VELOCARDIOFACIAL SYNDROME-MOLECULAR AND CLINICAL STUDIES

Children'S Hospital Of Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

Velocardiofacial syndrome (VCFS) is one of several disorders caused by a deletion of 22q11.2. It occurs with a frequency of 1/4000 livebirths and the deletion endpoints appear to cluster. VCFS patients have a spectrum of abnormalities including: cleft palate, speech language and learning disabilities, a typical facial appearance and cardiac defects. The frequency of the 22q11.2 deletion and complexity of the phenotype makes VCFS a significant health problem in the population. Understanding the pathogenesis of this disorder will require characterization of the deleted genes and investigations into the role that these genes play in normal embryonic and postnatal development. Thus, we will analyze the function, cell biology and expression of the genes in the deleted region as well as perform mutational analysis of the of "candidate" genes in non- deleted VCFS patients (Project 1). By chromosome engineering we will create and carefully characterize mouse models of VCFS, creating haploinsufficiency for the gens that have been identified to assess their role in the etiology of the phenotype (Project 2). The cytogenetic mechanism(s) responsible for the frequent 22q11.2 deletions will be examined by isolating and analyzing the recurrent deletion endpoints, searching for atypical deletions, studying 22q11.2 organization and analysis of chromosomal segregation/recombination (Project 3). Finally, we will seem to identify factors that influence the palatal phenotype in order to determine the source(s) of phenotypic variability seen in the deleted population (Project 4). The studies will be supported by three technical cores: A) a Clinical Core to perform detailed genetic, physical and neuropsychological examinations on the patients and manage/analyze the patient data; B) a Cell Culture Core to establish a bank of patient cell lines and DNAs; and C) a Histology core to assist in gene characterization. Capitalizing on extensive preliminary data generated by this consortium of collaborators we will continue or clinical and laboratory-based investigation of VCFS. The latest technologies in molecular genetics, mouse genetics, clinical genetics, developmental biology and physical diagnosis will be applied to dissection of this syndrome. This renewal represents a team effort aimed at detailed molecular characterization of the region of 22q11.2 deleted in VCFS to ascertain and analyze the factors responsible for creating the deletion and the complex phenotype it produces.