Research Interests

Our laboratory is studying the role of epigenetics and de novo and inherited mutations in human disease with particular emphasis on genomic imprinting and its role in Prader-Willi syndrome (PWS), Angelman syndrome (AS), and autism. Genomic imprinting is the phenomenon of differential expression of the two alleles at an autosomal locus based on their parent of origin; usually one allele is expressed and the other silenced. PWS and AS are distinct human disorders characterized by neurobehavioral abnormalities and intellectual disability. They are caused by deficiency of paternally (PWS) or maternally (AS) expressed genes within chromosome 15q11-q13. Our laboratory has contributed to identification of molecular defects causing PWS and AS, identified the UBE3A locus encoding E6-AP ubiquitin-protein ligase as the AS gene, and made numerous mouse models related to PWS and AS. The molecular findings in PWS and AS and evidence that genomic imprinting of 15q11-q13 also plays a role in autism have led us to propose a mixed epigenetic and genetic and mixed de novo and inherited (MEGDI) model for oligogenic inheritance of autism. This proposes a radically different model with recent or new mutations in one or a few major genes causing autism in any one individual. This is in contrast to the widely held hypothesis that many genes with ancient mutations cause autism through a multilocus epistasis model. The lab is also focused on the use of array comparative genomic hybridization (aCGH) to detect novel mutations causing intellectual disability, autism, and schizophrenia. Recent results suggest that deletions of chromosome 15q13 cause a phenotype of intellectual disability, autism, schizophrenia, and aggressive behavior. This has led to detailed genotyping for the CHRNA7 gene which maps to 15q13.3 and encodes a neuronal nicotinic acetylcholine receptor, which we believe is important in genetic causes of neurobehavioral disorders. Very recently, we discovered a novel inborn error of carnitine biosynthesis caused by deficiency of the X-linked TMLHE gene. This deficiency is present in 1 in 350 control males and is a risk factor for autism. This has led us to hypothesize that neuronal carnitine deficiency may play a broader role in non-dysmorphic autism, and that some forms of autism may be preventable or treatable through dietary supplementation with carnitine

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Section 41: Medical Genetics, Hematology, and Oncology