title: Genomics of Immune Diseases and New Therapies.
abstract: Genomic DNA sequencing technologies have been one of the great advances of the 21st century, having decreased in cost by seven orders of magnitude and opening up new fields of investigation throughout research and clinical medicine. Genomics coupled with biochemical investigation has allowed the molecular definition of a growing number of new genetic diseases that reveal new concepts of immune regulation. Also, defining the genetic pathogenesis of these diseases has led to improved diagnosis, prognosis, genetic counseling, and, most importantly, new therapies. We highlight the investigational journey from patient phenotype to treatment using the newly defined XMEN disease, caused by the genetic loss of the MAGT1 magnesium transporter, as an example. This disease illustrates how genomics yields new fundamental immunoregulatory insights as well as how research genomics is integrated into clinical immunology. At the end, we discuss two other recently described diseases, CHAI/LATAIE (CTLA-4 deficiency) and PASLI (PI3K dysregulation), as additional examples of the journey from unknown immunological diseases to new precision medicine treatments using genomics.
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; email: lenardo@nih.gov.
authors.forename: Michael
authors.initials: M
authors.lastname: Lenardo
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; email: lenardo@nih.gov.
authors.forename: Bernice
authors.initials: B
authors.lastname: Lo
authors.affiliation: Molecular Development of the Immune System Section, Laboratory of Immunology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; email: lenardo@nih.gov.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Lucas
mesh_terms: D000818:Animals; D060908:CTLA-4 Antigen / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics* / Q000628:therapy; D008297:Male; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics* / Q000628:therapy
chemical_list: D060908:CTLA-4 Antigen; D027682:Cation Transport Proteins; C509698:MagT1 protein, human; D019869:Phosphatidylinositol 3-Kinases
keywords: biochemical; genomics; immune disorder; mechanism; targeted therapy