Defining the Genetic and Phenotypic Landscape of Primary Immune Regulatory Disorders Using the ClinGen Validation Framework
- 1Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA
Abstract
BackgroundPrimary 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.
ObjectiveWe sought to systematically evaluate the evidence for proposed PIRD gene-disease relationships and identify conserved phenotypic features across this heterogeneous group of disorders.
MethodsUsing 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).
ResultsAs 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.
ConclusionThe 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.
CAPSULE SUMMARYUsing the ClinGen framework, this study describes the first global initiative to validate gene-disease relationships for primary immune regulatory disorders, identifying 49 relationships and three phenotypic clusters, providing a resource for genetic testing and diagnosis.
KEY MESSAGESO_LIThe PIRD-GCEP applied ClinGens standardized framework to curate 46 genes (49 gene-disease relationships) linked to primary immune regulatory disorders. Thirty of these relationships were classified as definitive or strong, giving clinicians a validated basis for variant interpretation in this heterogeneous disease group. C_LIO_LIStandardized HPO phenotyping revealed that, despite their genetic diversity, PIRDs converge onto a small number of clinically meaningful patterns including: (1) lymphoproliferation with systemic inflammation, (2) atopic and gastrointestinal inflammation, and (3) immune deficiency with autoimmunity. C_LIO_LIThis validated set of gene-disease relationships and phenotypic clusters represents a resource for the genetic testing and diagnosis of PIRDs, potentially reducing diagnostic delays and aiding in the recognition of novel PIRD gene-disease relationships. C_LI
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BibTeX
@misc{solomon2026defining,
title = {{Defining the Genetic and Phenotypic Landscape of Primary Immune Regulatory Disorders Using the ClinGen Validation Framework}},
author = {B. D. Solomon and J. Ross and E. P. Fensterle and R. S. Soliman and M. K. Paczosa and A. Brittain and E. M. Forbes and O. F. Sarmento and I. Stojkic and S. Alkotob and J. Aluri and J. D. Da Silva and A. R. Soares and M. Sulit and A. Chandra and F. Hauck and S. Jolles and P. J. Maglione and H. Lesmana and C. D. Platt and M. G. Seidel and A. L. Snow and K. E. Sullivan and T. R. Torgerson and T. P. Vogel and K. Warnatz and K. Zhang and P. Khatri and F. Raval and S. G. Tangye and R. S. Abraham},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.26362285},
url = {https://www.medrxiv.org/content/10.64898/2026.09.11.26362285v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Defining the Genetic and Phenotypic Landscape of Primary Immune Regulatory Disorders Using the ClinGen Validation Framework
AU - B. D. Solomon
AU - J. Ross
AU - E. P. Fensterle
AU - R. S. Soliman
AU - M. K. Paczosa
AU - A. Brittain
AU - E. M. Forbes
AU - O. F. Sarmento
AU - I. Stojkic
AU - S. Alkotob
AU - J. Aluri
AU - J. D. Da Silva
AU - A. R. Soares
AU - M. Sulit
AU - A. Chandra
AU - F. Hauck
AU - S. Jolles
AU - P. J. Maglione
AU - H. Lesmana
AU - C. D. Platt
AU - M. G. Seidel
AU - A. L. Snow
AU - K. E. Sullivan
AU - T. R. Torgerson
AU - T. P. Vogel
AU - K. Warnatz
AU - K. Zhang
AU - P. Khatri
AU - F. Raval
AU - S. G. Tangye
AU - R. S. Abraham
PY - 2026
DA - 2026/09/11
PB - medRxiv
DO - 10.64898/2026.09.11.26362285
UR - https://www.medrxiv.org/content/10.64898/2026.09.11.26362285v1
AB - BackgroundPrimary 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. ObjectiveWe sought to systematically evaluate the evidence for proposed PIRD gene-disease relationships and identify conserved phenotypic features across this heterogeneous group of disorders. MethodsUsing 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). ResultsAs 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. ConclusionThe 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. CAPSULE SUMMARYUsing the ClinGen framework, this study describes the first global initiative to validate gene-disease relationships for primary immune regulatory disorders, identifying 49 relationships and three phenotypic clusters, providing a resource for genetic testing and diagnosis. KEY MESSAGESO_LIThe PIRD-GCEP applied ClinGens standardized framework to curate 46 genes (49 gene-disease relationships) linked to primary immune regulatory disorders. Thirty of these relationships were classified as definitive or strong, giving clinicians a validated basis for variant interpretation in this heterogeneous disease group. C_LIO_LIStandardized HPO phenotyping revealed that, despite their genetic diversity, PIRDs converge onto a small number of clinically meaningful patterns including: (1) lymphoproliferation with systemic inflammation, (2) atopic and gastrointestinal inflammation, and (3) immune deficiency with autoimmunity. C_LIO_LIThis validated set of gene-disease relationships and phenotypic clusters represents a resource for the genetic testing and diagnosis of PIRDs, potentially reducing diagnostic delays and aiding in the recognition of novel PIRD gene-disease relationships. C_LI
ER -