Whole-genome array-CGH identifies novel contiguous gene deletions and duplications associated with developmental delay, mental retardation, and dysmorphic features
Whole-genome array-CGH identifies novel contiguous gene deletions and duplications associated with developmental delay, mental retardation, and dysmorphic features
复制标题
DOI：
10.1002/ajmg.a.31773
复制
发表时间：
2007-07-01
影响因子：
2
通讯作者：
Cherry, Athena M.
中科院分区：
文献类型：
--
作者：
Aradhya, Swaroop;Manning, Melanie A.;Cherry, Athena M.
细胞遗传学失衡是最常见的发育迟缓或智力低下的原因，影响1-3%的儿童，通常与生长迟缓，畸形特征和各种先天性异常有关。大量发育迟缓或智力低下的患者被预测具有细胞遗传学失衡，但是用于鉴定这些失衡的常规方法仅在这些患者的一小部分中产生阳性结果。我们使用基于微阵列的比较基因组杂交（aCGH）来研究一组20例基于发育迟缓或智力低下、生长迟缓、畸形特征和/或先天性异常的临床表现预测具有染色体畸变的患者。所有患者的G-手染色体核型和荧光原位杂交结果均正常。在同一组患者中，使用基于阿托伐他汀和基于细菌人工染色体（BAC）的阵列，我们确定了10个独特的缺失和重复，大小从280 kb到8.3 Mb不等。全基因组寡核苷酸阵列识别出的不平衡几乎是低分辨率全基因组BAC阵列的两倍。这对在临床环境中使用aCGH具有影响。对亲本DNA样本的分析表明，大多数不平衡是从头发生的。此外，10个不平衡中有7个代表了新的疾病，增加了越来越多的由大规模缺失或重复引起的疾病。这些结果强调了高分辨率基因组阵列在诊断未知遗传病因病例中的优势，并表明连续的基因组改变是大量发育迟缓病例的潜在致病原因。(c)2007 Wiley-Liss，Inc.
Cytogenetic imbalances are the most frequently identified Cause of developmental delay or mental retardation, which affect 1-3% of children and are often seen in conjunction with growth retardation, dysmorphic features, and various congenital anomalies. A substantial number of patients with developmental delay or mental retardation are predicted to have cytogenetic imbalances, but conventional methods for identifying these imbalances yield positive results in only a small fraction of these patients. We used microarray-based comparative genomic hybridization (aCGH) to study a panel of 20 patients predicted to have chromosomal aberrations based on clinical presentation of developmental delay or mental retardation, growth delay, dysmorphic features, and/or congenital anomalies. Previous G-handed karyotypes and fluorescence in situ hybridization results were normal for all of these patients. Using both oligonucleotide-based and bacterial artificial chromosome (BAC)-based arrays on the same panel of patients, we identified 10 unique deletions and duplications ranging in size from 280 kb to 8.3 Mb. The whole-genome oligonucleotide arrays identified nearly twice as many imbalances as did the lower-resolution whole-genome BAC arrays. This has implications for using aCGH in a clinical setting. Analysis of parental DNA samples indicated that most of the imbalances had occurred de novo. Moreover, seven of the 10 imbalances represented novel disorders, adding to an increasing number of conditions caused by large-scale deletions or duplications. These results underscore the strength of high-resolution genomic arrays in diagnosing cases of unknown genetic etiology and suggest that contiguous genomic alterations are the underlying pathogenic cause of a significant number of cases of developmental delay. (c) 2007 Wiley-Liss, Inc.