是唐氏综合征（DS）的常见但不普遍的组成部分，而其他正常个体的房室间隔缺损没有明确的遗传基础。拷贝数变异（CNV）对包括AVSD在内的特定先天性心脏病（CHD）表型的贡献尚不清楚。我们假设21号染色体上的新生CNVs可能导致分离的散发性AVSD，另外，整个基因组的CNVs可能构成DS患者AVSD的额外遗传危险因素。我们使用了一个定制的寡核苷酸阵列针对CNV热点，两侧是高序列一致性的大重复片段。我们分析了29个整倍体和50个DS个体的AVSD，并与一般人群对照进行了比较。在分离散发性AVSD患者中，我们在21号染色体外发现了两个独特的大缺失，在扩展的8635个对照组中没有发现，每个缺失都与破译数据库中报道的与类似冠心病相关的大缺失重叠。在一名DS和AVSD患者中存在少量重复。我们的结论是，分离的散发性AVSDs可能偶尔与21号染色体外的大的从头开始的基因组结构变异有关。在孤立的散发性AVSD患者中，21号染色体上CNVs的缺失表明，21号染色体上大于150kbp的亚染色体重复或缺失不会导致散发性AVSD。在DS人群中，较大的CNVs似乎不是AVSD的附加危险因素。(c) 2012 Wiley期刊有限公司
Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150 kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population. (c) 2012 Wiley Periodicals, Inc.