Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
N Engl J Med. 2012 Oct 4;367(14):1321-31. doi: 10.1056/NEJMoa1200395. Epub 2012 Sep 12.
Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management.
We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization.
Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02).
Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).
一些拷贝数变异与表型极端异质性的基因组疾病有关。其致病原因尚不清楚，这给遗传诊断、咨询和管理带来了挑战。
我们使用阵列比较基因组杂交技术，分析了已知携带与智力障碍和先天性异常相关拷贝数变异的 2312 名儿童的基因组。
在所研究的患儿中，除主要遗传病变外，有 10.1%的患儿还携带第二种大的拷贝数变异。我们发现，在受影响的患儿中，有七种基因组疾病，每种疾病都由特定的拷贝数变异定义，这些患儿比对照组更有可能携带多种拷贝数变异。我们发现，基于拷贝数变异的总数以及变异是遗传的还是新发的，可以将综合征性疾病与表型极端异质性疾病区分开来。携带两个大的、临床意义不明的拷贝数变异的患儿发生发育迟缓的可能性是对照组的八倍（比值比，8.16；95%置信区间，5.33 至 13.07；P=2.11×10(-38)）。在受影响的患儿中，遗传拷贝数变异倾向于与第二个大的拷贝数变异共同发生（Spearman 相关系数，0.66；P<0.001）。与女孩相比，男孩发生表型异质性疾病的可能性更大（P<0.001），并且母亲比父亲更有可能将第二个位点的拷贝数变异传递给后代（P=0.02）。
多种大的拷贝数变异，包括那些临床意义不明的变异，共同导致严重的临床表现，并且二级拷贝数变异优先从母体携带者遗传。（由西蒙斯基金会自闭症研究倡议和美国国立卫生研究院资助）。
