Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome

Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome we investigated 130 regions which we hypothesized as candidates for novel genomic disorders 1. We tested 290 patients with mental retardation by BAC array CGH, identifying sixteen pathogenic rearrangements, including four patients with de novo microdeletions of 17q21.31. Using oligonucleotide arrays we refined the breakpoints of this microdeletion, defining a 478 kb critical region containing six genes that were deleted in all four cases. The breakpoints of this deletion, and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 were mapped to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are also sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions. Keywords: BAC comparative genomic hybridization of individuals with mental retardation and congenital anomalies 290 individuals were analysed using a custom BAC array (Sharp et al. 2005, Am J Hum Genet. v77, p78). Each individual was analysed using dye-swap replicate hybs. 316 normal control individuals were analysed using identical methods, and have been reported previously (Sharp et al. 2005, Am J Hum Genet. 77, 78-88 and Locke et al. 2006, Am J Hum Genet, v79 p275). All hybridizations used a single male reference DNA (Coriell ID NA15724).