This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACTRare cases of genetic or epigenetic diseases can provide major insights into more common factors of the same or similar phenotypes as exemplified by studies of homozygous familial hypercholesterolemia and more recently when a single deletion case led to the discovery of a gene causing CHARGE syndrome A few genetic or epigenetic conditions can present with typical autism including mutations in MECP2, mutations within chromosome 15q11-q13, rarely mutations in neuroligin genes, fragile X syndrome, and tuberous sclerosis. We hypothesize that more patients dianosed with autism spectrum disorders have mutations or epimutations involving MECP2, genes within chromosome 15q11-q13, and the loci causing fragile X syndrome and tuberous sclerosis than is currently recognized. We also hypothesize that genes that interact with MECP2 and UBE3A are candidate genes for mutation or epimutation causing autism. Careful studies of autism patients for changes in these loci have already led to additional insights into autism, especially for MECP2 and 15q11-q13. We propose to carry out in depth genotype/phenotype and epigenotype/phenotype correlations in autistic patients with known abnormalities in these genes and regions with the goal of achieving further insights into more common forms of autism. In addition, we will anlayze typical autism patients for novel forms of mutationor epimutation involving MECP2, genes within 15q11-q13, or other genes. We will perform mutation and epimutation alalyses for other autism candidate genes based on a) potential for explaining the male predominant sex ratio in autism as for brain- or synapse-related genes on the X or Y chromosome; or b) functional, biochemical, or regulatory relationships to MECP2, genes in the 15q11-q13 region, FRAXA, or the tuberous sclerosis genes.HYPOTHESIS1. We hypothesize that more patients diagnosed with autism spectrum disorders have mutations or epimutations involving MECP2, genes within chromosome 15q11-q13, and the loci causing fragile X syndrome and tuberous sclerosis than is currently realized.2. We hypothesize that more extensive genetic analysis and especially epigenetic analysis of these loci in autism patients will identify new causes of autism.3. We hypothesize that patients with clinical diagnoses of Rett or Angelman syndrome without an identifiable molecular abnormality may have regulatory genetic or epigenetic defects involving the MECP2 or UBE3A, respectively.4. We hypothesize that detailed phenotypic analysis of patients with known mutations or epimutations involving MECP2, chromosome 15q11-q13, and the other loci will allow selection and identification of additional autism patients with abnormalities of these loci.5. We hypothesize that genes that interact with MECP2 and UBE3A are candidates for mutation or epimutation causing autism.6. We hypothesize that brain- or synapse-related genes on the X or Y chromosome are candidates for mutations or epimutations causing autism.
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