The laboratory uses a translational research approach to study human malformations. In the clinical arena, we operate several clinical research protocols to assess the range of severity, spectrum of malformations, and natural history of pleiotropic developmental anomalies. We use clinical evaluations that include history and physical examination, imaging studies including radiography, ultrasound, and tomography, as well as EEG, pulmonary function testing, etc. to characterize functional and structural anomalies. In selected cases we also perform surgical treatments if they offer clinical benefit and can advance our understanding of the disease under study. In addition, we perform fieldwork among the Anabaptist sects (Amish and Mennonites) to study human genetic diseases prevalent in that population. Finally, we collaborate with NCBI to develop the Anabaptist Genealogy Database, which is a research resource for genetic research that includes over 400,000 entries. Some of the disorders that we are currently studying include Pallister-Hall, Greig cephalopolysyndactyly, McKusick Kaufman, Proteus, Bardet-Biedl, Lenz microphthalmia, and Oculofaciocardiodental syndromes. We use the tools of modern molecular biology to determine the molecular pathogenesis of these disorders. These include positional cloning, microarray expression and microarray CGH analysis, cell and tissue culture studies to assess cell biologic functions and abnormalities of gene products, and the creation and analysis of animal models of human genetic disease (mouse and zebrafish). Using these techniques we have elucidated the etiology of Pallister-Hall, McKusick-Kaufman, Lenz microphthalmia and Oculofaciocardiodental syndromes. In addition, we have demonstrated the functional defect of Pallister-Hall syndrome by comparing the function of the causative gene in that disorder (GLI3) to its Drosophila homologue (cubitus interruptus) and correlating those functions with mutations in over 150 patients. In so doing, we have determined that the mechanism of Pallister Hall syndrome is distinct from that of Greig cephalopolysyndactyly syndrome. We have also clinically redefined the Proteus syndrome, a disorder of mosaic overgrowth with tumor susceptibility. We did this through evaluating a series of 35 patients and an exhaustive survey of all cases reported in the literature. This allowed us to establish new clinical diagnostic criteria for this disorder and delineate a novel disease entity, the hemihyperplasia-multiple lipomatosis syndrome. In our studies of Lenz microphthalmia syndrome we determined that this disorder is actually an amalgamation of two distinct X-linked diseases and that one form of Lenz is allelic to Oculofaciocardiodental syndrome and that both of these diseases are caused by mutations in the BCOR gene. Finally, we are using animal models to study two disorders, Amish microcephaly syndrome, which we determined to be caused by mutations in the DNC gene, and a phenocopy of Greig cephalopolysyndactyly syndrome. For Amish microcephaly, we have created a mouse knockout model of that disease using transgenic technology and are studying the pathophysiology of that disorder using genetic and biochemical analysis. We are also performing a positional cloning analysis of the Greig cephalopolysyndactyly phenotype in the mouse using a sporadic mutant identified at a large breeding facility. This disorder has now been mapped to a 500 KB interval and candidate genes are being sequenced.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Intramural Research (Z01)
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Human Genome Research
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Biesecker, Leslie G (2018) Mosaic disorders and the Taxonomy of Human Disease. Genet Med 20:800-801
Al-Olabi, Lara; Polubothu, Satyamaanasa; Dowsett, Katherine et al. (2018) Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest 128:1496-1508
Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A et al. (2018) Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med 20:1175-1185
Biesecker, Leslie G (2009) A silent majority? Am J Med Genet A 149A:1623
Sapp, Julie C; Turner, Joyce T; van de Kamp, Jiddeke M et al. (2007) Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients. Am J Med Genet A 143A:2944-58
Johnston, Jennifer J; Walker, Robert L; Davis, Sean et al. (2007) Zoom-in comparative genomic hybridisation arrays for the characterisation of variable breakpoint contiguous gene syndromes. J Med Genet 44:e59
Biesecker, Leslie G (2007) A maneuver to assess the presence of metacarpal or metatarsal osseous syndactyly: a physical finding useful for the differential diagnosis of polydactyly. Am J Med Genet A 143A:1788-9
Turner, Joyce; Biesecker, Barbara; Leib, Jennifer et al. (2007) Parenting children with Proteus syndrome: experiences with, and adaptation to, courtesy stigma. Am J Med Genet A 143A:2089-97
Hilton, Emma N; Manson, Forbes D C; Urquhart, Jill E et al. (2007) Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination. Hum Mol Genet 16:1773-82
Lipinski, Shawn E; Lipinski, Michael J; Biesecker, Leslie G et al. (2006) Uncertainty and perceived personal control among parents of children with rare chromosome conditions: the role of genetic counseling. Am J Med Genet C Semin Med Genet 142C:232-40

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