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Hedgehog (Hh) signaling is vital for the patterning and organogenesis of almost every system. The specificity of these developmental processes is achieved through a tight spatio-temporal regulation of Hh signaling. Mice with defective Hh signal exhibit a wide spectrum of anomalies, including Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Renal dysplasia, and Limb defects, that resemble strikingly the phenotypes observed in VACTERL association in humans. In this review, we summarize our current understanding of mammalian Hh signaling and highlight the relevance of various mouse models for studying the etiology and pathogenesis of VACTERL association. In addition, recent advances in genetic study for unraveling the complexity of genetic inheritance of VACTERL and the implication of the Sonic hedgehog pathway in disease pathogenesis are also discussed.

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.