Molecular Analysis of the Cornelia de Lange Syndrome

Childrens Hospital Of Philadelphia, Philadelphia PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The Cornelia de Lange syndrome (CdLS) is a dominantly inherited genetic developmental disorder. The syndrome is characterized predominantly by characteristic facial features, defects of the upper extremities, gastroesophageal dysfunction, cardiac and ophthalmologic abnormalities, growth retardation, and neurodevelopmental delay. The phenotype is variable, but diagnosis is based solely on clinical findings as molecular markers have not been identified. Chromosome abnormalities have been found in several patients, but have not been consistent. Familial cases are extremely rare, as most affected individuals do not reproduce. Linkage analysis has not been undertaken in the past due to a paucity of informative families. [unreadable] [unreadable] We have identified a unique group of familial cases of CdLS that will permit us to undertake genetic analyses that will lead to the identification of the disease-causing gene. We hypothesize that by using our unique CdLS patient samples we will identify and characterize the responsible gene(s) using a multifaceted approach including linkage analysis, genome-wide molecular cytogenetic methodologies, and evaluation of candidate loci, pathways, and genes. Identification of the CdLS disease gene, while a difficult undertaking given the paucity of familial cases and the lack of consistent cytogenetic markers, will lead to improved clinical management of affected families and expand our understanding of human somatic and cognitive development. It will also shed light on the pathogenesis of more common multigenic conditions such as autism, orofacial clefting, and congenital heart disease. [unreadable] [unreadable] The goal of our proposal is to expand our current unique collection of samples from familial cases of CdLS and to completely characterize, at the clinical, cytogenetic and molecular levels, our large cohort of patients with CdLS and carry out a multi-faceted approach to identify loci within which candidate disease gene(s) can be identified and studied.