An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities.
An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities.
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DOI：
10.1097/gim.0b013e31822c79f9
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发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Martin CL
中科院分区：
文献类型：
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作者：
Kaminsky EB;Kaul V;Paschall J;Church DM;Bunke B;Kunig D;Moreno-De-Luca D;Moreno-De-Luca A;Mulle JG;Warren ST;Richard G;Compton JG;Fuller AE;Gliem TJ;Huang S;Collinson MN;Beal SJ;Ackley T;Pickering DL;Golden DM;Aston E;Whitby H;Shetty S;Rossi MR;Rudd MK;South ST;Brothman AR;Sanger WG;Iyer RK;Crolla JA;Thorland EC;Aradhya S;Ledbetter DH;Martin CL
拷贝数变异（CNVs）已成为人类疾病（如自闭症和智力残疾）的主要原因。由于CNVs在正常个体中很常见，因此确定罕见CNVs在患者中的功能和临床意义仍然具有挑战性。采用全基因组染色体微阵列分析（CMA）作为不明原因发育障碍个体的第一级诊断测试，提供了一个独特的机会来获得通过常规患者护理生成的大型CNV数据集。建立了一个诊断实验室联盟[细胞基因组阵列国际标准（ISCA）联盟]，在一个中央公共数据库中共享CNV和表型数据。我们提出了迄今为止最大的CNV病例对照研究，包括15，749例ISCA病例和10，118例已发表的对照，重点是我们对涉及14个CNV区域的复发性缺失和重复的初步分析。与对照组相比，14个缺失和7个重复在病例中显著过高，提供了致病性的临床诊断。鉴于临床CMA检测的快速扩展，将有非常大的数据集可用于确定日益罕见的CNV的功能意义。这些数据将为参与这些患者及其家属的诊断，管理和护理的许多学科的临床医生提供循证指南。
Copy number variants (CNVs) have emerged as a major cause of human disease such as autism and intellectual disabilities. Because CNVs are common in normal individuals, determining the functional and clinical significance of rare CNVs in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis (CMA) as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large CNV datasets generated through routine patient care. A consortium of diagnostic laboratories was established [the International Standards for Cytogenomic Arrays (ISCA) consortium] to share CNV and phenotypic data in a central, public database. We present the largest CNV case-control study to date comprising 15,749 ISCA cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 CNV regions. Compared to controls, fourteen deletions, and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. Given the rapid expansion of clinical CMA testing, very large datasets will be available to determine the functional significance of increasingly rare CNVs. This data will provide an evidenced-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.