CTLA-4 Variant Interpretation and Clinical Impact

Background The cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a well-known immune checkpoint inhibitor. Heterozygous germline mutations in CTLA4 in humans lead to immune deficiency, autoimmunity, auto-inflammation, lymphoproliferation, and infection. A reduced penetrance of approx. 70% is published. This project aims to classify all known variants of the human CTLA4 gene into five categories: pathogenic, likely pathogenic, variant of uncertain significance, likely benign, and benign. Method A comprehensive literature research was conducted and included 63 papers, along with unpublished patients that were referred to us by their treating physicians. We identified a total of 767 subjects with 133 different unique variants. Patient information was curated into the GenIA database (https://geniadb.net), focusing on demographic information, phenotypes, laboratory values, functional assays, and treatment. Results In this cohort, 84.76% of CTLA4 mutation carriers were affected or mildly affected. This penetrance of 84.76% is substantially higher than previously published. Moreover, 46.3% of patients were repeatedly reported in different studies. Disease-modifying antirheumatic drugs and systemic corticosteroids were the most used treatments. We found that GenIA is a suitable platform for comprehensive literature research. Not all variants had been tested or functionally validated. Outlook Our future work seeks to analyze genotype–phenotype correlation and advise medical professionals on typical presentation and treatment options for patients with CTLA-4 (haplo)insuffiency.

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Publication Details

Journal
Journal of Human Immunity
Published
2026-05-01
DOI
https://doi.org/10.70962/cis2026abstract.135
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
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article

CTLA-4 Variant Interpretation and Clinical Impact

Xavier Ayrignac, Julia Padilha da Silva, Akihiro Hoshino, Faranaz Atschekzei et al.
Journal of Human Immunity
Immunodeficiency and Autoimmune Disorders
article

CTLA-4 Variant Interpretation and Clinical Impact

Xavier Ayrignac, Julia Padilha da Silva, Akihiro Hoshino, Faranaz Atschekzei, Francesco Licciardi, Susana Lopes Silva, Mohammed Nashawi, Máté Krausz, Maria Carrabba, Sara Posadas‐Cantera, Sebastian Zeißig, Ben Carpenter, Emtenan Basahl, Christo Tsilifis, Sabine Heine, Ewa Więsik–Szewczyk, Jérémie Rosain, Georgios Sogkas, Jennifer Dantzer, Bodo Grimbacher, Britt-Sabina Löscher, Michele Proietti, Elena Sindram, Alan M. Leichtner, Antonios Kolios, Richard Blumberg, Talal Chatila, Charlotte Cunningham-Rundles, Nathalie Aladjidi, Victoria Paul, Hirokazu Kanegane, Andre Franke, Laura Gamez-Dias, Francesca Conti, Jenny Lingman, Andres Caballero Garcia de Oteyza, Safa Baris, Piero Accardo, Eric Jeziorski, Frederic Rieux-Laucat, Mary Slatter
article en

Abstract

Background The cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a well-known immune checkpoint inhibitor. Heterozygous germline mutations in CTLA4 in humans lead to immune deficiency, autoimmunity, auto-inflammation, lymphoproliferation, and infection. A reduced penetrance of approx. 70% is published. This project aims to classify all known variants of the human CTLA4 gene into five categories: pathogenic, likely pathogenic, variant of uncertain significance, likely benign, and benign. Method A comprehensive literature research was conducted and included 63 papers, along with unpublished patients that were referred to us by their treating physicians. We identified a total of 767 subjects with 133 different unique variants. Patient information was curated into the GenIA database (https://geniadb.net), focusing on demographic information, phenotypes, laboratory values, functional assays, and treatment. Results In this cohort, 84.76% of CTLA4 mutation carriers were affected or mildly affected. This penetrance of 84.76% is substantially higher than previously published. Moreover, 46.3% of patients were repeatedly reported in different studies. Disease-modifying antirheumatic drugs and systemic corticosteroids were the most used treatments. We found that GenIA is a suitable platform for comprehensive literature research. Not all variants had been tested or functionally validated. Outlook Our future work seeks to analyze genotype–phenotype correlation and advise medical professionals on typical presentation and treatment options for patients with CTLA-4 (haplo)insuffiency.

Journal of Human ImmunityVol. 2(CIS2026)
DePauw University (US), Tokyo Medical and Dental University (JP), Brigham and Women's Hospital (US), Boston Medical Center (US), University College London Hospitals NHS Foundation Trust (GB), University of Lisbon (PT), Johns Hopkins University (US), Inserm (FR), University of Zurich (CH), University Medical Center Freiburg (DE), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Christian-Albrechts-Universität zu Kiel (DE), Medizinische Hochschule Hannover (DE), Université Sorbonne Paris Nord (FR), Centre Hospitalier Universitaire de Montpellier (FR), Assistance Publique – Hôpitaux de Paris (FR), Zurich University of Teacher Education (CH), Hôpital Pellegrin (FR), Medical Genetics Center (DE), National Institute of Health (AM), Department of Medical Sciences (BY), King Abdulaziz Hospital (SA), Institute of Cardiology (PL), Department of Public Health (US), University College London (GB), University of Turin (IT), University of Baltimore (US), Halmstad University (SE), Marmara University (TR), Newcastle University (GB), University of Palermo (IT), Saarland University (DE), University of Bologna (IT), Politecnico di Milano (IT), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 12%
Immunodeficiency and Autoimmune Disorders
DOIOpen Access PDFOpenAlex
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