Project Summary / Abstract Severe chronic neutropenia (SCN) is an immunodeficiency that leads to severe, often life-threatening, infections in patients with both congenital and acquired forms of neutropenia. Despite granulocyte colony- stimulating factor therapy, patients remain at long term, often life-long, risk of serious infections and additional comorbidities. The Severe Chronic Neutropenia International Registry (SCNIR) was established in 1994 to study the natural history and clinical consequences of SCN and its treatment. Based on the research resources of the Registry, SCNIR investigators have published 255 journal articles, and 41 reviews and book chapters related to SCN. The SCNIR has provided evidence-based clinical guidance, advanced our understanding of neutrophil biology, and broadly informed the care of neutropenia and immunodeficiencies. Scientific technology developments have opened new opportunities to investigate SCN biology. Ongoing evolution of clinical medicine and diagnostics requires continued reassessment of natural history, treatments, and outcomes. The objective of the SCNIR is to provide a platform to leverage innovations in database science, molecular and computational biology, patient-reported outcomes, and other advances in basic and clinical research to enable discovery of new treatments and inform medical management. This project builds on the history of productive collaborations within and outside the SCNIR to expand available NIAID resources and provide a model for the study of other immunodeficiencies and rare diseases. Our SPECIFIC AIMS are: Aim 1: Transition the SCNIR database to a hybrid model at Boston Children’s Hospital We will transition SCNIR operations to Boston, with a hybrid data collection system engaging both physicians and patients; collect and analyze patient-reported outcomes for SCN; and develop a pilot project in natural language processing for data extraction and entry. Aim 2: Generate clinically annotated genomic datasets for translational research in SCN We will characterize the germline genomic features of chronic neutropenia for the study of genetic interactions, and novel genetic causes of SCN by the research community; characterize the somatic mutational landscape of SCN; and provide resources for innovative translational research and clinical trials. Aim 3: Provide resources and outreach for education, recruitment, and retention. The SCNIR will engage patients, families, and medical providers to provide education and promote retention and will share expertise and foster collaborations with related patient advocacy and research groups. Continued operation of this longstanding, productive registry will permit otherwise unfeasible long-term assessments of SCN natural history, generate resources for both clinical and scientific research investigators, and provide up-to-date educational resources and outreach to medical and patient communities.