The Dobyns and Millen labs have identified the first genes for the most common cerebellar birth defect, Dandy-Walker malformation (DWM) and are actively working to identify genes underlying other cerebellar malformations, including cerebellar vermis hypoplasia and rhombencephalosynapsis (see figure below). The cerebellum is a brain structure that lies between the brainstem and the cerebrum and plays important roles in sensory perception, motor output, balance and posture in addition to cognition and emotion. Cerebellar malformations are caused by disruptions of brain development during early embryogenesis and are often accompanied by other birth defects, including hydrocephalus and agenesis of the corpus callosum. They are relatively common, collectively affecting 1/5000 live births and can cause significant developmental delays and contribute to autism. The Dobyns lab has also identified the genetic lesions in several brain overgrowth syndromes, including megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP) (see figure below). These two related syndromes are of sporadic occurrence and consist of megalencephaly associated with growth dysregulation, distal limb malformations, polymicrogyria, and connective tissue dysplasia, as well as vascular malformations. (see figure below). Drs. Dobyns’s lab maintains the world’s largest clinical database of human brain malformation patients, including structural MRI scans and DNA samples. Qualitative and quantitative analysis of MRI scans is underway to determine the association between specific brain abnormalities and specific gene mutations.
The image on the left shows brain MRI scans from children with deletions or duplications of the FOX C1 gene who have Dandy Walker Malformation or less severe malformations in the Dandy-Walker spectrum. The image on the right shows the brain MRI of a child with megalencephaly associated with a mutation of the PIK3CA gene.