Brosens E, Eussen H, van Bever Y, van der Helm R M, Ijsselstijn H, Zaveri H P, Wijnen R, Scott D A, Tibboel D, de Klein A
Department of Clinical Genetics, Erasmus Medical Centre, The Netherlands ; Department of Pediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
Mol Syndromol. 2013 Feb;4(1-2):20-6. doi: 10.1159/000345577.
Copy number variations (CNVs), either DNA gains or losses, have been found at common regions throughout the human genome. Most CNVs neither have a pathogenic significance nor result in disease-related phenotypes but, instead, reflect the normal population variance. However, larger CNVs, which often arise de novo, are frequently associated with human disease. A genetic contribution has long been suspected in VACTERL (Vertebral, Anal, Cardiac, TracheoEsophageal fistula, Renal and Limb anomalies) association. The anomalies observed in this association overlap with several monogenetic conditions associated with mutations in specific genes, e.g. Townes Brocks (SALL1), Feingold syndrome (MYCN) or Fanconi anemia. So far VACTERL association has typically been considered a diagnosis of exclusion. Identifying recurrent or de novo genomic variations in individuals with VACTERL association could make it easier to distinguish VACTERL association from other syndromes and could provide insight into disease mechanisms. Sporadically, de novo CNVs associated with VACTERL are described in literature. In addition to this literature review of genomic variation in published VACTERL association patients, we describe CNVs present in 68 VACTERL association patients collected in our institution. De novo variations (>30 kb) are absent in our VACTERL association cohort. However, we identified recurrent rare CNVs which, although inherited, could point to mechanisms or biological processes contributing to this constellation of developmental defects.
拷贝数变异（CNV），即DNA的增加或减少，已在整个人类基因组的常见区域被发现。大多数CNV既没有致病意义，也不会导致与疾病相关的表型，相反，它们反映了正常人群的变异。然而，通常新生的较大CNV常常与人类疾病相关。长期以来，人们一直怀疑VACTERL（脊柱、肛门、心脏、气管食管瘘、肾脏和肢体异常）综合征存在遗传因素。在该综合征中观察到的异常与一些与特定基因突变相关的单基因疾病重叠，例如Townes Brocks综合征（SALL1基因）、Feingold综合征（MYCN基因）或范可尼贫血。到目前为止，VACTERL综合征通常被认为是一种排除性诊断。识别VACTERL综合征患者中的复发性或新生基因组变异，可能会使区分VACTERL综合征与其他综合征变得更容易，并有助于深入了解疾病机制。文献中偶尔会描述与VACTERL综合征相关的新生CNV。除了对已发表的VACTERL综合征患者的基因组变异进行文献综述外，我们还描述了在我们机构收集的68例VACTERL综合征患者中存在的CNV。在我们的VACTERL综合征队列中没有发现新生变异（>30 kb）。然而，我们识别出了复发性罕见CNV，尽管这些是遗传性的，但可能指向导致这一系列发育缺陷的机制或生物学过程。
