Audio: Genome Architecture and Genomic Disease: A Targeted Approach to Disease Discovery

Summary: Genomic disorders are conditions that result from recurrent rearrangement of DNA caused by unequal crossing over between duplicated genomic sequences. Most studies of genomic disorders have focused on patients with cognitive disability and/or peripheral nervous system defects. In an effort to broaden the phenotypic spectrum of this disease model, we assessed 155 autopsy samples from fetuses with well-defined developmental pathologies in regions predisposed to recurrent rearrangement by array CGH. We found that 6% of fetal material showed evidence of microdeletion or microduplication, One of the microdeletions, identified in a fetus with multicystic dysplastic kidneys, encompasses the TCF2 gene on 17q12, previously shown to be mutated in maturity-onset diabetes as well as a subset of pediatric renal abnormalities. Fine-scale mapping with custom oligonucleotide arrays of the breakpoints in different patient cohorts reveals a recurrent 1.5 Mb de novo deletion in individuals with phenotypes ranging from congenital renal abnormalities to maturity-onset diabetes of the young type 5. Array analysis also reveals significant copy number and structural variation at the breakpoints. The 17q12 microdeletion is the first genomic disorder associated with diabetes and accounts for a significant proportion of previously unexplained pediatric renal disease.