Primary Antibody Deficiencies: Curation Of Gene-Disease Relationships Using A ClinGen Validation Framework.

Abstract

BACKGROUND The Clinical Genome Resource (ClinGen) is an international collaborative effort between scientists and clinicians, diagnostic and research laboratories as well as the patient community. Using a standardized framework, ClinGen has established guidelines to classify gene-disease relationships as Definitive, Strong, Moderate, and Limited based on 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. OBJECTIVES AND METHODS The ClinGen Antibody Deficiencies Gene Curation Expert Panel (AD-GCEP), using the ClinGen framework, has classified genes related to Primary Antibody Deficiencies (PAD) that primarily affect B cell development and/or function and accounts for the largest proportion of Inborn Errors of Immunity (IEI) or Primary Immunodeficiencies (PIDs). RESULTS The AD-GCEP curated a total of 65 genes associated with humoral immune defects to validate 74 gene-disease relationships. Of these, 40 gene-disease relationships were classified as Definitive, 1 as Strong, 16 as Moderate, 15 as Limited, and two as Disputed. The curation process involved the review of 490 patient records and 3,546 associated Human Phenotype Ontology (HPO) entries. The most frequently observed HPO terms related to PAD was decreased circulating antibody (Ab) level, pneumonia and lymphadenopathy. CONCLUSIONS These curations represent the first effort by the Immunology Clinical Domain Working Group (CDWG) of ClinGen to provide a comprehensive genetic and phenotypic revision of genetic disorders affecting humoral immunity, and these were reviewed and approved by experts in the field. The curations are publicly available at www.clinicalgenome.org.