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 MICRODUPLICATION 22q11

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

LINKS:

22q11 microduplication Facebook Group

OMIM - 22q11 microduplication

References

Alberti A, Romano C, Falco M, Cali F., Schinocca P, Galesi O, Spalletta A, Di Benedetto D, Fichera M. 2007. 1.5 Mb de novo 22q11.21 microduplication in a patient with cognitive deficits and dysmorphic facial features. Clinical Genetics. 71:177-182.

Brunet A, Gabau E, Perich RM, Valdesoiro L, Brun C, Caballin, MR, Guitart M. 2006. Microdeletion and Microduplication 22q11.2 screening in 295 patients with clinical features of DiGeorge/Velocardiofacial Syndrome. American Journal of Medical Genetics, Part A 140A: 2426-2432.

Brunet A, Armengol L, Pelaez T, Guillamat R, Valles V, Gabau E, Estivill X, Guitart M. 2008. Failure to detect the 22q11.2 duplication syndrome rearrangement among patients with schizophrenia. Behavioral and Brain Functions. 4:10.  FREE FULL TEXT ONLINE

Clark RA, Fang ZM, Diwan AD, Gilbert DL.2009. Tourette Syndrome and Klippel-Feil Anomaly in a child with chromosome 22q11 duplication. Case Reports in Medicine. Volume 2009. Article ID 361518.  FREE FULL TEXT ONLINE

Cotter PD, Nguyen H, Tung G, Rauen KA. 2005. Incidence of microduplication 22q11.2 in patients referred for FISh testing for velocardiofacial and DiGeorge syndromes. European Journal of Human Genetics. 13: 1245:1246. FREE FULL TEXT ONLINE

Courtens W, Schramme I, Laridon A. 2008. Microduplication 22q11.2: A benign polymorphism or a syndrome with a very large clinical variability and reduced penatrance? – Report of two families. American Journal of Medical Genetics, Part A 146A: 758-763.

de la Rochebrochard C, Joly-Helas G, Goldenberg A, Durand I, Laquerriere A, Ickowicz V, Saugier-Veber P, Eurin D, Moirot H, Diguet A, de Kergal F, Tiercin C, Mace B, Marpeau L, Frebourg T. 2006. The intrafamilial variability of the 22q11.2 microduplication encompasses a spectrum from minor cognitive deficits to severe congenital anomalies. American Journal of Medical Genetics Part A 140A: 1608-1613.

Descartes M, Franklin J, Diaz de Stahl T, Piotrowski A, Bruder CEG, Dumanski JP, Carroll AJ, Mikhail FM. 2008. Distal 22q11.2 microduplication encompassing the BCR gene. American Journal of Medical Genetics Part A. 146A: 3075-3081.

Ensenauer RE, Adeyinka A, Flynn HC, Michels VV, Lindor NM,  Dawson DB, Torland EC, Lorentz CP, Goldstein JL, McDonald MT, Smith WE, Simon-Fayard E, Alexander AA, Kulharya AS, Ketterling RP, Clark RD, Jala SM. 2003. Microduplication 22q11.2, an emerging syndrome: Clinical, cytogenetic, and molecular analysis of thirteen patients. American Journal of Medical Genetics. 73:1027-1040. FREE FULL TEXT ONLINE 

Fernández L, Nevado J, Santos F, Heine-Suñer D, Martinez-Glez V, García-Miñaur S, Palomo R, Delicado A, Pajares IL, Palomares M, García-Guereta L, Valverde E, Hawkins F, Lapunzina P. 2009. A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review. BMC Med Genet. 2;10:48.  FULL TEXT FREE ONLINE

Hassed SJ, Hopcus-Niccum D, Zhang L, Li S, Mulvihill JJ. 2004. A new genomic duplication syndrome complementary to the velocardiofacial (22q11 deletion) syndrome. Clinical Genetics. 65:400-404.

Laitenberger G, Donner B, Gebauer J, Hoehn T. 2007. D-Transposition of the great arteries in a case of microduplication 22q11.2. Pediatric Cardiology.

Lamb. A, Kumar R, Pellegrino JE, Chavez D, Morris T, Challinor P, Ravnan JB. 2004. Searching for patients with the 22q11.2 duplication syndrome: Confirmation that some patients have phenotypic overlap with DiGeorge/Velocardiofacial syndrome. American Journal of Human Genetics. 75:191.

Meins M, Burfeind P, Motsch S, Trappe R, Bartmus D, Langer S, Speicher MR, Mühlendyck H, Bartels I, Zoll B. 2003. Partial trisomy of chromosome 22 resulting from an interstitial duplication of 22q11.2 in a child with typical cat eye syndrome. Journal of Medical Genetics;40(5):e62.  FREE FULL TEXT ONLINE

Mosca AL, Callier P, Faivre L, Marle N, Mejean N, Thauvin-Robinet C, Masurel-Paulet A, Madinier N, Durand C, Couillaud G, Ragot S, Huet F, Teyssier JR, Mugneret F. 2009. Polymicrogyria in a child with inv dup del(9p) and 22q11.2 microduplication. American Journal of Medical Genetics Part A 149A:475-481.

Mukaddes NM, Hurguner S., 2007. Autistic disorder and 22q11.2 duplication. The World Journal of Biological Psychiatry. 8(2): 127-130

Ou Z, Berg JS, Yonath H, Enciso VB, Miller DT, Picker J, Lenzi T, Keegan CE, Sutton VR, Belmont J, Chinault AC, Lupski JR, Cheung SW, Roeder E, Patel A, 2008. Microduplcations of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genetics in Medicine. 10:267-277.

Portnoi MF, Lebas F, Grunchy N, Ardalan A, Biran-Mucignat V, Malan V, Finkel L, Roger G, Ducrocq S, Gold F, Taillemite JL, Marlin S. 2005. 22q11.2 duplication syndrome: two new familial cases with some overlapping features with DiGeorge/Velocardiofacial syndromes. American Journal of Medical Genetics 137A: 47-51.

Portnoi MF. 2009. Microduplication 22q11.2: a new chromosomal syndrome. European Journal of Medical Genetics. 52(2-3):88-9.

Ramelli GP, Ferrarini A, Cattaneo C, Visconti P, Pescia G. 2008. Microduplication 22q11.2 in a child with autism spectrum disorder: clinical and genetic study. Developmental Medicine and Child Neurology, 50: 953-955.

Rosa RF, Zen PR, Ricachinevsky CP, Pilla CB, Pereira VL, Roman T, Varella-Garcia M, Paskulin GA. 2009.  22q11.2 duplication and congenital heart defects. Arq Bras Cardiol. 93(4):e67-9, e55-7. English, Portuguese, Spanish.  FREE FULL TEXT ARTICLE

Somerville MJ, Morrison W, Christiansen J, et al, 2004. Microduplication 22q11.2 causes isolated cognitive and/or behavioural disability. American Journal of Human Genetics. 75(Suppl):55.

Sparkes R, Chernos J, Dicke F. 2005. Duplication of the 22q11.2 region associated with congenital cardiac disease. Cardiology in the Young. 15:229-231.

Torres-Juan L, Rosell J, Morla M, Vidal-Pou C, García-Algas F, de la Fuente MA, Juan M, Tubau A, Bachiller D, Bernues M, Perez-Granero A, Govea N, Busquets X, Heine-Suñer D.2007. Mutations in TBX1 genocopy the 22q11.2 deletion and duplication syndromes: a new susceptibility factor for mental retardation. Eur J Hum Genet. 15(6):658-63.

Yobb TM, Somerville MJ, Willatt L, Firth HV, Harrison K, MacKenzie J, Gallo N, Morrow BE, Shaffer LG, Babcock M, Chernos J, Bernier F, Sprysak K, Christiansen J, Hasse Shelagh, Elyas B, Lilley M, Bamforth S, McDermid HE. 2005. Microduplication and triplication of 22q11.2: A highly variable syndrome. American Journal of Medical Genetics. 76: 865-876.  FREE FULL TEXT ONLINE

Yu S, Cox K, Friend K, Smith S, Buchheim R, Bain S, Liebelt J, Thompson E, Bratkovic D. 2008. Familial 22q11.2 duplication: a three-generation family with a 3-Mb duplication and a familiar 1.5-Mb duplication. Clinical Genetics. 73:160-164.

Wentzel C, Fernstrom M, Ohrner Y, Anneren G, Thuresson A. 2008. Clinical variability of the 22q11.2 duplication syndrome. European Journal of Medical Genetics. 51: 501-510.

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