Mechanistic analysis of novel genetic loci for split hand foot malformation

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Summary A fundamental question in developmental biology and genetics is how defects in cell fate specification and differentiation results in specific birth defects. This represents an important problem, because defects in limb and neural crest development underlie many human congenital birth defects including split hand foot malformation (SHFM). SHFM is a devastating congenital birth defect that presents with hands and feet that have a median cleft as well as craniofacial abnormalities that occurs in about 1:18,000 live births. Because there is limited information regarding genetic loci for SHFM, there is a critical need for clinical scientists to partner with basic developmental biologists to identify novel genetic loci and provide a mechanistic basis for this malformation such that treatments and genetic counseling can be developed. Here, we will identify novel loci for SHFM including the newly identified linkage with PRDM1. We hypothesize that PRDM1 functions as a transcriptional and epigenetic regulator required for NCC and limb development and when mutated, results in SHFM. The rationale for the proposed studies is that an in depth understanding of specific genetic loci responsible for SHFM will provide insights into both basic biology and the etiology of congenital birth defects. We will test this hypothesis in the following specific aims: 1) Determine the comprehensive patient phenotype and causative genetic loci for SHFM in humans. 2) Test the hypothesis that PRDM1 functions to regulate craniofacial and limb development and when mutated is causative for SHFM. Together, these studies will identify and test the function of new genetic loci for SHFM and once identified, determine the cellular and molecular mechanisms by which specific variant mutations function and the basis of the variability in phenotype. These data will provide a foundation for the design of therapeutic strategies for neural crest associated birth defects.