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. Some of the disorders that we are currently studying include non-syndromic polydactyly, Proteus syndrome, non-Proteus asymmetric overgrowth syndrome, Bardet-Biedl syndrome, PIGA-related CNS dysplasia, Ogden syndrome, and Lenz microphthalmia syndrome. We use the tools of modern molecular biology to determine the molecular pathogenesis of these disorders. These include high throughput sequencing, 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 in the past year we have elucidated the etiology of PIGA-related CNS dysplasia, TARP syndrome (Talipes, Atrial septal defect, Right superior vena cava, and cleft Palate), Pallister-Hall, McKusick-Kaufman, two forms of Lenz microphthalmia, Oculofaciocardiodental syndromes, combined malonic and methylmalonic acidemia, Proteus syndrome, and PIK3CA-related non-Proteus overgrowth. In addition, Dr. Biesecker is a co-founder and co-director of the Elements of Morphology dysmorphology standards working group. This group is working to standardize malformation descriptions to increase the utility of clinical descriptions and journal reports. The group is currently working on definitions for genital anomalies and an expanded set of limb morphology terms.

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National Human Genome Research Institute
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Doucet, Meggie E; Bloomhardt, Hadley M; Moroz, Krzysztof et al. (2016) Lack of mutation-histopathology correlation in a patient with Proteus syndrome. Am J Med Genet A 170:1422-32
Keppler-Noreuil, Kim M; Baker, Eva H; Sapp, Julie C et al. (2016) Somatic AKT1 mutations cause meningiomas colocalizing with a characteristic pattern of cranial hyperostosis. Am J Med Genet A 170:2605-10
Bennett, James T; Tan, Tiong Yang; Alcantara, Diana et al. (2016) Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. Am J Hum Genet 98:579-87
Wentzensen, Ingrid M; Johnston, Jennifer J; Patton, John H et al. (2016) Exome sequencing identifies a mutation in OFD1 in a male with Joubert syndrome, orofaciodigital spectrum anomalies and complex polydactyly. Hum Genome Var 3:15069
Keppler-Noreuil, Kim M; Rios, Jonathan J; Parker, Victoria E R et al. (2015) PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A 167A:287-95
Johnston, Jennifer J; Sanchez-Contreras, Monica Y; Keppler-Noreuil, Kim M et al. (2015) A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome. Am J Hum Genet 97:465-74
Hannoush, H; Sachdev, V; Brofferio, A et al. (2015) Myocardial fat overgrowth in Proteus syndrome. Am J Med Genet A 167A:103-10
Russell, Bianca; Johnston, Jennifer J; Biesecker, Leslie G et al. (2015) Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance. Am J Med Genet A 167A:2122-31
Wentzensen, Ingrid M; Johnston, Jennifer J; Keppler-Noreuil, Kim et al. (2015) Exome sequencing identifies novel mutations in C5orf42 in patients with Joubert syndrome with oral-facial-digital anomalies. Hum Genome Var 2:15045
Lindhurst, Marjorie J; Yourick, Miranda R; Yu, Yi et al. (2015) Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome. Sci Rep 5:17162

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