STAT3 Gene Sequencing
Hyper-IGE Recurrent Infection Syndrome
The STAT3 gene encodes the transcription factor protein, STAT3. STAT3 plays a crucial role in immunologic pathways by signaling cytokines which induce T helper cells (TH17 lineage). TH17 cells upregulate chemokine receptors that release cytokines with antifungal and antimicrobial properties. Deficient STAT3 signals lead to recurrent infection and immune deficiency, as seen in Hyper IgE syndrome.
Hyper IgE Syndrome (AD-HIES) is an autosomal dominant primary immune deficiency characterized by elevated serum IgE, eczema, recurrent skin and respiratory tract infections, and connective tissue and skeletal abnormalities. Generally, recurrent infections and skin findings manifest in the first few years of life. Survival is usually into adulthood, but a shortened life span is typical. Death is often caused by complications associated with infections. A diagnosis of this AD-HIES is made using a clinical scoring system with molecular genetic testing of STAT3. More than 95% of individuals with typical findings are found to have a STAT3 mutation.Infantile-onset multisystem autoimmune disease is characterized by early childhood onset of a spectrum of autoimmune disorders affecting multiple organs. The most common manifestations are insulin-dependent diabetes mellitus and autoimmune enteropathy, or celiac disease. Other features include short stature and nonspecific dermatitis. More variable features include hypothyroidism, autoimmune arthritis, and delayed puberty. STAT3 gain of function mutations have been described in this multiorgan autoimmunity.
Confirmation of diagnosis in a patient with the following:
- Job Syndrome / Autosomal Dominant Hyper IgE Syndrome/ Hyper IgE recurrent infection Syndrome
- Multisystem autoimmune disease, infantile onset
- Family members with previously identified STAT3 mutation
Testing is performed by Sanger sequencing of the entire coding regions and intron/exon boundaries of the STAT3 gene.
More than 95% of individuals with findings typical of signal hyper IgE syndrome have a STAT3 mutation encoding an altered, expressed protein (Holland et al 2007; Woellner et al 2010).
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.
Chandesris, M., et al. (2012). “Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome Molecular, Cellular, and Clinical Features From a French National Survey.” Medicine (Baltimore,) 91(4), e1-19.
Engelhardt, K. R., et al. (2012). “Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects.” J Allergy Clin Immunol, 129 (2), 294-305.
Flanagan, S.E. et al. (2014) ‘Activating Germline Mutations in STAT3 Cause Early-Onset Multi-Organ Autoimmune Disease’, Nature Genetics 46 (8): 812–4.
Heimall, J. et al. (2011). “Paucity of genotype-phenotype correlations in STAT3 mutation positive Hyper IgE Syndrome (HIES).” Clinical Immunology, 139, 75-84
Holland, S.M., et al. (2007). “STAT3 Mutations in the Hyper-IgE Syndrome.” The New England Journal of Medicine, 357. 1608-1619.
Huppler, A. R., et al. (2012). “Mucocutaneous candidiasis: the IL-17 pathway and implications for targeted immunotherapy.” Arthritis Research & Therapy, 14(217), 1-9.
Jiao, H., et al. (2008). “Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups.” Molecular Immunology, 46, 202-206.
Milner, J.D. et al. (2015) ‘Early-Onset Lymphoproliferation and Autoimmunity Caused by Germline STAT3 Gain-of-Function Mutations’, Blood 125 (4): 591–9.
Minegishi, Y., et al. (2007). “Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.” Nature, 448(30), 1058-1062.
Renner, E.D., et al. (2008). “Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced Th17 cell numbers, and defective STAT3 phosphorylation in hyper-IgE syndrome.” Journal of Allergy and Clinical Immunology, 122(1), 181-187.
Schimke, L.F., et al. (2010). “Diagnostic approach to the hyper-IgE syndromes: Immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis.” J Allergy Clin Immunol, 126 (3), 611-617.
Siegel, A.M., et al. (2011). “A Critical Role for STAT3 Transcription Factor Signaling in the Development and Maintenance of Human T Cell Memory.” Immunity, 35, 806-818.
Woellner, C., et al. (2010). “Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.” Journal of Allergy and Clinical Immunology, 125(1), 424-432.