Tiling Resolution Array-CGH Shows That Somatic Mosaic Deletion of the EXT Gene is Causative in EXT Gene Mutation Negative Multiple Osteochondromas Patients
Tiling Resolution Array-CGH Shows That Somatic Mosaic Deletion of the EXT Gene is Causative in EXT Gene Mutation Negative Multiple Osteochondromas Patients
复制标题
DOI：
10.1002/humu.21423
复制
发表时间：
2011-02-01
期刊：
影响因子：
3.9
通讯作者：
Hogendoorn, Pancras C. W.
中科院分区：
文献类型：
--
作者：
Szuhai, Karoly;Jennes, Ivy;Hogendoorn, Pancras C. W.
多发性骨软骨瘤（MO）是一种遗传性骨骼疾病，其特征是在骨表面存在软骨覆盖的骨生长物。在85- 90%的MO病例中描述了EXT 1或EXT 2基因的致病突变。然而，在约10- 15%的MO病例中，不能检测到基因组改变，这意味着其他改变的潜在作用。我们设计了一个定制的基于Agilent的微阵列，包含44，000个探针，覆盖了EXT 1/2基因，并添加了68个参与硫酸乙酰肝素生物合成和其他相关途径的基因。在17个具有先前未检测到的突变的患者样本中，在两个患者中检测到约10-15%的血细胞中的低水平的EXT 1基因缺失，并且在一个患者中检测到EXT 2的嵌合缺失。在这里，我们表明，第一次体细胞嵌合体与大基因组缺失的潜在机制MO形成被确定。我们认为，镶嵌突变的存在，而不是其他硫酸乙酰肝素生物合成相关基因的改变在外生骨素突变检测阴性的患者中MO的发展中起着重要作用。(C)2010 Wiley-Liss，Inc.
Multiple osteochondromas (MO) is a hereditary skeletal disorder characterized by the presence of cartilage capped bony outgrowths at bone surface. Causative mutations in EXT1 or EXT2 genes have been described in 85-90 % of MO cases. However, in about 10-15 % of the MO cases, genomic alterations can not be detected, implying the potential role of other alterations. We have designed a custom-made Agilent oligonucleotide-based microarray, containing 44,000 probes, with tiling coverage of EXT1/2 genes and addition of 68 genes involved in heparan sulfate biosynthesis and other related pathways. Out of the 17 patient samples with previously undetected mutations, a low level of deletion of the EXT1 gene in about 10-15% of the blood cells was detected in two patients and mosaic deletion of the EXT2 was detected in one patient. Here we show that for the first time somatic mosaicism with large genomic deletions as the underlying mechanism in MO formation was identified. We propose that the existence of mosaic mutations and not alterations of other heparan sulfate biosynthesis related genes play a significant role in the development of MO in patients who are tested negative for mutations in Exostosins. (C) 2010 Wiley-Liss, Inc.