Project Grant R21NS135321

UNDERSTANDING THE MECHANISMS OF CONGENITAL HYDROCEPHALUS USING GENOMIC SEQUENCING APPROACHES - CONGENITAL HYDROCEPHALUS (CH) IS A CONDITION THAT AFFECTS THE BRAIN AND RESULTS FROM AN ABNORMAL ACCUMULATION OF CEREBROSPINAL FLUID (CSF) WITHIN THE CEREBRAL VENTRICLES. THE CURRENT TREATMENTS FOR HYDROCEPHALUS ARE SURGICAL INTERVENTIONS, WHICH ACCOMPANIES A HIGH FAILURE RATE. ALTHOUGH EXTRINSIC FACTORS SUCH AS HEMORRHAGE OR INFECTIONS MAY CAUSE CH, RECENT STUDIES HAVE IDENTIFIED SOME CH-ASSOCIATED GENES OR MUTATIONS, EMPHASIZING THE ROLE OF GENETICS IN CH. HOWEVER, THESE GENETIC FACTORS ONLY ACCOUNT FOR APPROXIMATELY 22% OF SPORADIC CH CASES, AND MANY CASES REMAIN UNSOLVED. THEREFORE, THERE IS AN URGENT NEED TO ACCELERATE THE UNDERSTANDING OF CH THROUGH THE CUTTING-EDGE TECHNOLOGIES. WITHOUT LEVERAGING THESE NOVEL METHODS, THE DISCOVERY OF ADDITIONAL CAUSAL GENETIC FACTORS OF CH AND THE ADVANCEMENT OF ACCURATE DIAGNOSES AND TREATMENTS MAY BE HINDERED. THE LONG- TERM GOAL IS TO UNDERSTAND THE MOLECULAR MECHANISMS AND CONSEQUENCES UNDERLYING CH USING ORTHOGONAL PHENOMIC, GENETIC, AND MULTI-OMICS APPROACHES. THE OVERALL OBJECTIVE IS TO DEVELOP AND APPLY NEW GENOMICS TOOLS TO ADVANCE OUR UNDERSTANDING OF THE BIOLOGICAL MECHANISMS OF CH. THE CENTRAL HYPOTHESIS IS THAT THERE ARE ADDITIONAL GENETIC VARIATIONS IN GERMLINE OR SOMATIC AND/OR SPECIFIC MALFUNCTIONING CELL TYPES THAT CONTRIBUTE TO THE ETIOLOGY OF CH. TO TEST THIS HYPOTHESIS, THE PIS AND TEAM WILL PURSUE THE FOLLOWING AIMS. 1) COMPREHENSIVE CHARACTERIZATION OF ALL FORMS OF VARIATIONS IN BOTH GERMLINE AND SOMATIC TISSUE FROM CH PATIENTS WITH SHORT- AND LONG- READ WHOLE GENOME SEQUENCING. 2) IDENTIFICATION OF ABNORMAL CELL TYPES AND UNDERSTANDING THEIR FUNCTION AND CONTRIBUTION TO CH THROUGH SINGLE-CELL GENOMICS ANALYSIS. UPON COMPLETION, IT IS EXPECTED THAT NEW VARIATIONS EITHER IN THE GERMLINE OR SOMATIC MAY CONTRIBUTE TO CH.