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.
A comprehensive literature research was conducted and included 63 papers, along with unpublished patients that were referred to us by their treating physicians.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.
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.
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.
