Genetics and Genomics Diagnostic Laboratory
Custom Gene Sequencing | CTLA4

CTLA4 Gene Sequencing


Autoimmune Lymphoproliferative Syndrome, Type V


The CTLA4 gene encodes the cytotoxic T lymphocyte antigen-4 (CTLA-4) protein, an inhibitory receptor which is constitutively expressed by regulatory T-cells and activated T-cells. The CTLA-4 protein functions as a critical checkpoint in suppressing excessive T-cell proliferation. Kuehn et al. (2014) described a syndrome of immune dysregulation caused by loss of CTLA-4 expression. This is characterized by autoimmune cytopenias, hypogammaglobulinemia, CD4 T-cell lymphopenia, and lymphocytic infiltrations of non-lymphoid organs in patients with heterozygous CTLA4 mutations (Kuehn et al. 2014). Schubert et al. (2014) identified CTLA4 mutations in six additional families with hypogammaglobulinemia, recurrent infections, and autoimmune features. The inheritance pattern of immune dysregulation caused by CTLA4 mutations is autosomal dominant and penetrance may be incomplete (Kuehn et al. 2014).



Confirmation of diagnosis in a patient with the following:

  • Lymphoproliferation, autoimmune cytopenias, hypogammaglobulinemia, and B-cell abnormalities (with accumulation of CD21 B-cells), with or without recurrent infections

  • Family member with a previously identified CTLA4 mutation

Testing Methodology

Testing is performed by Sanger sequencing of the entire coding regions and intron/exon boundaries of the CTLA4 gene. 

Test Sensitivity

Clinical Sensitivity

In a cohort of 23 patients with autoimmune cytopenias, hypogammaglobulinemia, CD4 T cell lymphopenia, and lymphocytic infiltration of nonlymphoid organs, Kuehn et al. (2014) identified a CTLA4 mutation in four patients, providing a clinical sensitivity of approximately 17%.

Analytical Sensitivity

The sensitivity of DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed.

Mutations in regulatory regions or other untranslated regions are not detected by this test. Large deletions involving entire single exons or multiple exons, large insertions and other complex genetic events have been reported in many of these genes and will not be identified using this test methodology. Rare primer site variants may lead to erroneous results.


Turnaround Time

28 days


Chen, Z., S.R. Brant, et al. (2010) "CTLA4 -1661A/G and 3’UTR Long Repeat Polymorphisms Are Associated with Ulcerative Colitis and Influence CTLA4 mRNA and Protein Expression." Genes and Immunity 11(7): 573–83.

Kuehn, H.S., W. Ouyang, et al. (2014) "Immune Dysregulation in Human Subjects with Heterozygous Germline Mutations in CTLA4." Science (New York, N.Y.) 345(6204): 1623–7.

Pawlak, E., L. Karabon, et al. (2010) "Influence of CTLA-4/CD28/ICOS Gene Polymorphisms on the Susceptibility to Cervical Squamous Cell Carcinoma and Stage of Differentiation in the Polish Population." Human Immunology 71(2): 195–200.

Schubert, D., C. Bode, et al. (2014) "Autosomal Dominant Immune Dysregulation Syndrome in Humans with CTLA4 Mutations." Nature Medicine 20(12): 1410–6.

Yanagawa, T., Y. Hidaka, et al. (1995) "CTLA-4 Gene Polymorphism Associated with Graves’ Disease in a Caucasian Population." The Journal of Clinical Endocrinology and Metabolism 80(1): 41–5.

Zhernakova, A., P. Eerligh, et al. (2005) "CTLA4 Is Differentially Associated with Autoimmune Diseases in the Dutch Population." Human Genetics 118(1): 58-66.