Detailed molecular and clinical characterization of three patients with 21q deletions.

We have investigated three patients with 21q deletions, two with developmental delay, dysmorphic features and internal organ malformations, and one with cognitive function within the normal range but with some deficits in gross and fine motor development. All aberrations were characterized by array-comparative genomic hybridization (array-CGH). In addition, extensive fluorescence in situ hybridization (FISH) mapping on metaphase chromosomes and mechanically stretched chromosomes was performed on patient 1 who had an extremely complex intrachromosomal rearrangement with 16 breakpoints, four deletions and four duplications. Patients 2 and 3 had interstitial deletions comprising 21q21.1-21q22.11 and 21q11.2-21q21.3, respectively. Partial deletions of 21q are rare and these patients display a highly variable phenotype depending on the size and position of the deletion. A review of the literature identified 38 cases with pure 21q deletions. Twenty-three of these had reliable mapping data. The combined information of present and previous cases suggests that the ITSN1 gene is involved in severe mental retardation in patients with 21q deletion. In addition, a critical region of 0.56 Mb containing four genes, KCNE1, DSCR1, CLIC6 and RUNX1, is associated with severe congenital heart defects, and deletions of the most proximal 15-17 Mb of 21q is associated with mild or no cognitive impairment, but may lead to problems with balance and motor function.