Genetic Underpinnings of CM and SM and Effect on Brain Development

PROJECT SUMMARY Chiari type I malformation (CM1), the herniation of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions, found in approximately 1 in 1000 individuals. CM1 is characterized by the herniation of the cerebellum through the foramen magnum into the spinal canal, often leading to syringomyelia (SM), a fluid-filled cyst within the spinal canal, obstruction of normal cerebrospinal fluid flow, compression of the brainstem and numerous neurological symptoms. We now have identified some of the first genetic causes of CM1 and have identified idiopathic macrocephaly as a major etiological subtype of CM1. By identifying additional genetic factors underlying CM1 and CM1-related imaging biomarkers, we hope to uncover additional CM1 subtypes and their genetic basis. Additionally, our goal is to understand the role of CM1- associated genetic variation that we have already identified by modeling specific genetic variants in zebrafish to determine what systems are affected (brain, spine, skull, ventricular system) that lead to the common outcome of hindbrain displacement. Earlier and more accurate diagnoses for CM1 patients will have profound effects, informing clinical decisions regarding who should undergo surgery (versus CSF shunting vs surgery+spinal fusion vs observation, etc) and along what time frame.