The objective of this proposal is to assess the efficacy of new fluorescence in situ hybridization techniques as adjunct diagnostic tests for pervasive developmental delay (PDD) and mental retardation (MR). In addition it is proposed to identify chromosoma loci that may harbor genes important in neural development and cognitive function. The hypothesis is that the screening of patients with PDD and/or MR with chromosome-specific painting probes, telomere-specific probe sets, and microdeletion probe sets is an effective method to identify unknown causes of PDD and MR and to identify genes involved in neurodevelopment or cognitive attributes. The investigator's laboratory currently has the capacity to produc a complete karyotype, including banding, from a signal hybridization using multicolor fluorescence in situ hybridization (M-FISH) and to test for rearrangements of telomeric and subtelomeric regions using a set of telomere-specific probes for all chromosomes except the p arms of acrocentric chromosomes. It is proposed to develop robust screening methods for karyotypic analysis, for monitoring telomere integrity and for assessing microdeletion syndrome regions using multicolor combinatorial labeled probe sets. The development of such screening methods for us in clinical cytogenetic laboratories should result in better diagnosis and prognosis assessment, and, ultimately, in better therapies for these individuals. Specifically, it is proposed to screen 300 individuals with PDD, 300 with MR, and approximately 500 normal control subjects for chromosomal abnormalities using state-of-the-art multiplex hybridization and imaging technology. The relative rates of karyotypic aberrations in these populations and the background rate of karyotypic aberrations in normal individuals will be assessed. The relative sensitivity of the new screening methods will be compared with standard cytogenetic methods. It is anticipated that this proposal will permit the investigators to make an estimate of the efficacy of karyotypic screening of patients in these diagnostic groups. In addition, specific probes will be identified that will be made available to other researchers for testing specific translocation breakpoint sites and should permit the future cloning of cDNAs that are associated with pervasive developmental delay or mental retardation.
