Microduplication 22q11.2 – Overview and Review of the Literature 

Microduplication 22q11.2 is a relatively newly recognized syndrome. While its counterpart, the 22q11.2 microdeletion syndrome, is relatively common (estimated in 1 in 4000 births) (Shaffer and Lupski, 2000), the 22q11.2 microduplication was first reported in 1999 (Edelmann, 1999). Since then, fewer than 100 individuals with this genetic finding have been reported in the medical literature. However, it is probably not as rare as it would seem, because the technology sensitive enough to detect it has only become widely available in the last few years.  

Some individuals with this microduplication are “normal”- that is, they have average intelligence, no major birth defects, and no major medical illnesses. We also know that individuals with the samemicroduplication can have significant problems with learning, behaviour, growth, muscle tone, and a variety of minor birth defects have been reported as well. Individuals with the same duplication but very different problems can be found in the same family (eg., parent-child, siblings). In fact, the findings are so variable that it is almost impossible to determine whether the presence of a microduplication at 22q11.2 is the cause of these problems, or simply one of many genetic and environmental risk factors that work together to contribute to a given individual’s phenotype. An article by Courtens, Schramme and Laridon (2008) actually suggested that the 22q11.2 microduplication could be a benign polymorphism (a variation in the chromosome which has no adverse effects on the individual). However, large numbers of normal individuals have now been screened for microduplications such as this, and it is not a common finding. 

There is good reason to suspect that the 22q11.2 microduplication has at least some effect on phenotype, although it may be quite mild. Most of the reported individuals have a rather large region of the chromosome duplicated – about 3 Mb. This region contains about 40 genes that we already know are important for normal development. Others have an even larger region (from 4 to 6 Mb) duplicated, which still others have a smaller duplication (about 1.5 Mb). Thus far, there does not seem to be a direct correlation between the size of the duplication and the severity of the symptoms, suggesting that the rest of the individual’s genetic make-up is more important than the size of the duplicated region itself.

Clinical Characteristics

The clinical characteristics of individuals reported thus far with the 22q11.2 microduplication are extremely variable. The original reports were of individuals who had been investigated for the 22q11.2 deletion syndrome (also known as Velocardiofacial syndrome or VCFS), and instead of finding the expected deletion, they found a duplication of the same region. Because of the way the duplication was discovered, the reports are biased towards those who have features in common with VCFS, such as cleft palate, velopharyngeal insufficiency, heart defects, absent thymus, learning disabilities, and certain dysmorphic facial features. Later reports are less biased, because they were discovered using a newer, different technology called microarray analysis. This test scans the entire genome (ie, all the chromosomes) for deletions and duplications. The indications for doing this test range from birth defects (single or multiple), learning difficulties (mild to severe), dysmorphic features, unusual health conditions, or any combination of these. Because this testing is rarely done in healthy, non-dysmorphic people of average intelligence, so we do not know the frequency of this duplication in an unbiased population.

Keeping the above in mind, some of the reported features in individuals with the duplication are:

• Dysmorphic facial features (including widely spaced eyes, superior placement of eyebrows, down-slanting palpebral fissures, long narrow face, small chin, ear pits and other minor ear anomalies)without a specific recognizable pattern
• Speech delay (isolated, or in combination with other cognitive delays)
• Hearing loss (both conductive and sensorineural types reported)
• Failure to thrive (ie, poor growth) in about half of reported probands
• Velopharyngeal insufficiency/hypernasal speech/cleft palate
• Absent thymus in one patient (Ensenauer 2003)
• Asplenia in one patient (Ensenauer 2003)
• Heart defects:
  • In Ensenauer 2003, 2/12 of probands had congenital heart defects; (one had Fallot tetralogy, and the other had hypoplastic left heart syndrome and interrupted aortic arch)
  • Laitenberger 2007 reported one patient with transposition of the great arteries with Ebstein anomaly
  • de la Rochebrochard 2006, reported a complex, non-conotruncal heart defect with abnormal abdominal situs (a lethal heart defect that was present in a fetus)
  • In Yobb (2005), 2/7 probands had heart defects (Tetralogy of Fallot and HLHS)
  • Sparkes (2005) reported 2 probands, a newborn female with Tetralogy of Fallot and a right-sided aortic arch, and a newborn male with hypoplastic left heart syndrome
• Intellectual disability (even within the same family with the same size duplication, different degrees of impairment are found, as well as average IQ)
• Behaviour challenges/psychiatric issues (autism, hyperactivity, obsessive-compulsive disorder, Tourette syndrome)
• Seizures (uncommon)
• Urogenital anomalies (ambiguous genitalia in one male patient, but not in his father who also had the duplication; urethral stenosis, hypospadias, and hydronephrosis and cryptorchidism)

Risk of Inheritance: Like any deletion or duplication present on one of the non-sex chromosomes, if a parent carries it, each child will have a 50% chance of inheriting it. However, it is impossible to predict the phenotype that the child will have based on this finding.

Unlike the 22q11.2 deletion, which is only rarely (about 7% of the time) inherited from a parent, the 22q11.2 duplication seems to be more frequently inherited. This may be because the phenotype is generally milder (and therefore individuals who carry it are more likely to reproduce), but further studies are needed to confirm this.

Prevalence: Although the exact prevalence of the 22q11.2 microduplication is unknown, the most unbiased study to date (Ou, 2008) looked at 7000 samples from individuals with any degree of intellectual disability and/or congenital anomalies, and found 10 cases of the microduplication, for an approximately prevalence of 1/700. Incidentally, they found more than three times as many (33) cases of the 22q11.2 microdeletion. They also found a further 9 cases with “atypical” duplications in and around the 22q11.2 region. These atypical duplications overlapped somewhat with the commonly duplicated region.

As mentioned above, the prevalence in the general population is not known, but the full duplication appears to be rare.   

© 2010, Dr. Melissa Carter, medical advisor to C22C

22q11 Microduplication Reference Articles