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.