Project 1: Longitudinal Registries

PROJECT 1 ABSTRACT Sex chromosome aneuploidies (SCA) were defined over 70 years ago, but there are still more questions than answers for these under-recognized, understudied, multisystem conditions. The overarching goal of this multicenter longitudinal natural history study is to comprehensively evaluate the natural history of SCA conditions that will support the development of future clinical trials. This project will leverage two recently established, community-engaged clinic registries, INSIGHTS (Inspiring New Science in Guiding Healthcare in Turner Syndrome) and GALAXY (Generating Advancements for Longitudinal Analysis in X&Y Chromosome Variations). This multicenter collaboration aims to 1) Develop a high-yield longitudinal clinical data and biospecimen repository of individuals with SCA utilizing the foundation of the INSIGHTS and GALAXY registries; 2) Describe the systemic morbidity associated with each SCA across the lifespan, and 3) Determine phenotypic traits that are common among all SCAs (or SCA subcategories), as well as those that are unique to individual SCA conditions. Individuals with SCAs will be recruited from national clinics as well as through community outreach, with the ambitious but feasible goal to reach 2,000 participants by the end of the funding period. Rigorous methods ensure the database contains high-quality, multidisciplinary clinical data with low participant burden and broad future utility. Community advocates, clinicians, and researchers serve on the Steering Committees that will lead the Registries along with a strong team of SCA investigators at the lead site, close collaboration with NASCARR leadership and consortia sites, and RDCRN infrastructure including the Data Management and Coordinating Center and NIH programmatic input. This project addresses several of the RDCRN goals including 1) characterization of the cohort including genetic, phenotypic, imaging, and laboratory data to identify subtypes and/or severity of outcomes, 2) multisystem phenotyping, 3) understanding the clinical course of the condition to facilitate future clinical trials, 4) addressing evidence gaps for newborn screening panels (genetic-based panels will incidentally identify SCAs even if these are not specifically targeted), and 5) community-engaged approaches to improve participant recruitment. Successful completion of these aims will escalate the SCA field toward clinical trial readiness by mapping the current SCA-specific natural history, defining SCA populations best suited for targeted therapies, and generating a contact, data and biospecimen repository.