Mutation Screening and Array Comparative Genomic Hybridization Using a 180K Oligonucleotide Array in VACTERL Association

In order to identify genetic causes of VACTERL association (V vertebral defects, A anorectal malformations, C cardiac defects, T tracheoesofageal fistula, E esophageal atresia, R renal anomalies, L limb deformities), we have collected DNA samples from 20 patients diagnosed with VACTERL or with a VACTERL-like phenotype as well as samples from 19 aborted fetal cases with VACTERL. To investigate the importance of gene dose alterations in the genetic etiology of VACTERL association we have performed a systematic analysis of this cohort using a 180K array comparative genomic hybridization (array-CGH) platform. In addition, to further clarify the significance of PCSK5, HOXD13 and CHD7 genes in the VACTERL phenotype, mutation screening has been performed. We identified pathogenic gene dose imbalances in two fetal cases; a hemizygous deletion of the FANCB gene and a (9;18)(p24;q12) unbalanced translocation. In addition, one pathogenic mutation in CHD7 was detected, while no apparent disease-causing mutations were found in HOXD13 or PCSK5. Our study shows that although large gene dose alterations do not seem to be a common cause in VACTERL association, array-CGH is still important in clinical diagnostics to identify disease cause in individual cases.为明确VACTERL综合征（VACTERL association，即V：脊柱缺陷、A：肛门直肠畸形、C：心脏缺陷、T：气管食管瘘、E：食管闭锁、R：肾异常、L：肢体畸形）的遗传病因，我们收集了20例确诊为VACTERL综合征或具有类VACTERL表型的患者的DNA样本，以及19例流产的VACTERL综合征胎儿样本。为探究基因剂量改变在VACTERL综合征遗传病因中的重要性，我们采用180K阵列比较基因组杂交（array-CGH）平台对该队列开展了系统性分析。此外，为进一步阐明PCSK5、HOXD13与CHD7基因在VACTERL表型中的意义，我们进行了突变筛查。我们在2例胎儿样本中检出致病性基因剂量失衡：分别为FANCB基因的半合子缺失，以及(9;18)(p24;q12)不平衡易位。另外，在CHD7基因中检测到1个致病性突变，而在HOXD13和PCSK5基因中未发现明确的致病突变。本研究表明，尽管大尺度基因剂量改变似乎并非VACTERL综合征的常见病因，但阵列-CGH在临床诊断中仍对明确个体病例的致病原因具有重要价值。