Department of Child and Adolescent Psychiatry, University Medical Centre, Utrecht, The Netherlands.
Neurogenetics. 2011 Nov;12(4):315-23. doi: 10.1007/s10048-011-0297-2. Epub 2011 Aug 12.
Recent array-based studies have detected a wealth of copy number variations (CNVs) in patients with autism spectrum disorders (ASD). Since CNVs also occur in healthy individuals, their contributions to the patient's phenotype remain largely unclear. In a cohort of children with symptoms of ASD, diagnosis of the index patient using ADOS-G and ADI-R was performed, and the Social Responsiveness Scale (SRS) was administered to the index patients, both parents, and all available siblings. CNVs were identified using SNP arrays and confirmed by FISH or array CGH. To evaluate the clinical significance of CNVs, we analyzed three families with multiple affected children (multiplex) and six families with a single affected child (simplex) in which at least one child carried a CNV with a brain-transcribed gene. CNVs containing genes that participate in pathways previously implicated in ASD, such as the phosphoinositol signaling pathway (PIK3CA, GIRDIN), contactin-based networks of cell communication (CNTN6), and microcephalin (MCPH1) were found not to co-segregate with ASD phenotypes. In one family, a loss of CNTN5 co-segregated with disease. This indicates that most CNVs may by themselves not be sufficient to cause ASD, but still may contribute to the phenotype by additive or epistatic interactions with inherited (transmitted) mutations or non-genetic factors. Our study extends the scope of genome-wide CNV profiling beyond de novo CNVs in sporadic patients and may aid in uncovering missing heritability in genome-wide screening studies of complex psychiatric disorders.
近年来，基于阵列的研究已经在自闭症谱系障碍（ASD）患者中检测到了大量的拷贝数变异（CNVs）。由于 CNVs 也存在于健康个体中，它们对患者表型的贡献在很大程度上仍不清楚。在一组有 ASD 症状的儿童中，使用 ADOS-G 和 ADI-R 对索引患者进行了诊断，并对索引患者、其父母和所有可用的兄弟姐妹进行了社会反应量表（SRS）的评估。使用 SNP 阵列识别 CNVs，并通过 FISH 或 array CGH 进行确认。为了评估 CNVs 的临床意义，我们分析了三个有多个受影响孩子的家庭（多）和六个有一个受影响孩子的家庭（单），其中至少有一个孩子携带了一个具有脑转录基因的 CNV。包含参与先前与 ASD 相关途径的基因的 CNVs，例如磷酸肌醇信号通路（PIK3CA、GIRDIN）、细胞通讯的接触蛋白网络（CNTN6）和小头畸形（MCPH1），并未与 ASD 表型共分离。在一个家庭中，CNTN5 的缺失与疾病共分离。这表明大多数 CNVs 本身可能不足以导致 ASD，但仍可能通过与遗传（传递）突变或非遗传因素的加性或上位性相互作用对表型做出贡献。我们的研究将全基因组 CNV 分析的范围扩展到散发性患者中的新生 CNVs 之外，并且可能有助于在全基因组筛查复杂精神障碍的研究中发现缺失的遗传率。
