Defining the Genetic and Phenotypic Landscape of Primary Immune Regulatory Disorders Using the ClinGen Validation Framework
TL;DR
The PIRD-GCEP framework provides validated gene-disease classifications and identifies three distinct phenotypic clusters, facilitating improved diagnosis while revealing genes requiring further investigation to confirm their role in immune regulatory disorders.
Abstract
Background: Primary immune regulatory disorders (PIRDs) represent a rapidly growing group of inborn errors of immunity (IEIs) characterized by infection susceptibility, autoimmunity, inflammation, and lymphoproliferation. However, the core features of the gene-disease relationships underlying these conditions are often obscured by limitations in available published data. The Clinical Genome Resource (ClinGen) is an international collaborative effort that seeks to address this challenge for PIRDs and other monogenic diseases through a standardized framework for classifying the strength of gene-disease relationships. Objective: We sought to systematically evaluate the evidence for proposed PIRD gene-disease relationships and identify conserved phenotypic features across this heterogeneous group of disorders. Methods: Using the standardized ClinGen framework, the ClinGen PIRD Gene Curation Expert Panel (GCEP) identified potential gene-disease relationships for monogenic conditions characterized predominantly by immune dysregulation. We subsequently curated evidence relevant to these relationships, classified the strength of evidence for these gene-disease relationships, and evaluated clinical patterns among these conditions through standardized phenotyping using the Human Phenotype Ontology (HPO). Results: As of April 2026, the PIRD-GCEP has curated a total of 46 genes corresponding to 49 gene-disease relationships characterized by immune dysregulation. Of these, 28 were categorized as definitive, 2 as strong, 9 as moderate, 7 as limited, and 3 as disputed. Analysis of HPO-based phenotyping revealed 3 major phenotypic clusters corresponding to lymphoproliferation and systemic inflammation, atopic and gastrointestinal inflammation, and combined immune deficiency with autoimmunity. Conclusion: The PIRD-GCEP framework provides validated gene-disease classifications and identifies three distinct phenotypic clusters, facilitating improved diagnosis while revealing genes requiring further investigation to confirm their role in immune regulatory disorders.