Holoprosencephaly (HPE) is the most common malformation of the brain and face in humans (1 in 250 fetuses, and 1/16,000 live births). It is extremely genetically heterogeneous with over 80% of HPE genes presently unknown. Generally, its etiology is attributed to either de novo or autosomal dominant inheritance of deleterious mutations (or deletions) of at least a dozen different HPE genes. Clinically, it displays incomplete penetrance, and its expressivity is extremely variable. HPE can range from a single eye (cyclopia) and un-divided forebrain, at one extreme, to simple microforms, consisting of isolated subtle facial manifestations such as a single central incisor (Figure 1a) We have been leaders in the identification of HPE genes and confirming disease mechanisms (Figure 1b). However, despite these advances, its etiology, pathogenesis and any explanations for the underlying genetic and environmental sources of this variability are incomplete. Therefore, there are many challenges ahead. Here we propose to use animal models in concert with conventional and the latest in genomic tools (targeted capture, exome, whole genome) to advance our understanding of HPE. Our past efforts have helped formulate the most comprehensive molecular and clinical descriptions of HPE. In doing so, weve synergized efforts between intramural and extramural scientists and clinicians, set evolving diagnostic standards, and established successful international collaborative efforts aimed at future progress in HPE research and related conditions. Our studies guide an understanding of both normal and abnormal brain development. The best summary of our successes can be found in our Amer J Med Genet issue 154C, which is devoted exclusively to HPE. This issue illustrates our insistence on a multi-disciplinary, multi-center approach to the description of the clinical/molecular spectrum of HPE and the genotype-phenotype associations with individual genes. Our approach aims to uncover the molecular basis of HPE through a search for associative genes using cytogenetic analysis, copy number variation analysis, mutational analysis, specific diagnostic algorithms, in conjunction with present and next generation genomics strategies. Our past and future goals include the determination to marshal the resources of the NIH community and extramural scientists to perform functional studies on the mutations detected among our probands. Although often expensive and time consuming, we consider this one of our primary responsibilities to a family that participates.

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Kruszka, Paul; Addissie, Yonit A; Yarnell, Colin M P et al. (2016) Muenke syndrome: An international multicenter natural history study. Am J Med Genet A 170A:918-29
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