Chromosomal abnormalities are responsible for a significant fraction of children with mental retardation. Advances in molecular cytogenetic techniques as well as the tremendous progress of the Human Genome Project, have now made it possible to determine the molecular basis of chromosomal abnormalities. From patients with specific chromosome rearrangements including (i) balanced translocations, (ii) interstitial deletion/duplication and (iii) terminal deletion. The q11 region of chromosome 22 is susceptible to a multitude of rearrangements including translocations, leading to congenital anomalies and malignant disorders. Deletions and duplications of 17p11.2 are associated with Smith-Magenis syndrome and a mental retardation syndrome, respectively. Both the 22qll and 17p11.2 rearrangements may be mediated by low-copy repeat sequences that occur in the vicinity of recurrent chromosome breakpoints. Novel terminal deletions of the 1p36 region delineate a new mental retardation disorder with a different mechanism of rearrangement since the deletion end-points very significantly among patients. The three chromosomal regions will serve as models for our Program. We will examine the intervals that harbor the chromosome breakpoints by fluorescence in situ hybridization in situ hybridization (FISH) and pulse- field gel electrophoresis (PFGE) mapping approaches and breakpoint junctions will be cloned and sequenced to determine the mechanism of rearrangement. This projects will be integrated with a fourth project to determine the evolutionary basis of these regions that are prone to breakage in humans. Our functional genomics approach will capitalize on vast resources of DNA samples, cell lines, and Genome Project, as well as cell lines and reagents from non-human primates, that are available to the individual Project P.I.'s. Results from these studies will greatly impact our understanding of chromosome rearrangement causing mental retardation, will likely lead to development of novel diagnostic tools and may change the way medical genetics is practiced with regard to families having an individual with a chromosome rearrangement.

P01HD039420

2000-07-01

2007-05-31