Krutzke Sophia K, Engels Hartmut, Hofmann Andrea, Schumann Madita M, Cremer Kirsten, Zink Alexander M, Hilger Alina, Ludwig Michael, Gembruch Ulrich, Reutter Heiko, Merz Waltraut M
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
Birth Defects Res A Clin Mol Teratol. 2016 Jan;106(1):16-26. doi: 10.1002/bdra.23458. Epub 2015 Dec 17.
For the majority of congenital brain malformations, the underlying cause remains unknown. Recent studies have implicated rare copy number variations (CNVs) in their etiology.
Here, we used array-based molecular karyotyping to search for causative CNVs in 33 fetuses of terminated pregnancies with prenatally detected brain malformations and additional extracerebral anomalies.
In 11 fetuses, we identified 15 CNVs (0.08 Mb to 29.59 Mb), comprising four duplications and eleven deletions. All larger CNVs (> 5 Mb) had also been detected by prenatal conventional karyotyping. None of these CNVs was present in our 1307 healthy in-house controls (frequency < 0.0008). Among these CNVs, we prioritized six chromosomal regions (1q25.1, 5q35.1, 6q25.3-qter, 11p14.3, 15q11.2-q13.1, 18q21.1) due to their previous association with human brain malformations or owing to the presence of a single gene expressed in human brain. Prioritized genes within these regions were UBTD2, SKA1, SVIP, and, most convincingly, GPR52. However, re-sequencing of GPR52 in 100 samples from fetuses with brain malformations or patients with intellectual disability and brain malformations revealed no disease-causing mutation.
Our study suggests chromosomal regions 1q25.1, 5q35.1, 6q25.3-qter, 11p14.3, 15q11.2-q13.1, and 18q21.1 to be involved in human brain development. Within three of these regions, we suggest UBTD2, GPR52, and SKA1 as possible candidate genes. Because the overall detection rate of array-based molecular karyotyping was slightly higher (23%) than that of conventional prenatal karyotyping (20%), we suggest it's use for prenatal diagnostic testing in fetuses with nonisolated brain malformations.
对于大多数先天性脑畸形，其潜在病因仍不清楚。最近的研究表明罕见的拷贝数变异（CNV）与它们的病因有关。
在此，我们使用基于芯片的分子核型分析来寻找33例经产前检测有脑畸形及其他脑外异常的引产胎儿中的致病性CNV。
在11例胎儿中，我们鉴定出15个CNV（0.08 Mb至29.59 Mb），包括4个重复和11个缺失。所有较大的CNV（>5 Mb）也已通过产前常规核型分析检测到。在我们1307例内部健康对照中均未发现这些CNV（频率<0.0008）。在这些CNV中，我们将6个染色体区域（1q25.1、5q35.1、6q25.3 - qter、11p14.3、15q11.2 - q13.1、18q21.1）列为重点，因为它们之前与人脑畸形有关，或者由于存在在人脑中表达的单个基因。这些区域内的重点基因是UBTD2、SKA1、SVIP，最有说服力的是GPR52。然而，对100例有脑畸形的胎儿样本或有智力残疾和脑畸形的患者样本中的GPR52进行重测序，未发现致病突变。
我们的研究表明染色体区域1q25.1、5q35.1、6q25.3 - qter、11p14.3、15q11.2 - q13.1和18q21.1参与人脑发育。在其中三个区域内，我们认为UBTD2、GPR52和SKA1是可能的候选基因。由于基于芯片的分子核型分析的总体检测率（23%）略高于传统产前核型分析（20%），我们建议将其用于非孤立性脑畸形胎儿的产前诊断检测。
