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Principal Investigator: Alexandra Freeman
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $423,120
Funding agency: National Heart Lung and Blood Institute
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 genetic diagnostic capabilities and optimization
of management strategies for patients presenting with chronic suppurative respiratory disease.
Terms: <0-11 years old><21+ years old><Accessory Sinuses><Adult><Adult Human><Affect><American><Antibodies><Biological><Biological Agent><Biological Products><Bronchiectasis><Bronchitis><Categories><Child><Child Youth><Children (0-21)><Chronic><Clinical><Complement><Complement Proteins><Diagnosis><Diagnostic><Diagnostic Findings><Disease><Disorder><Ear><Early Diagnosis><Evaluation><Funding><Gene Targeting><Gene variant><Genes><Genetic><Genetic Diseases><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic propensity><Genotype><HSC transplantation><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Impairment><Individual><Infection><Inflammation><Inherited Predisposition><Inherited Susceptibility><Kartagener Syndrome><Kartagener Triad><Laboratories><Life><Mediating><Morbidity><Morbidity - disease rate><Mucociliary Clearance><Mucociliary Transport><NIAID><NIH><Nasal Sinuses><Nasal cavity/Paranasal><Nasal cavity/Paranasal sinuses><National Institute of Allergy and Infectious Disease><National Institutes of Health><North Carolina><Otitis Media><Outcome><Paranasal Sinuses><Pathogenicity><Pathway interactions><Patients><Persons><Phenotype><Polynesian bronchiectasis><Precision therapeutics><Primary Ciliary Dyskinesias><Primary Immunodeficiency><Process><Protocol><Protocols documentation><Pulmonary Body System><Pulmonary Organ System><Recurrence><Recurrent><Resolution><Respiratory Disease><Respiratory System><Respiratory System Disease><Respiratory System Disorder><Respiratory Tract Diseases><Respiratory Tracts><Respiratory tract structure><Signs and Symptoms><Sinus><Sinusitis><Site><Specialty><Testing><Therapeutic><United States National Institutes of Health><Universities><Variant><Variation><accurate diagnosis><adulthood><allele variant><allelic variant><biologic><biologics><biopharmaceutical><biotherapeutic agent><chronic infection><clinical center><clinical phenotype><complementation><congenital immune deficiency><congenital immunodeficiency><decline in function><decline in functional status><design><designing><diagnostic ability><diagnostic capability><diagnostic power><diagnostic utility><diagnostic value><disease diagnosis><early detection><entire genome><exome sequencing><exome-seq><experience><full genome><functional decline><functional status decline><gene corrected><gene correction><gene panel test><gene transplantation><gene transplantation for gene therapy><genetic condition><genetic diagnosis><genetic disorder><genetic disorder diagnosis><genetic etiology><genetic immune defect><genetic immune deficiency><genetic immunodeficiency><genetic mechanism of disease><genetic panel test><genetic variant><genetic vulnerability><genetically predisposed><genome sequencing><genomic correction><genomic variant><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic progenitor cell transplantation><host response><immune system response><immunoresponse><improved><inborn errors in immunity><inborn errors of immunity><inborn immunodeficiency><infection recurrence><inherited immune defect><inherited immune deficiency><inherited immunodeficiency><kids><medical specialties><middle ear infection><multigene panel test><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><participant enrollment><pathway><patient enrollment><persistent infection><precision therapies><precision treatment><primary immune defect><primary immune deficiency><programs><recurrence prevention><recurrent infection><recurring infection><resolutions><response><transplant therapy><transplant treatment><transplantation therapy><transplantation treatment><whole genome><youngster>