We have assembled a cohort of >1500 CM patients and family members and have performed exome sequencing to identify genetic factors that contribute to CM1 risk. It is our goal to leverage the vast infrastructure of the Park-Reeves Syringomyelia Research Consortium to assemble the largest cohort of CM1 patients in the world. Further, we have access to >20,000 unrelated control exome sequenced individuals through long-time collaboration at Washington University which greatly aid in association studies. We compare the frequency of genetic variants in patients to the frequency in our large control cohort to identify genes and variants associated with CM1. Variants with significantly higher or lower frequency in patients will give a better understanding of disease pathophysiology.
We are NIH funded to perform high-throughput functional assessment in genes that cause Limb-girdle muscular dystrophy (LGMD) and congenital muscular dystrophy (CMD). These assays allow us to produce look-up tables of the probable pathogenicity of every possible amino acid change in the genes assayed. We have completed this for the sarcoglycan beta gene (SGCB) (see above heat map for real data!). In collaboration with Chris Weihl, MD, PhD in the Department of Neurology at Washington University, we are working to complete these maps for all sarcoglycan genes (alpha, beta, delta and gamma) and many alpha-dystroglycanopathy genes.
To explore variant pathogenicity predictions for SGCB, go to: https://hallerlab.shinyapps.io/shinyapp/
We are performing proteomic measurements using cerebral spinal fluid (CSF) from patients with post-hemorrhagic hydrocephalus, congenital hydrocephalus and unaffected age-matched controls to understand the changes that occur to the brain after intraventricular hemorrhage, after onset of hydrocephalus and during normal brain development.
We use zebrafish as a model system to study the development of various neurological disorders including Chiari I malformation, syringomyelia and hydrocephalus. By “knocking-out” disease-assiciated genes in zebrafish, we are able to see what role these genes play in the development of analogous traits in the zebrafish.