The Genetics of 22q11.2DS

Individuals with 22q11.2DS have a deletion at the 22q11.2 region of one chromosome 22. The parental origin of the deletion does not appear to affect the clinical expression of the 22q11.2 deletion. Most of these individuals have de novo deletions, which reflects the inherent instability of the 22q11.2 region (see Mechanism of Deletions below). The disease is transmitted in an autosomal dominant-like manner. In other words, each child of a person with 22q11.2DS has a 50% chance of being affected. Currently, less than 10% of newly diagnosed cases of 22q11.2DS are found to be inherited.

There have also been rare cases of:

For further information, please consult the Practical Guidelines for Managing Patients with 22q11.2 Deletion Syndrome.

Demographics

The 22q11.2 Deletion Syndrome is present in at least 1 in 2000 live births, affecting males and females equally. The prevalence is similar among different ethnic populations, and no founder effect is known.

The overall prevalence of this syndrome is expected to rise because:

  • The number of individuals with 22q11.2DS who survive cardiac anomalies is increasing as a result of pediatric surgical and medical advances. They are in turn having children;
  • Parents who have affected children are now being diagnosed because of the availability of genetic testing;
  • Atypical 22q11.2 deletions previously missed due to the limitations of FISH (Fluorescence in situ hybridization) are now detectable by newer technologies.

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Mechanism of 22q11.2 deletions as a de novo event

Background:

  • The 22q11.2 region contains multiple segmental duplications also known as low copy repeat (LCR)sequences, each of which have high DNA sequence similarities. For the locations of the LCRs in 22q11.2, please see the bottom half of Figure 1 in the article by Stachon et al. 2007.

  • During gamete production in all humans, including those with 22q11.2 deletions, DNA replication at 22q11.2 occurs in an asynchronous manner. The paternal chromosome replicates earlier than the maternal homolog.

During asynchronous DNA replication of the 22q11.2 region, one LCR can line up with the wrong LCR on the homologous chromosome. The misalignment causes the looping and thus deletion of DNA flanked by the LCRs. Some of the typical 22q11.2DS deletions result from this non-allelic homologous replication mechanism. In cases where the breakpoints are not flanked by LCRs, the deletion mechanism is currently unknown. It is also unclear whether some individuals are more or less prone to such deletions.

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Mechanism of the disease

Delineating the mechanisms for the main clinical features of 22q11.2DS is an area of intense research. No correlation between specific clinical expression and the extent of 22q11.2 deletions has been established.

There is debate as to whether all of the 44 coding genes that typically are deleted contribute to the phenotype. One gene that is commonly deleted and implicated in the etiology is TBX1. TBX1 codes for a transcription factor called T-box 1, which regulates the expression of several growth factors and transcription factors involved in thymic and parathyroid development. TBX1 also contributes to the development of areas such as: heart, palate, face, and hearing. Modifier genes likely play a role in the phenotype. In addition, genotype variations of 22q11.2 region on the non-deleted chromosome may contribute to the variable expression of symptoms.

For further information, please refer to reviews by McDonald-McGinn and Sullivan (2011) and Philip and Bassett (2011).

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Gene therapy?

Individuals with 22q11.2DS may inquire about the possibility of gene therapy for this syndrome. The 22q11.2 deletion is present in every single diploid cell in the individual's body from conception and through development and life. At this time, there is no technology available to "fix" all these cells. A variety of surgeries, medical treatments, and therapies can however help with most of the health problems of 22q11.2 Deletion Syndrome.

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Genetic counselling and the testing of family members

Parents of affected individuals can be assured that there is nothing that they did (or did not do) that led to the deletion in their child. Nevertheless, as some individuals exhibit very mild symptoms, their parents, and where indicated siblings should undergo testing to determine if anyone else in the family has the deletion. Because of potential germline mosaicism, even when neither parents has the 22q11.2 deletion, there is a small possibility of having additional affected children.

An explanation of the molecular genetics techniques used to test for or confirm 22q11.2 deletions can be found here.

Since there is a 50% chance at each pregnancy that a person with 22q11.2DS can pass his/her deletion to a child, prospective parents are strongly advised to have genetic counselling. Counselling about 22q11.2DS wil usually include discussion about the prevalence, etiology, detection, variability, interventions, and prenatal/preconception options. For further information, please consult Genetic counseling for the 22q11.2 deletion and the Practical Guidelines for Managing Patients with 22q11.2 Deletion Syndrome.

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