Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, via dei Giacinti, 2, 56128 Calambrone, Pisa, Italy.
Eur J Paediatr Neurol. 2013 Nov;17(6):589-99. doi: 10.1016/j.ejpn.2013.04.010. Epub 2013 May 24.
Submicroscopic chromosomal rearrangements are the most common identifiable causes of intellectual disability and autism spectrum disorders associated with dysmorphic features. Chromosomal microarray (CMA) can detect copy number variants <1 Mb and identifies size and presence of known genes. The aim of this study was to demonstrate the usefulness of CMA, as a first-tier tool in detecting the etiology of unexplained intellectual disability/autism spectrum disorders (ID/ASDs) associated with dysmorphic features in a large cohort of pediatric patients.
We studied 349 individuals; 223 males, 126 females, aged 5 months-19 years. Blood samples were analyzed with CMA at a resolution ranging from 1 Mb to 40 Kb. The imbalance was confirmed by FISH or qPCR. We considered copy number variants (CNVs) causative if the variant was responsible for a known syndrome, encompassed gene/s of known function, occurred de novo or, if inherited, the parent was variably affected, and/or the involved gene/s had been reported in association with ID/ASDs in dedicated databases.
91 CNVs were detected in 77 (22.06%) patients: 5 (6.49%) of those presenting with borderline cognitive impairment, 54 (70.13%) with a variable degree of DD/ID, and 18/77 (23.38%) with ID of variable degree and ASDs. 16/77 (20.8%) patients had two different rearrangements. Deletions exceeded duplications (58 versus 33); 45.05% (41/91) of the detected CNVs were de novo, 45.05% (41/91) inherited, and 9.9% (9/91) unknown. The CNVs caused the phenotype in 57/77 (74%) patients; 12/57 (21.05%) had ASDs/ID, and 45/57 (78.95%) had DD/ID.
Our study provides further evidence of the high diagnostic yield of CMA for genetic testing in children with unexplained ID/ASDs who had dysmorphic features. We confirm the value of CMA as the first-tier tool in the assessment of those conditions in the pediatric setting.
亚显微染色体重排是最常见的可识别病因，与发育异常特征相关的智力障碍和自闭症谱系障碍都与这些病因有关。染色体微阵列（CMA）可以检测<1Mb 的拷贝数变异，并确定已知基因的大小和存在。本研究旨在证明 CMA 在作为一种一线工具，在检测具有发育异常特征的不明原因智力障碍/自闭症谱系障碍（ID/ASD）的病因方面的有用性，该研究纳入了大量儿科患者。
我们研究了 349 名个体，其中男性 223 名，女性 126 名，年龄 5 个月至 19 岁。血液样本采用分辨率为 1Mb 至 40kb 的 CMA 进行分析。通过 FISH 或 qPCR 确认不平衡。如果变异导致已知综合征，包含已知功能的基因，为新生变异，或者如果是遗传的，父母存在不同程度的变异，并且/或者相关基因已在专门的数据库中与 ID/ASD 相关报道，则我们认为拷贝数变异（CNV）是致病的。
在 77 名（22.06%）患者中发现了 91 个 CNV：5 名（6.49%）患者有边缘认知障碍，54 名（70.13%）患者有不同程度的 DD/ID，18 名/77 名（23.38%）患者有不同程度的 ID 和 ASD。77 名患者中有 16 名（20.8%）有两种不同的重排。缺失超过重复（58 比 33）；45.05%（41/91）的检测到的 CNV 是新生的，45.05%（41/91）是遗传的，9.9%（9/91）是未知的。CNV 导致 77 名患者中的 57 名（74%）出现表型；12 名/57 名（21.05%）患有 ASD/ID，45 名/57 名（78.95%）患有 DD/ID。
本研究进一步证明 CMA 在检测具有发育异常特征的不明原因 ID/ASD 儿童遗传检测中的高诊断率。我们确认 CMA 作为儿科评估这些疾病的一线工具的价值。
