PROJECT SUMMARY/ABSTRACT Chronic suppurative respiratory disease is characterized by persistent and recurrent otitis media, sinusitis, bronchitis as well as bronchiectasis. Genetic etiologies include inborn errors of immunity (IEI) with defective cellular and antibody-mediated responses and disorders of impaired mucociliary clearance like primary ciliary clearance (PCD). Early and accurate diagnosis of these genetic etiologies can lead to more effective prevention of recurring infections, functional decline, and structural respiratory tract damage. Prior studies conducted by the NIH-funded Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) focused on characterizing patients presenting with suspected PCD. These led to better understanding of the clinical phenotype and contributed to the discovery and characterization of over 50 genes causing this disease. Those studies also showed that some patients presenting with signs and symptoms of PCD actually had milder or later onset manifestations of IEI identified genetically. This project seeks to complement the extensive PCD clinical, genetic and management experience of the GDMCC with the corresponding IEI expertise of the NIAID Sequencing and Primary Immune Deficiency Programs to test our central hypothesis that tiered clinical and genetic evaluation of patients with suppurative respiratory disease will identify people whose confirmed genetic diagnosis of PCD or IEI requires whole genome sequencing and expertise in variant significance resolution. Utilizing patients identified from a multicenter GDMCC suppurative respiratory disease protocol, we propose the following aims: Specific Aim 1: Assess the potential of Whole genome sequencing (WGS) for diagnosis of IEI or PCD in patients who have undergone a systematic evaluation for suppurative respiratory tract disease and have negative commercial IEI and PCD gene testing panels. Expertise in variant curation and significance resolution for gene variants not currently categorized as pathogenic or likely pathogenic will be utilized to confirm the genetic diagnoses. Specific Aim 2: Referral of GDMCC patients to the NIH Clinical Center for NIAID protocol directed clinical, laboratory, or genetic diagnostic evaluation will facilitate confirmation of genetic IEI diagnosis. Patients will have the opportunity to participate in NIAID protocols designed to more precisely define immune disorders at the NIH Clinical Center. Specific Aim 3: Referral of GDMCC IEI patients to the NIH Clinical Center for NIAID protocol directed biologic, gene correctional or transplant treatment will enhance therapeutic options. Patients diagnosed with a genetic IEI will have access to potential lifesaving therapeutic advances. The collaborative efforts between the multi-site GDMCC based at the University of North Carolina at Chapel Hill and the NIAID Centralized Sequencing Program, and Primary Immune Deficiency Program based at the NIH Clinical Center will lead to improved g...