Thienpont Bernard, Mertens Luc, de Ravel Thomy, Eyskens Benedicte, Boshoff Derize, Maas Nicole, Fryns Jean-Pierre, Gewillig Marc, Vermeesch Joris R, Devriendt Koen
Center for Human Genetics, Catholic University of Leuven, Belgium.
Eur Heart J. 2007 Nov;28(22):2778-84. doi: 10.1093/eurheartj/ehl560. Epub 2007 Mar 23.
Congenital heart defects (CHDs) are frequently caused by chromosomal imbalances, especially when associated with additional malformations, dysmorphism, or developmental delay. Only in a subset of such patients, a chromosomal aberration can be identified with current cytogenetic tests. Array Comparative Genomic Hybridization (Array-CGH) now enables the detection of submicroscopic chromosomal imbalances at high resolution. In this report, we evaluate for the first time the use of array-CGH as a diagnostic tool in a selected group of patients with a CHD.
Sixty patients with a CHD of unknown cause but with features suggestive of a chromosomal aberration were selected. Array-CGH was performed using an in-house made 1 Mb micro-array. Chromosomal imbalances not previously described as polymorphisms were detected in 18/60 patients (30%). Ten of these (17%) are considered to be causal. In three deletions, genes known to cause CHDs were implicated (NKX2.5, NOTCH1, NSD1, EHMT). One patient carried a duplication of chromosome 22q11.2, previously associated with CHD. In the other six patients, both the de novo occurrence as well as the size of the imbalance indicated causality. In addition, seven inherited aberrations unreported thus far were detected. Their causal relationship with CHDs remains to be established. Finally, a mosaic monosomy 7 was not considered as causal but did enable to make a diagnosis of Fanconi anaemia.
This study shows that array-CGH is able to provide an etiological diagnosis in a large proportion of patients with a CHD, selected for a 'chromosomal phenotype'. Besides their usefulness in genetic counselling, identified chromosomal aberrations may aid in the medical follow-up of these individuals.
先天性心脏病（CHD）常由染色体失衡引起，尤其是与其他畸形、发育异常或发育迟缓相关时。目前的细胞遗传学检测仅能在部分此类患者中识别出染色体畸变。阵列比较基因组杂交技术（Array-CGH）现在能够高分辨率检测亚微观染色体失衡。在本报告中，我们首次评估了Array-CGH作为一种诊断工具在一组特定先天性心脏病患者中的应用。
选取60例病因不明但具有染色体畸变特征的先天性心脏病患者。使用自制的1 Mb微阵列进行Array-CGH检测。在18/60例患者（30%）中检测到先前未描述为多态性的染色体失衡。其中10例（17%）被认为具有因果关系。在3例缺失中，涉及已知可导致先天性心脏病的基因（NKX2.5、NOTCH1、NSD1、EHMT）。1例患者携带22q11.2染色体重复，此前已发现与先天性心脏病相关。在其他6例患者中，新发失衡以及失衡大小均表明具有因果关系。此外，还检测到7例迄今未报道的遗传性畸变。它们与先天性心脏病的因果关系尚待确定。最后，嵌合性单体7不被认为具有因果关系，但有助于诊断范科尼贫血。
本研究表明，Array-CGH能够在很大一部分因“染色体表型”而入选的先天性心脏病患者中提供病因诊断。除了在遗传咨询中的作用外，已识别的染色体畸变可能有助于这些个体的医学随访。
