Beaujard Marie-Paule, Chantot Sandra, Dubois Michèle, Keren Boris, Carpentier Wassila, Mabboux Philippe, Whalen Sandra, Vodovar Michel, Siffroi Jean-Pierre, Portnoï Marie-France
Laboratoire de Cytogénétique, Institut de Puériculture, Paris, France.
Eur J Med Genet. 2009 Sep-Oct;52(5):321-7. doi: 10.1016/j.ejmg.2009.05.010. Epub 2009 May 23.
Despite the heterogeneous clinical presentations, the majority of patients with 22q11.2 deletion syndrome (22q11.2 DS) have either a common recurrent 3 Mb deletion or a less common, 1.5 Mb nested deletion, with breakpoint sites in flanking low-copy repeats (LCR) sequences. Only a small number of atypical deletions have been reported and precisely defined. Haploinsufficiency of the TBX1 gene was determined to be the likely cause of 22q11.2 DS. The diagnostic procedure usually used is FISH using commercially probes (N25 or TUPLE1). However, this test does not contain TBX1, and fails to detect deletions that are either proximal or distal to the FISH probes. Here, we report on two patients with clinical features suggestive of 22q11.2 DS, a male infant with facial dysmorphia, pulmonary atresia, ventricular septal defect, neonatal hypocalcemia, and his affected mother, with facial dysmorphia, learning disabilities, and hypernasal speech. They were tested negative for 22q11.2 DS using N25 or TUPLE1 probes, but were shown deleted for a probe containing TBX1. Delineation of the deletion was performed using high-density SNP arrays (Illumina, 370K). This atypical deletion was spanning 1.89 Mb. The distal breakpoint resided in LCR-D, sharing the same distal breakpoint with the 3 Mb common deletion. The proximal breakpoint was located 105 kb telomeric to TUPLE1, representing a new breakpoint variant that does not correspond to known LCRs of 22q11.2. We conclude that FISH with the TBX1 probe is an accurate diagnostic tool for 22q11.2 DS, with a higher sensitivity than FISH using standard probes, detecting all but the rarest deletions, greatly reducing the false negative rate.
尽管临床表现具有异质性，但大多数22q11.2缺失综合征（22q11.2 DS）患者要么存在常见的复发性3 Mb缺失，要么存在较罕见的1.5 Mb嵌套缺失，断点位于侧翼低拷贝重复序列（LCR）中。仅有少数非典型缺失被报道并精确界定。TBX1基因单倍剂量不足被确定为22q11.2 DS的可能病因。通常使用的诊断方法是使用商业探针（N25或TUPLE1）进行荧光原位杂交（FISH）。然而，该检测不包含TBX1，无法检测FISH探针近端或远端的缺失。在此，我们报告两名具有22q11.2 DS临床特征的患者，一名患有面部畸形、肺动脉闭锁、室间隔缺损、新生儿低钙血症的男婴，以及他患有面部畸形、学习障碍和鼻音过重的母亲。他们使用N25或TUPLE1探针检测22q11.2 DS呈阴性，但使用包含TBX1的探针检测显示缺失。使用高密度单核苷酸多态性阵列（Illumina，370K）对缺失进行了界定。这种非典型缺失跨度为1.89 Mb。远端断点位于LCR-D中，与3 Mb常见缺失共享相同的远端断点。近端断点位于TUPLE1端粒105 kb处，代表一种新的断点变体，与22q11.2已知的LCR不对应。我们得出结论，使用TBX1探针进行FISH是诊断22q11.2 DS的准确工具，其灵敏度高于使用标准探针的FISH，能检测除最罕见缺失外的所有缺失，大大降低假阴性率。
