Cornelia de Lange syndrome (CdLS) is an autosomal dominant disorder of multiple congenital anomalies including characteristic facial features, upper extremity reduction defects, gastroesophageal dysfunction, growth retardation, and neurodevelopmental delay. Mutations in NIPBL have been identified that cause CdLS. NIPBL has been implicated in sister chromatid cohesion as a subunit of adherin, which plays a major role in loading cohesin onto chromosomes prior to DNA replication. Cohesin consists of four subunits: Smc1, Smc3, Stromalin, and Rad21. Among other roles, cohesin is believed to prevent premature separation of sister chromatids. In addition to NIPBL, a number of other proteins including Pds5 and Eco1 have been implicated in the proper loading, positioning, and regulation of cohesin. Recently, other members of the sister chromatid cohesion complex have been implicated in human congenital disease. Mutations in the human homolog of Eco1 have been found cause Roberts and SC phocomelia syndrome. Most recently, mutations in a human Smc1 homolog (SMC1L1) have been found in patients with an X-linked variant of CdLS. The candidate hypothesizes that mutations in additional members of the cohesin complex and its regulatory proteins will be found in CdLS and related developmental disorders. This application seeks to investigate the contribution that mutations in NIPBL and other cohesin complex members make to the pathogenesis of CdLS and related diseases, and to develop tools to manage data and characterize genotype-phenotype correlations. This application lays out a five-year research and training program with the ultimate goal to transition the candidate to an independent physician-scientist. His mentors and advisors are leaders in the fields of clinical dysmorphology, gene discovery, and human development. He will take advantage of the ample resources of his environment, both at The Children's Hospital of Philadelphia and at the University of Pennsylvania.
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