BACKGROUND: The Clinical Genome Resource (ClinGen) is an international collaborative effort among scientists and clinicians, diagnostic and research laboratories, and the patient community. Using a standardized framework, ClinGen has established guidelines to classify gene-disease relationships as definitive, strong, moderate, and limited on the basis of available scientific and clinical evidence. When the genetic and functional evidence for a gene-disease relationship has conflicting interpretations or contradictory evidence, they can be disputed or refuted. OBJECTIVE: We assessed genes related to primary antibody deficiencies. METHODS: The ClinGen Antibody Deficiencies Gene Curation Expert Panel, using the ClinGen framework, classified genes related to primary antibody deficiency that primarily affect B-cell development and/or function, and that account for the largest proportion of inborn errors of immunity or primary immunodeficiencies. RESULTS: The expert panel curated a total of 65 genes associated with humoral immune defects to validate 74 gene-disease relationships. Of these, 40 were classified as definitive, 1 as strong, 16 as moderate, 15 as limited, and 2 as disputed. The curation process involved reviewing 490 patient records and 3546 associated human phenotype ontology entries. The 3 most frequently observed terms related to primary antibody deficiency were decreased circulating antibody level, pneumonia, and lymphadenopathy. CONCLUSIONS: These curations (publicly available at ClinicalGenome.org) represent the first effort to provide a comprehensive genetic and phenotypic revision of genetic disorders affecting humoral immunity, as reviewed and approved by experts in the field.

Boston Children's Hospital Boston Mass

Department of Clinical Immunology Cambridge University Hospitals NHS Foundation Trust Cambridge United Kingdom; Department of Medicine University of Cambridge Cambridge United Kingdom

Department of Genetics University of North Carolina School of Medicine Chapel Hill NC

Department of Medical Genetics and Genomics Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland Ohio; Department of Pediatric Hematology Oncology and BMT Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland Ohio

Department of Medicine Boston University Chobanian and Avedisian School of Medicine Boston Mass

Department of Pediatrics Baylor College of Medicine Houston Tex; Department of Allergy Immunology and Rheumatology Center for Human Immunobiology Texas Children's Hospital Houston Tex; Departamento de Genética Hospital Infantil de México Federico Gómez Mexico City Mexico

Department of Rheumatology and Clinical Immunology Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany; Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany; Department of Immunology University Hospital Zurich Zurich Switzerland

Garvan Institute of Medical Research Darlinghurst Australia; School of Clinical Medicine Faculty of Medicine and Health UNSW Sydney Sydney Australia

GoBroad Healthcare Group GoBroad Clinical Research Center Boren Hospital Beijing China

Immunodeficiency Centre for Wales University Hospital of Wales Cardiff United Kingdom

Invitae Corporation San Francisco Calif

Milton S Hershey Medical Center Hershey Pa

Motol University Hospital and the 2nd Faculty of Medicine Charles University Prague Czech Republic

Nationwide Children's Hospital Columbus Ohio

Queen Mary University of London London United Kingdom

Quest Diagnostics Secaucus NJ

Sydney Children's Hospitals Network Sydney Australia; School of Clinical Medicine University of New South Wales Sydney Australia

The Children's Hospital of Philadelphia Philadelphia Pa

Université Paris Cité Paris France; Study Center for Primary Immunodeficiencies Necker Enfants Malades Hospital Assistance Publique Hôpitaux de Paris Paris France; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection Inserm UMR 1163 Institut Imagine Paris France

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