Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


DiGeorge syndrome ...; 22q11.2 deletion syndrome; VCFS; Shprintzen syndrome; Opitz syndrome; Cayler syndrome (DiGeorge syndrome; 22q11.2 deletion syndrome) - Genes COMT, TBX1 and chromosome 22  

DiGeorge syndrome, also called chromosome 22q11.2 deletion syndrome and VCFS is a very heterogeneous disease with genetic base characterized by neonatal hypocalcemia due to hypoplasia of the parathyroid glands and susceptibility to infection due to a deficit of cells T, hypoplasia or aplasia caused by the thymus. Multiple times a range of facial and cardiac malformations associated with the development of this syndrome can be observed, among the latter: tetralogy of Fallot, interrupted aortic arch type B, truncus arteriosus, right aortic arch aberrant, etc. Often, affected individuals develop frequent infections caused by problems with the immune system, and autoimmune disorders such as rheumatoid arthritis and Graves disease in which the immune system attacks our own tissues or organs. Affected individuals may also have breathing problems, kidney abnormalities, thrombocytopenia, feeding difficulties, gastrointestinal problems and hearing loss. They are also relatively frequent short stature and moderate learning difficulties and some psychiatric disorders (bipolar disorder, depressive disorder and paranoid schizophrenia).

Because the signs and symptoms of chromosomal 22q11.2 deletion syndrome are so varied, at the time were described as characteristics of different syndromes: DiGeorge syndrome, Velocardiofacial syndrome , also called syndrome Shprintzen- and syndrome abnormalities conotruncal and face. In addition, some children with 22q11.2 deletion were diagnosed with autosomal dominant form of Opitz G / BBB syndrome and Cayler or cardiofacial syndrome. Once the genetic basis of these alterations were identified, it was determined to be part of a single syndrome with many signs and symptoms possible. To avoid confusion, this disease usually is called the 22q11.2 deletion syndrome, based on their underlying genetic cause.

As one of their usual designations indicates, DiGeorge syndrome is due to a deletion, approximately 1.5 to 3.0 Mb in the region 11.2 of the long arm of chromosome 22 (22q11.2). This region contains 30 to 40 genes, many of which have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region. This situation is described as a withdrawal syndrome contiguous gene.

It is working to identify all the genes that contribute to the characteristics of 22q11.2 deletion syndrome. The loss of a particular gene on chromosome 22, TBX1, is probably responsible for many of the characteristic signs of the syndrome (such as heart defects, cleft palate, distinctive facial features, hearing loss, hypocalcemia and behavioral problems). The loss of another gene, COMT gene in the same region of chromosome 22 may also help explain the increased risk of behavioral problems and mental illness. Loss of additional genes in the deleted region probably contributes to the varied characteristics of 22q11.2 deletion syndrome.

The COMT gene, located on the long arm of chromosome 22 (22q11.21), encodes two versions of the enzyme catechol-O-methyltransferase. The longest form, called catechol-O-methyltransferase bound to the membrane (MB-COMT), is mainly produced in the nerve cells in the brain. Other tissues, including liver and kidney, produce a shorter form of the enzyme called catechol-O-methyltransferase soluble (S-COMT). This form of the enzyme helps control the amounts of certain hormones. In the brain, catechol-O-methyltransferase helps break down certain neurotransmitters. Catechol-O-methyltransferase is particularly important in the prefrontal cortex, which organizes and coordinates information from other parts of the brain. This region is involved with personality, planning, inhibition of behavior, abstract thinking, emotion and working memory (short - term). To function efficiently, the prefrontal cortex requires signaling by neurotransmitters such as dopamine and norepinephrine. Catechol-O-methyltransferase helps maintain adequate levels of these neurotransmitters in this part of the brain. A loss of one copy of the COMT gene in each cell causes abnormal regulation of concentrations of catechol-O-methyltransferase in the brain. It is believed that this enzyme involve changes in the prefrontal cortex increase the risk of behavioral problems and mental illness. No clutch, little is known about the relationship between the activity of catechol-O-methyltransferase and mental and emotional problems specific characteristic of this disease.

Meanwhile, gene TBX1 located on the long arm of chromosome 22 (22q11.21), encoding the T-box 1 protein, which acts as a transcription factor. This protein appears to be required for normal development of the muscles and the bones of the face and neck, the large arteries that pump blood out of the heart, the ear structures, and glands such as the thymus and parathyroid. In a small number of individuals affected and without a deletion of chromosome 22, it is believed that mutations in the gene TBX1 are responsible for the signs and symptoms of the syndrome. Identified mutations include base pair changes in gene TBX1 and deletions of a small amount of genetic material of the gene. Some of these mutations reduce the amount of T-box 1 protein produced in the cells, while others alter the function of the protein. These genetic changes are likely to affect the ability of the T-box 1 protein to bind to DNA and regulate the activity of other genes. It is believed that changes in gene TBX1 whether due to a mutation in the gene or a deletion of part of chromosome 22, are responsible for many of the features of 22q11.2 deletion syndrome. Specifically, a reduction in the amount of T-box 1 or changes in the normal function of the protein is associated with cardiac defects, cleft palate, distinctive facial features, hearing loss, and hypocalcemia. In addition, it is likely that a loss of TBX1 gene also may be associated with behavioral problems in affected individuals.

Heritage 22q11.2 deletion syndrome is considered an autosomal dominant because a deletion in one copy of chromosome 22 in each cell is sufficient to express the disease. However, most cases of 22q11.2 deletion syndrome are not inherited, but the deletion occurs most often as a random event during the formation of reproductive cells or early embryonic development. As a result, affected individuals often have no history of the disease in his family, but can transmit the disease to their children. In approximately 10% of cases, a person with disease inherited deletion on chromosome 22 from the father. In inherited cases, other family members may also be affected.

Tests in IVAMI: in IVAMI carry out detection of insertions or deletions in the chromosomal region 22q11.2, by quantitative real - time PCR (qPCR Real Time).

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).