Relative burden of large CNVs on a range of neurodevelopmental phenotypes.
Relative burden of large CNVs on a range of neurodevelopmental phenotypes.
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DOI：
10.1371/journal.pgen.1002334
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发表时间：
2011-11
期刊：
影响因子：
4.5
通讯作者：
Eichler EE
中科院分区：
文献类型：
--
作者：
Girirajan S;Brkanac Z;Coe BP;Baker C;Vives L;Vu TH;Shafer N;Bernier R;Ferrero GB;Silengo M;Warren ST;Moreno CS;Fichera M;Romano C;Raskind WH;Eichler EE
虽然许多研究表明拷贝数变异（cnv）存在于一系列神经表型中，但由于样本量小、缺乏表型细节以及用于发现的平台的异质性，很难确定其对疾病严重程度的影响。使用定制的基因组热点富集微阵列，我们检测了1,227名不同神经缺陷患者的大CNVs，包括阅读障碍（376），散发性自闭症（350）和智力残疾（501），以及337名对照。我们发现，与自闭症（p = 9.58×10−11，优势比= 4.59）、阅读障碍（p = 3.81×10−18，优势比= 14.45）或对照组（p = 2.75×10−17，优势比= 13.71）相比，id相关表型中大CNVs （>1 Mbp）的频率显著更高。与阅读障碍（2%）相比，自闭症（10%,p = 2.4×10−6，优势比= 6）或ID （16%, p = 3.55×10−12，优势比= 10）中罕见CNV （>50 kbp）的频率存在显著差异，而阅读障碍患者的大CNV负担与对照组相比基本没有差异。与自闭症（40%）或阅读障碍（0%）相比，罕见的CNVs更有可能在ID中从头出现（64%）。我们观察到，与单独患有先天性畸形（ID）相比，患有先天性畸形和多发性先天性畸形（MCA）的个体的大CNV负担显著增加（p = 0.001，优势比= 2.54）。我们的数据表明，大的CNV负担与儿童残疾的严重程度呈正相关：ID与MCA的影响最严重，阅读障碍与对照组难以区分。当单独考虑无ID自闭症时，与对照组相比，CNV负担的增加幅度不大（p = 0.07，优势比= 2.33）。被称为拷贝数变异（CNVs）的缺失和重复与多种神经发育障碍有关，包括智力残疾（ID）、自闭症和精神分裂症。由于这些研究仅限于使用不同的CNV检测平台一次分析一种疾病，样本量不足，缺乏详细的临床信息，因此我们很难理解大而罕见的CNV在一系列神经发育表型中的相关性，这些表型在严重程度和流行程度上都有所不同。我们使用相同的CNV检测平台测试了1,227名患有不同神经系统疾病的个体，包括阅读障碍、自闭症和ID。我们观察到这些队列中CNV负担和遗传特征的显著差异，并表明ID是大CNV负担的主要相关因素。通过对患有和不患有id的自闭症患者的比较，这种相关性得到了很好的说明，与对照组相比，后者的大CNV负担仅略有增加。我们还发现，与其他队列相比，阅读障碍中大CNVs的频率显著减少。为了详细了解遗传变异对神经发育障碍的相对贡献，有必要使用高分辨率阵列和下一代测序对更大组个体进行进一步研究。
While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID–associated phenotypes compared to autism (p = 9.58×10−11, odds ratio = 4.59), dyslexia (p = 3.81×10−18, odds ratio = 14.45), or controls (p = 2.75×10−17, odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4×10−6, odds ratio = 6) or ID (16%, p = 3.55×10−12, odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33). Deletions and duplications, termed copy number variants (CNVs), have been implicated in a variety of neurodevelopmental disorders including intellectual disability (ID), autism, and schizophrenia. Our understanding of the relevance of large, rare CNVs in a range of neurodevelopmental phenotypes, varying in severity and prevalence, has been difficult because these studies were restricted to the analysis of one disorder at a time using different CNV detection platforms, insufficient sample sizes, and a lack of detailed clinical information. We tested 1,227 individuals with different neurological diseases including dyslexia, autism, and ID using the same CNV detection platform. We observed striking differences in CNV burden and inheritance characteristics among these cohorts and show that ID is the primary correlate of large CNV burden. This correlation is well illustrated by a comparison of autism patients with and without ID—where the latter show only modest increases in large CNV burden compared to controls. We also find significant depletion in the frequency of large CNVs in dyslexia compared to the other cohorts. Further studies on larger sets of individuals using high-resolution arrays and next-generation sequencing are warranted for a detailed understanding of the relative contribution of genetic variants to neurodevelopmental disorders.
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影响因子：
9.8
作者：
Cardoso, C;Leventer, RJ;Ledbetter, DH
通讯作者：
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DOI：
10.1016/j.gep.2009.11.005
发表时间：
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期刊：
Gene expression patterns : GEP
影响因子：
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通讯作者：
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作者：
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