HomeResearchIntramural ResearchResearch Branches at NHGRIGenetic Disease Branch Biesecker Lab

Leslie G. Biesecker, M.D. Senior Investigator Genetic Disease Research Branch Head Human Development Section B.S. University of California, Riverside, 1979 M.D. University of Illinois College of Medicine, 1983 (301) 402-2041 (301) 402-2170 lesb@nhgri.nih.gov Building 49, Room 4A80 49 Convent Drive MSC 4472 Bethesda, MD 20892-4472 Selected Publications Pallister-Hall Syndrome

Our research focuses on the clinical and molecular delineation of human malformation syndromes. Our goals are to improve the medical care of patients affected by these disorders; to provide generalized knowledge about the broad field of birth defects; and to understand basic mechanisms of normal and abnormal human development. Currently, we are working on two classes of disorders: classic multiple congenital anomaly syndromes and progressive overgrowth disorders.

The multiple congenital anomaly syndromes include Pallister-Hall syndrome; Greig cephalopolysyndactyly syndrome; McKusick-Kaufman syndrome; Bardet-Biedl syndrome; and the Lenz microphthalmia syndrome. These disorders exhibit varying combinations of central nervous system malformations, visceral malformations, and polydactyly. Some have functional complications, such as mental retardation, seizures, and visual loss. We seek to describe the range of severity and long-term prognosis of these disorders through phenotypic characterization and natural history studies. Several of these disorders occur frequently in closed, Anabaptist sects, specifically the Old Order Amish and Mennonites of Lancaster County, Pennsylvania, and other regions of Ohio and Kentucky. We conduct field studies of these populations to evaluate and ascertain patients, perform computerized genealogical analysis, and develop clinical testing and treatment approaches. In the laboratory, we perform classical positional cloning studies to find the genes that cause these syndromes, determine genotype-phenotype correlations, and use animal models to investigate the pathogenetic mechanisms of these disorders.

We also study Proteus syndrome, a disorder of postnatal overgrowth. This disorder presents with severe disproportionate overgrowth of many tissues; occasional malformations of the limbs and central nervous system; and cutaneous nevi, among other manifestations. There is also an association between Proteus syndrome and two serious complications: massive pulmonary embolism and tumor predisposition. The current hypothesis says that Proteus syndrome is caused by somatic mosaicism for a mutation that is lethal in the non-mosaic state, which would explain the sporadic nature of the disorder, the patchy distribution of overgrowth, and the occurrence of the disorder in discordant monozygotic twins. We are testing this model by comparing affected and unaffected tissues of patients and screening these tissues for alterations in gene structure or expression. We are also determining the range of manifestations, severity and natural history of the disorder with a longitudinal natural history study. In the laboratory, we are using microarray expression analysis, representational difference analysis, and two-dimensional southern analysis in order to characterize gene alterations.

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Last Reviewed: October 2004