Molecular genetic studies of congenital craniofacial anomalies have greatly enhanced our understanding of human face and eye development. For example, studies of holoprosencephaly (HPE), a common brain abnormality associated with malformations of the face, eyes, palate, and teeth, have led to the identification of genes required for normal craniofacial development. The anomalies seen in HPE can be severe and include cyclopia, nasal anomalies, and cleft lip/palate. Recently, several genes have been shown to be associated with human HPE. However, most HPE patients still do not have a defined genetic defect. By further exploring the genetic basis of HPE, we seek to gain insight into HPE and the critical genes that regulate craniofacial and brain development. We hypothesize that additional genes and chromosomal regions are associated with human HPE. Since cytogenetically visible chromosomal abnormalities have been noted in a significant proportion of HPE patients, we hypothesize that a subset of HPE cases with a normal karyotype have a submicroscopic chromosomal alteration. We will perform array-based comparative genomic hybridization (aCGH) to identify subtle duplications and deletions. We will characterize the chromosomal rearrangements detected by this method. In addition, since more than 80% of the HPE cases with a normal karyotype in our cohort do not have a mutation in one of the known HPE genes, we will identify additional genes that are associated with human HPE. Based on the array CGH studies, candidate genes will be selected and analyzed. Also, candidate genes will be examined based on their role in signaling pathways implicated in HPE, their function in brain and craniofacial development, and/or their chromosomal location in a region associated with HPE. With these studies, we will further elucidate the genetic etiology of HPE and gain important insight into causes of congenital craniofacial and brain anomalies.
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