New York Regional Inborn Errors of Immunity Resource Initiative League (NY-ROYAL)

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Project Summary Inborn errors of immunity (IEI) are disorders of the immune system which are individually rare but collectively affect 1 in 10,000 individuals. Definitive genetic diagnosis is of essence for timely genetic counseling and clinical care. Such care may involve bone marrow transplantation, gene therapy or precision pharmacotherapeutics, all of which can be curative. The recent advancement of genome sequencing in quality and price has led to an increased rate of discovery of what are now over 400 causal genes underlying IEIs. However, about three quarters of IEI sequencing yields either variants of unknown significance (VUSs) in one of the 400+ genes or require discovery of novel causes. This leads to delays in diagnosis and treatment, especially since most of these VUSs cannot be validated using clinically available assays. As sequencing panels are increasingly utilized and being covered by insurance, the rate of genetic data production outpaces indiividuals’ capacity to interpret it. The primary purpose of this proposal is to build a regional resource which would formalize case review process, match providers and their patients carrying VUSs with research laboratories capable of targeted functional evaluation and/or bioinformatic assessment, thereby leading to VUS reclassification, diagnosis and treatment. It also will infuse research enterprises with clinically significant biological questions. We propose to streamline this process in the NY region by building a 1) patient referral platform and database where providers will be able to input deidentified patient clinical information alongside the associated genetic data (IEI gene panels, WES, and WGS sequencing), 2) a multidisciplinary review process where submitted data will be evaluated by an expert review panel at the forefront of IEI gene discovery and functional validation on a regular basis who will work to disposition relevant VUSs for 3) functional characterization by a collaborating expert team followed by 4) result reporting, VUS reclassification and its inclusion in the national clinically relevant genetic variation database. This multidisciplinary diagnostic NY regional immunology resource is key to supporting the discovery and functional characterization of novel IEI associated genetic variants. This resource will serve future, more broadly applied integration of genomics, artificial intelligence/machine learning, rapid functional assessment and precision medicine.