Submission Details

The relationship between CTLA4 and autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency, an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework (SOP8) as of November, 2020. CTLA4 is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency is a complex immune disorder with incomplete penetrance of ~70% (PMID: 30565239), characterized by autoimmune thrombocytopenias and abnormal lymphocytic infiltration of nonlymphoid organs, including the lungs, brain, and gastrointestinal tract, resulting in enteropathy (PMID: 25213377). CTLA4 variants (polymorphisms) are also reported as a risk factor or associated with susceptibility to celiac disease, diabetes mellitus, Hashimoto thyroiditis, and systemic lupus erythematosus (OMIM); however, these entities are considered within the context of autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency in this curation.

CTLA4 was first reported in relation to autosomal dominant autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency in 2014 by Kuehn et al and Schubert et al. (PMID: 25213377, PMID: 25213377). More than 20 nonsense, splice site, frameshift, deletion/duplication and missense variants have been reported in humans in the ClinVar database. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 16 probands in 5 publications (PMID: 25213377, 25213377, 25367873, 27102614, 26644313). More evidence is available in the literature, but the maximum score (12 points) for genetic evidence is reached. The mechanism for disease is reported to be loss of function/haploinsufficiency.

Digenic variants have been reported in the context of inborn errors of immunity. In a patient with a combination of a GOF JAK3 variant and LOF CTLA4 variant, there was evidence of both autoimmunity, lymphoproliferation, and humoral immunodeficiency with hypogammaglobulinemia and impaired memory B cell differentiation. The parents of this patient who carry one each of these heterozygous variants do not have a clinical phenotype (PMID: 29375547). This suggests there is epistatic modulation of the phenotype in the patient carrying heterozygous variants in these two genes. This patient is not scored for this curation, but noted for information.

Summary of experimental data (6 points): This gene-disease association is supported by in vitro functional assays and animal models. CTLA4 is expressed on the surface of activated T cells and functions in delivering an inhibitory signal to T cells (PMID: 7543139). Haploinsufficiency of CTLA4 leads to hyperproliferative T cells in patients (PMID: 25213377). Two different knock-out mouse models of CTLA4 recapitulate the human phenotype, including lymphadenopathy and splenomegaly (PMID: 7584144, 7481803). Overexpression of wild-type CTLA4 in patient T cells rescues hyperproliferation of cells (PMID: 25213377). Treatment with abatacept, a fusion protein drug incorporating the extracellular domain of WT CTLA4, has been successful in a patient with CTLA4 haploinsufficiency (PMID: 26478010).

In summary, CTLA4 is definitively associated with autosomal dominant autoimmune lymphoproliferative syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Data provided by the ClinGen Monogenic Diabetes GCEP on March 10, 2025:

Manifestation of diabetes in CTLA4 related autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency: As mentioned in the curation summary above, since 2014, more than 20 nonsense, splice site, frameshift, deletion/duplication and missense variants have been reported in humans as a cause of haploinsufficency of CTLA4 (PMID: 25213377, 25329329, 25367873, 27102614, 26644313), resulting in an autoimmune lymphoproliferative syndrome characterized by autoimmune thrombocytopenias and abnormal lymphocytic infiltration of nonlymphoid organs, including the lungs, brain, and gastrointestinal tract, with incomplete penetrance of about 70% and where diabetes has been described as a less common feature. Although diabetes has been reported as a feature of affected cases in several case series, minimal clinical detail about the diabetes is provided (such as age of diagnosis, treatment details, etc). One of the earliest case series (25329329) noted that several relatives carrying the variant who were previously classified as unaffected actually had features suggestive of autoimmunity such as “insulin-dependent” diabetes in one individual. Schwab et al (PMID: 29729943) collected case-level clinical data on 133 CTLA4 variant carriers (82 unpublished, others already reported) and found that of the 90 affected cases, 8% had type 1 diabetes, with 30/90 having any endocrinological manifestation. A systematic review of published reports by Jamee, et al (PMID: 33788257), found that of 222 CTLA4 haploinsufficiency cases, 23 (10.8%) were reported to have insulin-dependent diabetes mellitus. One case report was noted to develop insulin- requiring diabetes at 33 years old and was found to be GAD65 autoantibody positive (26644313). Diabetes could in theory be a presenting feature of CTLA4 related autoimmune lymphoproliferative syndrome, although unlike other gene causes such as FOXP3, the diabetes does not seem to frequently manifest at very young ages. Finding a P/LP CTLA4 variant on a sequencing panel in an individual with diabetes should prompt awareness of the possibility of other autoimmune conditions developing. Similarly in individuals discovered to have a P/LP CTLA4 variant but who have not been diagnosed with diabetes, glucose monitoring is advised, based on the ~8-10% prevalence of diabetes in this disorder.