Individuals with Down's syndrome (DS), for example, like those with other aneuploidies or with chromosomal deletions or duplications, vary greatly in their clinical features, capabilities, disabilities and prognosis. Although many of these people, with the necessary social and clinical support, can and do lead active and fulfilling lives, some DS sub-phenotypes are associated with increased morbidity and mortality in infancy. Congenital heart defects (CHD), for example, occur in *40% of DS; 50% of these require surgical correction within the first year of life and survival to one year is only *76% compared with *91% for non-CHD DS patients (Yang et al. 2002 ). An appreciation of the molecular mechanisms behind this phenotypic variation and the identification of susceptibility loci may provide diagnostic and prognostic markers to enable us to predict the occurrence of clinically serious phenotypes, such as CHD, in DS. Additionally, analysis of these loci might help elucidate the mechanisms of CHD in non-DS children.