Chiari type 1 malformation (CM1) is one of the most common pediatric neurological conditions, affecting ~3% of individuals undergoing brain imaging. 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 with the spinal canal, obstruction of normal cerebrospinal fluid flow, compression of the brainstem and numerous neurological symptoms. The genetic causes of CM1 and SM are poorly understood, but understanding these causes may improve diagnosis and treatment of these disorders, transforming the lives of affected individuals.
· Identify genetic variation associated with risk for Chiari type 1 malformation and syringomyelia (CM1/SM).
· Model disruption of CM1/SM-associated genes in zebrafish to understand the mechanisms of pathogenicity in humans.
· Functionally characterize the effects of genetic variation in disease-associated genes using high-throughput functional genomics/saturation mutagenesis.
Particularly in children, earlier and more accurate diagnoses will have profound effects, informing clinical decisions regarding who should undergo surgery (versus observation) and along what time frame. Avoiding known complications of these diseases—spinal deformity or craniocervical instability requiring fusion, for example—could have enormous implications for patient and family quality of life.