Curation of gene-disease relationships in primary antibody deficiencies using the ClinGen validation framework.

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.

Duke Scholars

Author Ermal Aliu Pediatrics, Medical Genetics