Defining the Genetic and Phenotypic Landscape of Primary Immune Regulatory Disorders Using the ClinGen Validation Framework
Year: 2026
Type: preprint
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.
Source: medRxiv
Authors: Benjamin D. Solomon, Justyne Ross, Eleanor P. Fensterle, Rasha S. Soliman, Michelle K. Paczosa, Alison Brittain, Elizabeth M. Forbes, Olga F. Sarmento, Ivana Stojkic, Shifaa Alkotob, Jahnavi Aluri, Jorge Diogo Da Silva, Ana Rita Soares, Monica Sulit, Anita Chandra, Fabian Hauck, Stephen Jolles, Paul J. Maglione, Harry Lesmana, Craig D. Platt, Markus G. Seidel, Andrew L. Snow, Kathleen E. Sullivan, Troy R. Torgerson, Tiphanie P. Vogel, Klaus Warnatz, Kejian Zhang, Purvesh Khatri, Forum Raval, Stuart G. Tangye, Roshini S. Abraham
Institutions: Stanford University, University of North Carolina at Chapel Hill, Cairo University hospitals, Quest Diagnostics (United States), Nationwide Children's Hospital, The University of Queensland, LabCorp (United States), The University of Texas Health Science Center at Houston, Hospital de Santo António, University of Minho, Baylor College of Medicine, University of Cambridge, Heidelberg University, Ludwig-Maximilians-Universität München, University Hospital of Wales, Boston University, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Boston Children's Hospital, Harvard University, Medical University of Graz, Uniformed Services University of the Health Sciences, Children's Hospital of Philadelphia, Allen Institute for Immunology, Texas Children's Hospital, University of Freiburg, University Medical Center Freiburg, University Hospital Zurich, University of Michigan, Michigan Medicine, Stanford Medicine, Garvan Institute of Medical Research, UNSW Sydney
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7213462581