Ben-Shachar Shay, Ou Zhishuo, Shaw Chad A, Belmont John W, Patel Millan S, Hummel Marybeth, Amato Stephen, Tartaglia Nicole, Berg Jonathan, Sutton V Reid, Lalani Seema R, Chinault A Craig, Cheung Sau W, Lupski James R, Patel Ankita
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Am J Hum Genet. 2008 Jan;82(1):214-21. doi: 10.1016/j.ajhg.2007.09.014.
Microdeletions within chromosome 22q11.2 cause a variable phenotype, including DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). About 97% of patients with DGS/VCFS have either a common recurrent approximately 3 Mb deletion or a smaller, less common, approximately 1.5 Mb nested deletion. Both deletions apparently occur as a result of homologous recombination between nonallelic flanking low-copy repeat (LCR) sequences located in 22q11.2. Interestingly, although eight different LCRs are located in proximal 22q, only a few cases of atypical deletions utilizing alternative LCRs have been described. Using array-based comparative genomic hybridization (CGH) analysis, we have detected six unrelated cases of deletions that are within 22q11.2 and are located distal to the approximately 3 Mb common deletion region. Further analyses revealed that the rearrangements had clustered breakpoints and either a approximately 1.4 Mb or approximately 2.1 Mb recurrent deletion flanked proximally by LCR22-4 and distally by either LCR22-5 or LCR22-6, respectively. Parental fluorescence in situ hybridization (FISH) analyses revealed that none of the available parents (11 out of 12 were available) had the deletion, indicating de novo events. All patients presented with characteristic facial dysmorphic features. A history of prematurity, prenatal and postnatal growth delay, developmental delay, and mild skeletal abnormalities was prevalent among the patients. Two patients were found to have a cardiovascular malformation, one had truncus arteriosus, and another had a bicuspid aortic valve. A single patient had a cleft palate. We conclude that distal deletions of chromosome 22q11.2 between LCR22-4 and LCR22-6, although they share some characteristic features with DGS/VCFS, represent a novel genomic disorder distinct genomically and clinically from the well-known DGS/VCF deletion syndromes.
22q11.2染色体上的微缺失会导致多种不同的表型，包括迪格奥尔格综合征（DGS）和腭心面综合征（VCFS）。约97%的DGS/VCFS患者存在常见的约3 Mb反复缺失或较小的、不太常见的约1.5 Mb嵌套缺失。这两种缺失显然都是由于位于22q11.2的非等位侧翼低拷贝重复（LCR）序列之间的同源重组所致。有趣的是，尽管在22q近端有8种不同的LCR，但利用其他LCR的非典型缺失病例仅报道了少数几例。通过基于阵列的比较基因组杂交（CGH）分析，我们检测到6例无关的22q11.2内缺失病例，这些缺失位于约3 Mb常见缺失区域的远端。进一步分析显示，这些重排具有聚集的断点，存在一个约1.4 Mb或约2.1 Mb的反复缺失，近端侧翼为LCR22-4，远端侧翼分别为LCR22-5或LCR22-6。父母荧光原位杂交（FISH）分析显示，所有可用的父母（12例中有11例可用）均无该缺失，表明为新发事件。所有患者均表现出特征性的面部畸形特征。早产、产前和产后生长发育迟缓、发育迟缓以及轻度骨骼异常病史在患者中很常见。2例患者被发现有心血管畸形，1例有共同动脉干，另1例有二叶式主动脉瓣。1例患者有腭裂。我们得出结论，22q11.2在LCR22-4和LCR22-6之间的远端缺失，尽管它们与DGS/VCFS有一些共同特征，但代表了一种新的基因组疾病，在基因组和临床上与著名的DGS/VCF缺失综合征不同。
