SCIENTIFIC BACKGROUND

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22q11.2

Category: VERACITY

Description

Scientific background

DiGeorge syndrome represents a part of the highly variable clinical spectrum of microdeletion 22q11.2. It is caused by a developmental defect of the third and fourth pharyngeal pouches or derived structures such as the thymus and parathyroid glands and the fourth-gill arch. In the complete clinical picture, thymic hypoplasia or aplasia is found, resulting in a cellular immunity defect. In about 10% a severe immunodeficiency is present. In about 60% there is a hypoplasia of the parathyroid glands, which may cause hypocalcemia and is sometimes accompanied by seizures. Hypocalcemia usually develops in the neonatal period but may occur later. Calcium levels can normalize spontaneously at any time, but long-term calcium substitution is often required. Heart defects are another leading symptom and aortic arch anomalies, conotruncal heart defects such as tetralogy of Fallot or truncus arteriosus, but also ventricular septal defects or patent ductus arteriosus have been observed. A cleft palate also occurs. Signs of velopharyngeal insufficiency include a hoarse voice or nasal speech later on.

Almost all patients have a mild developmental delay, and about 30 to 40% have short stature. External features include hypertelorism, epicanthus, a small mouth with a curved upper lip, microretrognathia, and round, wide ears.

In about 5 to 10% of cases, microdeletion 22q11.2 is inherited from one parent. Therefore, an examination of the parents of an affected child is recommended, especially for future family planning purposes.

References

Goldenberg 2018, Pediatr Ann, 47(5):e198 / Momma 2007, Int J Cardiol 114:147 / Arinami 2006, J Hum Genet 51:1037 / Simon et al. 2005, Dev Psychopathol 17:753 / Bassett 2005, Am J Med Genet 138A:307 / Sullivan 2004, Curr Opin Allergy Klin Immunol 4:505 / Yamagishi and Keio 2002, Med 51:77 / Jawad 2001, J Pediat 139:715 / Scambler 2000, Hum Mol Genet 9 16:2421 / Rost 2000, Monatsschr Kinderheilkd, 148:55 / Ryan et al. 1997, J Med Genet 34:798

DiGeorge syndrome - November 22 is 22q11.2 Awareness Day

The small deletion on the long arm (q) of chromosome 22 causes a syndrome with a diverse collection of symptoms. When the genetic basis of 22q11.2 syndrome was identified, it was discovered that several other conditions thought to be different disorders were all in fact part of the same condition.

Also known as DiGeorge syndrome, velocardiofacial syndrome, CATCH22, Opitz G/BBB syndrome, and Cayler cardiofacial syndrome, 22q11.2 deletion is often characterized as ‘the most common genetic disorder no one has heard of’. 22q11.2 deletion syndrome has a prevalence of 1 in 2,000 that is thought to be an underestimate due to the lack of syndrome familiarity and recognition by doctors, and the wide variability of symptoms. It is the second most common genetic disorder after Down syndrome, the most common cause of cleft lip and palate, and the second most common cause of developmental delays and heart defects – 1 in 68 children born with a cardiovascular abnormality are diagnosed with a 22q11.2 deletion.

The deleted region is thought to contain 30-40 genes – but could contain nearly 90 genes. The number of genes deleted in an individual varies. Most of these genes have not been well-characterized or characterized at all, but the significant number of genes deleted may be responsible for the variability of the features. Heart defects, learning difficulties, palate abnormalities which lead to feeding and speech difficulties, and immune system problems are the commonest symptoms of 22q11.2 deletion – occurring in over 70% of individuals affected. Other symptoms include low calcium levels which can cause seizures, autoimmune disorders that increase the risk of infections and autoimmune diseases, kidney abnormalities, hearing loss, eye abnormalities, and developmental and intellectual delays. Autism spectrum disorders and attention deficit hypersensitivity disorder (ADHD) are also observed. 22q11.2 is also the strongest known genetic risk factor for schizophrenia. Individuals affected by the 22q11.2 deletion usually have difficulty with verbal memory and visual-spatial skills, language, and reading comprehension, along with limited social and emotional function. However, they can demonstrate focused attention and excel in computer skills, spelling, and grammar due to their tendency to remember well-encoded information. A talent for rhythm and music has also been observed.

4% of the people affected die during infancy – a percentage that has been significantly reduced due to the availability and improvement of cardiovascular surgeries and antibiotics. In adults, the mortality rate for people with 22q11.2 deletion is higher than that of the general population. The prognosis is variable depending on disease severity and the specific collection of symptoms in each individual. A multidisciplinary team of doctors is needed to observe the patient throughout their lifetime, observe and address any emerging features.

About 90% of 22q11.2 cases occur sporadically – without any hereditary risk factor. Couples that already have a child with a 22q11.2 deletion but are not affected themselves have less than a 1% chance of having another child with the syndrome. People with the disorder can have children with a 50% chance of inheriting the condition from their offspring, as it is inherited in an autosomal dominant manner.

Due to the multidisciplinary care children with the 22q11.2 deletion receive, and the severity of the symptoms, screening and diagnosis at an early age are of paramount importance. Screening during pregnancy and universal neonatal screening can help reduce anxiety and improve medical and psychological preparedness. Although there is no cure for 22q11.2, there are many therapies – speech, language, behavioral, occupational, and physical – that can address developmental, learning, and motor delays and improve the outcome and the quality of life for the individual affected and their families.

VERACITY and VERAgene NIPT can detect 22q11.2 deletion syndrome, amongst other common genetic disorders, from the 10^th week of pregnancy. NIPT results, possible next steps, and clinical management should always be fully discussed with your healthcare provider.

For more information on support groups for 22q11.2 syndrome please visit: The 22q Family Foundation, The International 22q11.2 Foundation and http://www.maxappeal.org.uk/links/22q_groups_around_the_world.

Compiled using information from