Array-Based Molecular Karyotyping in Fetal Brain Malformations: Identification of Novel Candidate Genes and Chromosomal Regions
Array-Based Molecular Karyotyping in Fetal Brain Malformations: Identification of Novel Candidate Genes and Chromosomal Regions
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DOI：
10.1002/bdra.23458
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发表时间：
2016-01-01
影响因子：
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通讯作者：
Merz, Waltraut M.
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文献类型：
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作者：
Krutzke, Sophia K.;Engels, Hartmut;Merz, Waltraut M.
背景：对于大多数先天性脑畸形，其根本原因仍然未知。最近的研究表明，罕见的拷贝数变异（CNVs）在其病因。方法：在这里，我们使用基于阵列的分子核型分析，以寻找在33个胎儿的病因CNVs终止妊娠产前检测脑畸形和额外的脑外异常。结果：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）也通过产前常规核型分析检测到。在我们的1307名健康内部对照中，这些CNV均不存在（频率< 0.0008）。在这些CNV中，我们优先考虑了6个染色体区域（1q25.1，5q35.1，6q25.3-qter，11p14.3，15q11.2-q13.1，18q21.1），因为它们以前与人脑畸形相关，或者因为人脑中存在单个基因表达。这些区域内的优先基因是UBTD 2、SKA 1、SVIP，最令人信服的是GPR 52。然而，对100个来自脑畸形胎儿或智力残疾和脑畸形患者的样本中的GPR 52进行重新测序，没有发现致病突变。结论：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。在这些区域中的三个区域中，我们建议UBTD 2，GPR 52和SKA 1作为可能的候选基因。由于基于阵列的分子核型分析的总体检出率（23%）略高于传统的产前核型分析（20%），我们建议将其用于非孤立性脑畸形胎儿的产前诊断测试。(C)2015 Wiley Periodicals，Inc.
BACKGROUND: For the majority of congenital brain malformations, the underlying cause remains unknown. Recent studies have implicated rare copy number variations (CNVs) in their etiology. METHODS: 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. RESULTS: 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. CONCLUSION: 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. (C) 2015 Wiley Periodicals, Inc.