A copy number variation morbidity map of developmental delay
A copy number variation morbidity map of developmental delay
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DOI：
10.1038/ng.909
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发表时间：
2011-09-01
期刊：
影响因子：
30.8
通讯作者：
Eichler, Evan E.
中科院分区：
文献类型：
--
作者：
Cooper, Gregory M.;Coe, Bradley P.;Eichler, Evan E.
为了了解发育迟缓背后的遗传异质性，我们比较了15,767名患有智力残疾和各种先天性缺陷的儿童的拷贝数变异(CNV)与8,329名未受影响的成人对照组的CNV。我们估计，在这些儿童中，约有14.2%的疾病是由CNV>；400kb引起的。我们观察到，与癫痫或自闭症患者相比，患有颅面畸形和心血管缺陷的患者CNV的丰富程度更高。我们确定了59个致病CNV，其中包括14个新的或以前弱支持的候选基因，细化了一些基因组疾病的临界区间，如17q21.31微缺失综合征，并确定了940个候选剂量敏感基因。我们还开发了在大型且不断增长的诊断阵列数据集中机会性地发现小的、破坏性的CNV的方法。这张不断演变的CNV发病率图谱，结合外显子组和基因组测序，将对破译发育迟缓、智力残疾和自闭症谱系障碍的遗传基础至关重要。
To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that similar to 14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.