Project summary New urgency has been added to the ability to precisely diagnose inherited spastic paraplegia (HSP) patients by the advent of gene targeting therapies in motoneuron disorders. Similar to other rare diseases, exome sequencing in our highly select HSP sample resolves only ~30% of families. We hypothesize that many of the missing disease-causing alleles are in fact not accessible to whole exome studies (WES). Whole genome sequencing (WGS) has become affordable and will be required to expand current knowledge. We have made significant progress in the past nine years in applying the WES paradigm and published findings on novel genes and pathways, relatively common deep intronic changes, gene/pseudogene complications for bioinformatics, uniparental disomy, and extensive phenotype/genotype correlations [1-7]. We have aggregated the probably largest set of HSP exomes (1,461 + 3,500 related phenotypes), created a network of collaborating scientists, engaged patient advocacy groups, and performed preclinical studies in preparation of clinical trials. This competitive renewal application will build further on these resources and prepare the stage for therapies. We propose a systematic expansion of our sample, clinical data collection, and state of the art sophisticated WGS- based studies to identify additional alleles and genes in HSP patients. The latter are based on our in-house developed GENESIS phenotype/genome analysis software that holds exome and genome data on 12,403 well- defined patients with rare neurological diseases. Standardized clinical classification using open human phenotype ontologies (HPO) allows for real-time genotype/phenotype data mining and gene matching in a collaborative fashion. We also propose an integrated genetic modifier study in the most common form of HSP, SPG4. The latter benefits from our recent success in this area [8] and has the potential to uncover alternative targets to rescue SPG4 phenotypic features. All new genes will be followed up with functional experiments for an additional layer of confirmation. This study will result in significant progress towards closing the diagnostic gap and identifying new and innovative therapeutic targets.