• Scott B Drutman, Davood Mansouri, Seyed Alireza Mahdaviani, Anna-Lena Neehus, David Hum, Ruslana Bryk, Nicholas Hernandez, Serkan Belkaya, Franck Rapaport, Benedetta Bigio, Robert Fisch, Mahbuba Rahman, Taushif Khan, Fatima Al Ali, Majid Marjani, Nahal Mansouri, Lazaro Lorenzo-Diaz, Jean-François Emile, Nico Marr, Emmanuelle Jouanguy, Jacinta Bustamante, Laurent Abel, Stéphanie Boisson-Dupuis, Vivien Béziat, Carl Nathan, and Jean-Laurent Casanova.
• From St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University (S.B.D., D.H., N.H., S.B., F.R., B.B., R.F., E.J., J.B., L.A., S.B.-D., J.-L.C.), the Department of Microbiology and Immunology, Weill Cornell Medicine (R.B., C.N.), and Howard Hughes Medical Institute (J.-L.C.) - all in New York; the Pediatric Respiratory Diseases Research Center (D.M., S.A.M.), the Department of Clinical Immunology and Infectious Diseases (D.M., N. Mansouri), and the Clinical Tuberculosis and Epidemiology Research Center (D.M., M.M.), National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; the Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM Unité 1163 (A.-L.N., L.L.-D., E.J., J.B., L.A., S.B.-D., V.B., J.-L.C.), Paris University, Imagine Institute (A.-L.N., L.L.-D., E.J., J.B., L.A., S.B.-D., V.B., J.-L.C.), and the Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP) (J.B.), and the Pediatric Immunology-Hematology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, and the Department of Pathology, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt (J.-F.E.) - all in France; the Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany (A.-L.N.); the Research Branch, Sidra Medicine (M.R., T.K., F.A.A., N. Marr), and the College of Health and Life Sciences, Hamad Bin Khalifa University (N. Marr), Doha, Qatar; and the Division of Pulmonary Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (N. Mansouri).
• N. Engl. J. Med. 2020 Jan 30; 382 (5): 437-445.

BackgroundCytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 (Nos2) are susceptible to the related murine CMV infection.MethodsWe studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally.ResultsWe found a homozygous frameshift mutation in NOS2 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all NOS2 variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001.ConclusionsThese findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).Copyright © 2020 Massachusetts Medical Society.

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