Clinical and Molecular Studies of Malformations

该实验室采用转化研究方法来研究人体畸形。在临床领域，我们采用了几种临床研究方案来评估严重程度、畸形谱和多效性发育异常的自然史。我们使用临床评估，包括病史和体格检查，影像学研究，包括x线摄影，超声和断层扫描，以及脑电图，肺功能测试等来表征功能和结构异常。在选定的病例中，我们也会进行手术治疗，如果它们能提供临床益处，并能促进我们对所研究疾病的理解。此外，我们在再洗礼派教派（阿米什教派和门诺教派）中进行实地考察，以研究在该人群中流行的人类遗传疾病。最后，我们与NCBI合作开发了再洗礼派宗谱数据库，这是一个包含超过40万条目的遗传研究资源。我们目前正在研究的一些疾病包括Pallister-Hall， Greig头多指综合征，McKusick Kaufman, Proteus, Bardet-Biedl， Lenz小眼症和眼面心脑血管综合征。

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.