Looking down the atrioventricular canal.

Down’s syndrome (DS) is the most common aneuploidy diagnosed in liveborn babies ( 1/700 live births). While DS is typically associated with recognizable dysmorphic features, clinical anomalies exhibit variable expressivity. The DS phenotype includes many organ systems and affects all three embryonic germ layers. DS is the most frequent chromosomal cause of mental retardation, is a recognized genetic aetiology of Alzheimer disease, and is associated with congenital anomalies of the gastrointestinal and cardiac systems. It has been over 50 years since trisomy 21 was discovered as the genetic aetiology of DS. Despite progress in diagnosis and management of DS-related health problems, the definition of the pathogenetic mechanisms by which these gene dosage errors induce the DS phenotype and elucidation of DS genotype–phenotype correlations remains elusive. One of the barriers to progress in defining the underlying pathogenesis of this common genetic disorder has been the lack of a suitable animal model (reviewed in refs.). This has been especially true for DS-associated cardiovascular malformations. Nearly half of the DS patients have a congenital heart malformation; the signature cardiac defect is atrioventricular septal defect (AVSD), also known as atrioventricular (AV) canal defect or endocardial cushion defect. The paper by Dunlevy et al. in the current issue addresses this problem.