Project 2

Boston Children'S Hospital, Boston MA

Investigators

Abstract

ABSTRACT/SUMMARY: Genetics lies at the core of hereditary spastic paraplegia (HSP). Despite the identification of more than 80 causative genes - half of which were discovered through the efforts of SP-CERN consortium members - approximately 40% of HSP patients have yet to identify their causative gene. This gap impedes clinical studies, biomarker research, and the progression of future clinical trials. The SP-CERN - RDCRC will prioritize establishing a robust genetic foundation by systematically collecting blood, DNA, and RNA samples and generating advanced long-read genomic data as part of the core protocol. Dr. Stephan Zuchner, the Principal Investigator of Project 2 and Administrative Director of the SP-CERN at the University of Miami, has been a leading figure in HSP genetics for over 15 years. His team and collaborators have long been dedicated to the systematic aggregation of de-identified DNA samples and genomic data for broad sharing and collaborative gene and allele discovery studies in HSP and related disorders. Recently, human genomic studies have begun to expand significantly into the complex non-coding genome space - regions that have been challenging to analyze using short-read sequencing. High-quality long-read genome sequencing will accelerate new discoveries in this area. In Clinical Research Project 2, we are building on our recent successes in identifying important new disease loci for HSP-related diseases, as published in Nature Genetics (three times) and the New England Journal of Medicine. We anticipate additional breakthroughs in HSP genomics in the coming years. Our expertise includes software and bioinformatic tool development, access to a uniquely large long-read genome control cohort, and data from 2,288 exomes and short-read genomes from HSP patients, as well as approximately 7,000 exomes/genomes from related disorders. This SP-CERN - RDCRC Clinical Research Project 2 will closely collaborate with the SP-CERN Cores, training and career enhancement initiatives, and the other Clinical Research Projects. We will support the genetic needs of all SP-CERN investigators and serve as a bridge to other HSP genomics efforts worldwide (e.g., TreatHSP in Europe). This Project proposes an integrated set of genomics approaches to further elucidate HSP genetics and improve the quality of diagnostic efforts. Given the development of gene-targeting therapies for neurodegenerative diseases like HSP, there is a renewed urgency in uncovering the complete genetic basis of HSP.