SCIENTIFIC BACKGROUND

ADA, AK2, CD247, CD3D, CD3E, CD3G, CD40, CD40LG, CD8A, CIITA, CORO1A, DCLRE1C, DOCK8, FOXN1, IKZF1, IL2RG, IL7R, ITK, JAK3, LCK, LIG4, MAGT1, NHEJ1, ORAI1, PNP, PRKDC, PTPRC, RAG1, RAG2, RFX5, RFXANK, RFXAP, RHOH, RMRP, STAT5B, STIM1, STK4, TAP1, TAP2, TAPBP, UNC119, ZAP70

Category:

Scientific Background

Combined immunodeficiencies (CID), including severe combined immunodeficiencies (SCID), are a heterogeneous group of genetic diseases characterized by a deficiency in and/or a malfunction of T cells. In SCID, a distinction is made between diseases that also have a reduced number of circulating B cells (T-B-SCID, about 35% of SCID patients) and SCID forms in which B cells are present (T-B+SCID, about 65% of SCID patients), although B cell function is always impaired (even where there is normal development of these cells) due to the lack of T cell help for the antibody response. In addition, the number of NK cells may be reduced. While in CID, residual functions of the immune system remain intact and CID patients can be relatively healthy, SCID is lethal without a blood stem cell transplant before the age of two. Clinical manifestations of SCID usually occur within the first 6 months of life. They are usually protracted infections of the gastrointestinal tract and respiratory tract, severe varicella, complicated EBV, CMV or adenovirus infections or persistent thrush. In some cases, the persistence of maternal T cells, which are not rejected and can proliferate in SCID patients, can lead to symptoms of graft-versus-host disease (GvHD).

 

SCID disease mainly affects genes whose products are involved in the maturation of lymphocytes. These include cytokine receptors and their signal-transducing molecules, which are essential for the early differentiation and maturation of lymphocytes, as well as proteins that are necessary for the formation and function of B and/or T cell receptors. The most common form of SCID is caused by mutations in the IL2RG gene on the X chromosome and accounts for about 80% of SCID cases in male patients. Other more frequently affected genes (autosomal recessive) are RAG1/RAG2, DCLRE1C (Artemis), ADA and JAK3 (in total up to 40% of all SCID cases). Hypomorphic mutations in SCID-typical genes, which allow residual function of the affected protein, can lead to atypical SCID, where the clinical phenotype is currently not clearly defined. The course of the disease is not as severe as in typical SCID, and the diagnosis should also be considered in older children and even in adult patients. Hypomorphic mutations in some SCID-associated genes can lead to Omenn syndrome (OS), an inflammatory disease similar to GvHD. In addition to typical SCID symptoms, OS patients show additional inflammatory symptoms such as lymphadenopathy, hepatosplenomegaly, generalized erythroderma and alopecia. The use of NGS for the simultaneous analysis of CID/SCID-relevant genes (gene panel diagnostics) can be helpful in making an early genetic diagnosis.

 

References

Bousfiha et al. 2018, J Clin Immunol 38:129 / Picard et al. 2018, J Clin Immunol 38:96 / Routes et al. 2014, J Clin Immunol 34:398 / Felgengreff et al. 2011, Clin Immunol 141:73 / Fischer et al. 2005, Immunol Rev 203:98 / Buckley et al. 2004, Annu Rev Immunol 22:625 / Muller et al. 2001, Blood 98:1847

GENES

ADA, AK2, CD247, CD3D, CD3E, CD3G, CD40, CD40LG, CD8A, CIITA, CORO1A, DCLRE1C, DOCK8, FOXN1, IKZF1, IL2RG, IL7R, ITK, JAK3, LCK, LIG4, MAGT1, NHEJ1, ORAI1, PNP, PRKDC, PTPRC, RAG1, RAG2, RFX5, RFXANK, RFXAP, RHOH, RMRP, STAT5B, STIM1, STK4, TAP1, TAP2, TAPBP, UNC119, ZAP70

ASSOCIATED TESTS

How to order

LATEST ARTICLES

Exciting news in genetic research! The Human Pangenome Reference Consortium has unveiled an improved version of the human pangenome reference. This c...

Read more

Duchenne muscular dystrophy, a rare inherited muscle disorder characterized by progressive muscle weakness and degeneration that leads to difficultie...

Read more

May 12 is International Nurses Day. It is celebrated on Florence Nightingale’s birthday. She pioneered the field of modern nursing through her dedi...

Read more

Hair loss is a common problem that affects millions of men and women around the world. While genetics is believed to be the most significant factor c...

Read more

Depression is a serious mental health issue affecting over 280 million people worldwide. Recent research has revealed a potential link between gut he...

Read more

If you are unlucky enough to suffer from migraines, you will know that a migraine is not just a bad headache. The headache and accompanying symptoms ...

Read more

Autism spectrum disorder (ASD) is a neurological developmental disorder that affects brain development and function. This affects how people learn, b...

Read more

Researchers have developed a method called "Mendelian Phenotype Search Engine" (MPSE) to identify which sick infants in the neonatal intensive care u...

Read more

Did you know that wisdom teeth are actually an evolutionary leftover from our ancient ancestors that no longer serve their original purpose? These mo...

Read more

Azoospermia is a medical condition characterized by the absence of sperm in the ejaculate and is a major cause of male infertility. It affects 1 in 1...

Read more