HomeResearchIntramural ResearchResearch Branches at NHGRIGenetic Disease Research Branch Biesecker Lab

Leslie G. Biesecker, M.D. Chief & Senior Investigator Genetic Disease Research Branch Head Human Development Section Head Physician Scientist Development Program B.S. University of California, Riverside, 1979 M.D. University of Illinois College of Medicine, 1983 (301) 402-2041 (301) 402-2170 leslieb@helix.nih.gov Building 49, Room 4A80 49 Convent Dr, MSC 4472 Bethesda, MD 20892-4472 Selected Publications Pallister-Hall Syndrome DNA Identifications After the 9/11 World Trade Center Attack

Dr. Biesecker's research focuses on the clinical and molecular delineation of human malformation syndromes. Currently, his laboratory is working on two classes of disorders: classic multiple congenital anomaly syndromes and segmental overgrowth disorders. The goals of his research program are to improve the medical care of patients affected by these disorders, provide generalized knowledge about the broad field of birth defects, and better understand basic mechanisms of normal and abnormal human development.

Dr. Biesecker's group studies several multiple congenital anomaly syndromes, including Pallister-Hall syndrome, Greig cephalopolysyndactyly syndrome, McKusick-Kaufman syndrome, Bardet-Biedl syndrome, and Lenz microphthalmia syndrome. These disorders exhibit various combinations of central nervous system malformations, visceral malformations, and polydactyly (extra fingers and toes). Some patients have functional complications, such as mental retardation, seizures, and visual loss. To further elucidate the clinical manifestations of multiple congenital anomaly syndromes and improve treatment approaches, Dr. Biesecker's group conducts clinical research in the Mark O. Hatfield Clinical Research Center. They also conduct field studies of populations to ascertain and evaluate patients, perform computerized genealogical analyses, and develop clinical testing approaches. Several of these disorders occur frequently in closed, religious sects - specifically, the Old Order Amish and Mennonites in Lancaster County, Pennsylvania and regions of Ohio and Kentucky. His group maintains close relationships with local clinics that serve these populations.

In the laboratory, his group performs classical positional cloning studies to find the genes that are altered in these syndromes, determines genotype-phenotype correlations, and uses animal models to investigate the pathogenetic mechanisms of these disorders. For example, they recently investigated whether two multiple congenital anomaly syndromes- oculofaciocardiodental syndrome (OFCD) and MAA2-associated Lenz microphthalmia-were allelic because of their phenotypic overlap. This investigation identified a single base substitution in the BCOR gene (encoding BCL-6-interacting corepressor) on chromosome Xpll.4 in affected males from a family with Lenz syndrome and different frameshift, deletion, and nonsense mutations in the BCOR gene in seven families affected with OFCD. In addition, Dr. Biesecker's group cloned the zebrafish ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations - of the eye, skeleton, and central nervous system -consistent with Lenz microphthalmia. This study confirmed that BCOR is a key transcriptional regulator during early embryogenesis.

In addition, Dr. Biesecker's group is attempting to improve the diagnosis and management of segmental overgrowth disorders, a group of disorders that cause highly variable overgrowth of parts of the body, such as excessive postnatal growth of bones, organs, and fatty tissue. An increased risk of cancer accompanies a number of the overgrowth syndromes. The intrinsic variability of these disorders, combined with a dearth of longitudinal data on their natural history, has led to diagnostic confusion. A good example of this is Proteus syndrome, a rare but severe type of segmental overgrowth. It is a complex disorder with multisystem involvement and great clinical variability. It is believed that the many manifestations of Proteus syndrome - lipomas, several types of nerve disorders, and partial gigantism (with limb or digit overgrowth) - result from somatic mosaicism of a dominant lethal gene, but the gene locus has yet to be identified. Dr. Biesecker's laboratory is testing this hypothesis by comparing tissues of affected and unaffected patients and screening those tissues for alterations in gene structure or expression. They are also determining the range of manifestations, severity, and natural history of Proteus syndrome with a longitudinal study and are using microarray expression analysis, representational difference analysis, and two-dimensional Southern blot analysis to characterize gene alterations. Through these types of investigations, Dr. Biesecker's group found an association between Proteus syndrome and two serious complications: massive pulmonary embolism and tumor predisposition.

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Last Reviewed: July 28, 2008