Brosens Erwin, Marsch Florian, de Jong Elisabeth M, Zaveri Hitisha P, Hilger Alina C, Choinitzki Vera Gisela, Hölscher Alice, Hoffmann Per, Herms Stefan, Boemers Thomas M, Ure Benno M, Lacher Martin, Ludwig Michael, Eussen Bert H, van der Helm Robert M, Douben Hannie, Van Opstal Diane, Wijnen Rene M H, Beverloo H Berna, van Bever Yolande, Brooks Alice S, IJsselstijn Hanneke, Scott Daryl A, Schumacher Johannes, Tibboel Dick, Reutter Heiko, de Klein Annelies
Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
Department of Paediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
Eur J Hum Genet. 2016 Dec;24(12):1715-1723. doi: 10.1038/ejhg.2016.86. Epub 2016 Jul 20.
Oesophageal atresia (OA) with or without tracheoesophageal fistula (TOF) are rare anatomical congenital malformations whose cause is unknown in over 90% of patients. A genetic background is suggested, and among the reported genetic defects are copy number variations (CNVs). We hypothesized that CNVs contribute to OA/TOF development. Quantifying their prevalence could aid in genetic diagnosis and clinical care strategies. Therefore, we profiled 375 patients in a combined Dutch, American and German cohort via genomic microarray and compared the CNV profiles with their unaffected parents and published control cohorts. We identified 167 rare CNVs containing genes (frequency<0.0005 in our in-house cohort). Eight rare CNVs - in six patients - were de novo, including one CNV previously associated with oesophageal disease. (hg19 chr7:g.(143820444_143839360)_(159119486_159138663)del) 1.55% of isolated OA/TOF patients and 1.62% of patients with additional congenital anomalies had de novo CNVs. Furthermore, three (15q13.3, 16p13.3 and 22q11.2) susceptibility loci were identified based on their overlap with known OA/TOF-associated CNV syndromes and overlap with loci in published CNV association case-control studies in developmental delay. Our study suggests that CNVs contribute to OA/TOF development. In addition to the identified likely deleterious de novo CNVs, we detected 167 rare CNVs. Although not directly disease-causing, these CNVs might be of interest, as they can act as a modifier in a multiple hit model, or as the second hit in a recessive condition.
食管闭锁（OA）伴或不伴气管食管瘘（TOF）是罕见的解剖学先天性畸形，超过90%的患者病因不明。有研究提示其存在遗传背景，且在已报道的遗传缺陷中有拷贝数变异（CNV）。我们推测CNV与OA/TOF的发生有关。量化其发生率有助于遗传诊断和临床护理策略的制定。因此，我们通过基因组微阵列对荷兰、美国和德国的一个联合队列中的375例患者进行了分析，并将CNV图谱与其未受影响的父母以及已发表的对照队列进行了比较。我们鉴定出167个包含基因的罕见CNV（在我们的内部队列中频率<0.0005）。8个罕见CNV（在6例患者中）为新发突变，其中包括1个先前与食管疾病相关的CNV。（hg19 chr7:g.(143820444_143839360)_(159119486_159138663)del）1.55%的孤立性OA/TOF患者和1.62%合并其他先天性异常的患者存在新发CNV。此外，基于与已知的OA/TOF相关CNV综合征的重叠以及与发育迟缓的已发表CNV关联病例对照研究中的位点重叠，鉴定出三个（15q13.3、16p13.3和22q11.2）易感位点。我们的研究表明CNV与OA/TOF的发生有关。除了已鉴定出的可能有害的新发CNV外，我们还检测到167个罕见CNV。尽管这些CNV并非直接致病，但它们可能具有重要意义，因为它们可以在多重打击模型中作为修饰因子，或者在隐性疾病中作为第二次打击。
