Mendelian genetic studies of immune disorders to identify novel targets for therapeutic intervention. J. McElwee1, X. Chen1, J. Lyons2, G. Sun2, X. Yu2, J. Milner2, Y. Liuv3, Z. Deng3, A. Almeida de Jesus3, R. Goldbach-Mansky3, Y. Zhang4, H. Matthews4, H. Su4, M. Lenardo4 1) Merck Research Laboratories, Department of Genetics & Pharmacogenomics (GpGx), Boston, MA; 2) Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD; 3) Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, MD; 4) Laboratory of Immunology, NIAID, NIH, Bethesda, MD.

   Mendelian disorders that selectively affect the immune system provide a means to identify and understand new genes and pathways involved in human immunology which could represent new routes for therapeutic intervention for human disease. As part of a collaborative effort to identify novel therapeutic opportunities in immunobiology, Merck and the NIH Clinical Center have undertaken a focused study of Mendelian forms of primary immunodeficiencies, syndromic atopic disease, and severe auto-inflammatory conditions using next generation sequencing approaches. We have sequenced 711 exomes representing over 200 independent families exhibiting a range of suspected Mendelian immune diseases, including autoimmune lymphoproliferative syndrome, chronic active EBV infection, atopic disorders (such as familial tryptasemia, atopic dermatitis, or severe asthma), and diverse forms of primary immunodeficiencies or severe auto-inflammatory diseases. Analysis of these data using Mendelian filtering techniques, further supported by extensive molecular and cellular validation studies, has led to the successful identification of causal mutations in known and novel immune genes for over 25% of kindreds that have been analyzed to date. We will present highlights from the analysis of this unique cohort, including several newly-identified disease-causing genes. First we will describe a new form of immunodeficiency and atopic disease caused by loss-of-function mutations in the phosphoglucomutase-3 gene (PGM3). Affected individuals from 2 families exhibit severe atopy with marked serum IgE level increases, recurrent bacterial and viral infections, and neurocognitive impairment. The causal mutations in PGM3 affect an enzyme crucial in the generation of UDP-GlcNAc, pointing to an underappreciated role for glycosylation in the regulation of immune cell function. Next, we will describe a new auto-inflammatory disorder identified in 6 unrelated patients exhibiting severe skin vasculitis, chronic interstitial lung disease and systemic inflammation. Analysis of these families has identified de novo gain-of-function mutations in the ds-DNA sensor STING (encoded by TMEM173), a key adapter molecule that links innate nucleic acid sensing to IFN pathway activation. Finally, we will present an overview of our experience and success rate for Mendelian genetic studies within this cohort, and future plans for analysis and expansion of this collaborative discovery effort.

You may contact the first author (during and after the meeting) at