title: Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency.
abstract: Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes.
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maffucci
authors.affiliation: Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, NY , USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Filion
authors.affiliation: Rockefeller Branch, St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA; Necker Branch, Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Imagine Institute, Paris Descartes University, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.affiliation: Rockefeller Branch, St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University , New York, NY , USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: Rockefeller Branch, St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University , New York, NY , USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Shang
authors.affiliation: Rockefeller Branch, St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA; Necker Branch, Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Imagine Institute, Paris Descartes University, Paris, France; Howard Hughes Medical Institute, New York, NY, USA; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
keywords: common variable immunodeficiency; genetic diagnosis; next-generation sequencing; primary immunodeficiencies; whole exome sequencing