Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
J Med Genet. 2009 Dec;46(12):825-33. doi: 10.1136/jmg.2009.067637. Epub 2009 Jul 6.
Deletions in the 17p13.3 region are associated with abnormal neuronal migration. Point mutations or deletion copy number variants of the PAFAH1B1 gene in this genomic region cause lissencephaly, whereas extended deletions involving both PAFAH1B1 and YWHAE result in Miller-Dieker syndrome characterised by facial dysmorphisms and a more severe grade of lissencephaly. The phenotypic consequences of YWHAE deletion without deletion of PAFAH1B1 have not been studied systematically.
We performed a detailed clinical and molecular characterization of five patients with deletions involving YWHAE but not PAFAH1B1, two with deletion including PAFAH1B1 but not YWHAE, and one with deletion of YWHAE and mosaic for deletion of PAFAH1B1.
Three deletions were terminal whereas five were interstitial. Patients with deletions including YWHAE but not PAFAH1B1 presented with significant growth restriction, cognitive impairment, shared craniofacial features, and variable structural abnormalities of the brain. Growth restriction was not observed in one patient with deletion of YWHAE and TUSC5, implying that other genes in the region may have a role in regulation of growth with CRK being the most likely candidate. Using array based comparative genomic hybridisation and long range polymerase chain reaction, we have delineated the breakpoints of these nonrecurrent deletions and show that the interstitial genomic rearrangements are likely generated by diverse mechanisms, including the recently described Fork Stalling and Template Switching (FoSTeS)/Microhomology Mediated Break Induced Replication (MMBIR).
Microdeletions of chromosome 17p13.3 involving YWHAE present with growth restriction, craniofacial dysmorphisms, structural abnormalities of brain and cognitive impairment. The interstitial deletions are mediated by diverse molecular mechanisms.
17p13.3 区域的缺失与异常神经元迁移有关。该基因组区域中 PAFAH1B1 基因的点突变或缺失拷贝数变异导致无脑回畸形，而涉及 PAFAH1B1 和 YWHAE 的扩展缺失导致 Miller-Dieker 综合征，其特征为面部畸形和更严重的无脑回畸形。没有 PAFAH1B1 缺失的 YWHAE 缺失的表型后果尚未系统研究。
我们对五个涉及 YWHAE 但不涉及 PAFAH1B1 的缺失患者、两个包括 PAFAH1B1 但不涉及 YWHAE 的缺失患者和一个 YWHAE 缺失且 PAFAH1B1 缺失镶嵌的缺失患者进行了详细的临床和分子特征分析。
三个缺失为末端缺失，五个缺失为中间缺失。包括 YWHAE 但不包括 PAFAH1B1 的缺失患者表现出明显的生长受限、认知障碍、共享的颅面特征和大脑结构的可变异常。一个 YWHAE 和 TUSC5 缺失的患者未观察到生长受限，这表明该区域的其他基因可能在调节生长中起作用，CRK 是最有可能的候选基因。使用基于阵列的比较基因组杂交和长距离聚合酶链反应，我们描绘了这些非重复缺失的断点，并表明中间基因组重排可能由多种机制产生，包括最近描述的 Fork Stalling 和 Template Switching (FoSTeS)/Microhomology Mediated Break Induced Replication (MMBIR)。
涉及 YWHAE 的 17p13.3 染色体微缺失表现为生长受限、颅面畸形、脑结构异常和认知障碍。中间缺失由多种分子机制介导。
