Using Down's Syndrome as an example, an extra copy of chromosome 21 is not sufficient to cause the full range of phenotypes associated with this disorder, as individuals can present with a range of sub-phenotypes. Some features are almost always present, such as the characteristic facial appearance and mental retardation, although these can vary widely in the severity of their presentation (Kallen et al. e illustrates how a deletion on parent B and MII NDJ in parent A, however, that leads to a total of two copies of the gene in the trisomic child which could potentially ameliorate the pathological effects of trisomy 1996). Other features, however, are only present in a fraction of DS cases: for example, congenital heart defects (CHD) are present in *40% of cases (Park et al. 1977 ) and gastrointestinal (GI) defects in *8% of DS (Epstein et al. 1991) . Leukaemia is also common in DS, with an *20% increased risk of acute lymphoblastic leukaemia (ALL) (Hasle et al. 2000) , and transient myeloproliferative disorder occurring in *10% of DS newborns, of which 10-20% develop acute megakaryoblastic leukaemia (AMKL) before the age of 4 (reviewed in Hasle 2001) . A detailed knowledge of the genes on the affected chromosome is required to understand the phenotypic effects of aneuploidy. In addition, it is important to determine the overall effects of gene dosage imbalance, which may also be complex. Individuals with partial trisomy 21 resulting from unbalanced chromosomal translocations will only exhibit those features associated with the extra genomic material present. Molecular analysis of these patients enables 'phenotypic mapping' by defining the critical genomic regions that harbour genes associated with various phenotypes (Epstein et al. 1991) . As with all regions of the genome, many common CNVs and rarer genomic structural variants are found on chromosome 21. Two recent reports describe structural variations in which the presence of increased copies of genomic regions on chromosome 21 contributes to human phenotype. In one study, duplication of a region at 21q21 that included the amyloid precursor protein (APP) gene was found to cause familial Alzheimer's disease in five separate families (Rovelet-Lecrux et al. 2006) . The duplication varied in size from 0.58 to 6.37 Mb and contained from 5 to 12 annotated genes including APP. Despite the largest of these duplications being over 6 Mb, none of the families exhibited any clinical evidence of DS (Cabrejo et al. 2006) . A second duplication of a 4.3 Mb region at 21q22.13-q22.2, containing just over 30 genes, did help refine the map of the DS critical region (DCR) as it caused a DS phenotype in three family members (Ronan et al. 2007 ). These individuals had the facial characteristics of DS and mild cognitive disability indicating that this region includes part of the DCR but not all of it. It is apparent, therefore, that different sub-phenotypes of trisomy 21 are caused by increased copy number at different regions across chromosome 21. It is also evident that some DS individuals who are trisomic for a particular critical region do not always exhibit the associated phenotype, or display a much milder form.