A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease
A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease
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DOI：
10.1101/gr.094987.109
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发表时间：
2009-09-01
期刊：
影响因子：
7
通讯作者：
Eichler, Evan E.
中科院分区：
文献类型：
--
作者：
Mefford, Heather C.;Cooper, Gregory M.;Eichler, Evan E.
拷贝数变异（CNVs）是导致人类疾病的重要因素。cnv -疾病关联研究的一个核心挑战是描述罕见和可能不完全渗透事件的致病性，这需要在大量个体中准确检测罕见的cnv。成本和吞吐量问题限制了我们进行这些研究的能力。我们采用了Illumina BeadXpress SNP基因分型试验，并开发了一种算法，SNP条件离群检测（SCOUT），以快速准确地检测大型队列中罕见和常见的CNVs。这种方法是可定制的、成本有效的、高度并行的，并且在很大程度上是自动化的。我们应用这种方法筛选了1105名不明原因智力残疾儿童的69个基因座，其中3.1%的人发现了致病变异，另外2.3%的人发现了潜在致病变异。我们确定了7个人（0.7%）的16p11.2基因缺失，该基因先前与自闭症有关。我们的结果扩大了这些缺失的表型谱，包括非自闭症的智力残疾。我们还在1.1%的受影响个体中检测到16p13.11位点1.65-3.4 Mbp的重复，在0.8%的受影响个体中检测到15q11.2位点350 kbp的缺失，在Prader-Willi/Angelman综合征关键区域附近。与已发表的对照组相比，这些儿童的CNVs显著（P分别= 4.73 x 10（-5）和0.003）富集，支持了先前发表的假设，即它们是神经认知疾病的危险因素。更一般地说，这种方法在定制、成本和CNV分析吞吐量之间提供了以前无法获得的平衡，并且应该证明在研究和诊断设置中有针对性的CNV检测是有价值的。
Copy-number variants (CNVs) are substantial contributors to human disease. A central challenge in CNV-disease association studies is to characterize the pathogenicity of rare and possibly incompletely penetrant events, which requires the accurate detection of rare CNVs in large numbers of individuals. Cost and throughput issues limit our ability to perform these studies. We have adapted the Illumina BeadXpress SNP genotyping assay and developed an algorithm, SNP-Conditional OUTlier detection ( SCOUT), to rapidly and accurately detect both rare and common CNVs in large cohorts. This approach is customizable, cost effective, highly parallelized, and largely automated. We applied this method to screen 69 loci in 1105 children with unexplained intellectual disability, identifying pathogenic variants in 3.1% of these individuals and potentially pathogenic variants in an additional 2.3%. We identified seven individuals (0.7%) with a deletion of 16p11.2, which has been previously associated with autism. Our results widen the phenotypic spectrum of these deletions to include intellectual disability without autism. We also detected 1.65-3.4 Mbp duplications at 16p13.11 in 1.1% of affected individuals and 350 kbp deletions at 15q11.2, near the Prader-Willi/Angelman syndrome critical region, in 0.8% of affected individuals. Compared to published CNVs in controls they are significantly (P = 4.73 x 10(-5) and 0.003, respectively) enriched in these children, supporting previously published hypotheses that they are neurocognitive disease risk factors. More generally, this approach offers a previously unavailable balance between customization, cost, and throughput for analysis of CNVs and should prove valuable for targeted CNV detection in both research and diagnostic settings.