Clinical Diagnosis

22q11.2 duplication is a recently described condition, with the first report appearing in 2003 [Ensenauer et al 2003, Hassed et al 2004, Yobb et al 2005]. It is not detectable by routine G-banded karyotyping. Most individuals with 22q11.2 duplication are identified either by array comparative genomic hybridization (array CGH) testing or by multiplex ligation-dependent probe amplification (MLPA) testing for 22q11.2 deletion syndrome [Stachon et al 2007].

Because array CGH is commonly performed as part of the evaluation of developmental delay or intellectual disability, this significant ascertainment bias makes the phenotype associated with 22q11.2 duplication difficult to establish. The phenotype is not sufficiently distinct to be specifically suspected on clinical grounds alone.

Duplication 22q11.2 may be confirmed by molecular genetic testing. Note: (1) For this GeneReview, 22q11.2 duplication is defined as the presence of a common 3-Mb or 1.5-Mb proximal nested duplication. (2) Variant duplications involving this region occur; they have at least one break point that differs from those found in the common 3-Mb or proximal 1.5-Mb duplication.

Molecular Genetic Testing

Clinical testing

Duplication/deletion analysis. The utility of several methods of duplication/deletion analysis is described. Other test methods may also be employed.

• Array comparative genomic hybridization (aCGH). The common 3-Mb or 1.5-Mb proximal nested duplication in a proband can be detected by clinically targeted or whole-genome aCGH.
  
  Note: The ability to size the duplication and the need or otherwise for independent confirmation depends on the type of array used and the density of probes in the 22q11.2 region.
• Interphase FISH. Interphase FISH is used primarily for confirmation of the duplication after aCGH analysis and for evaluating relatives of the proband for presence of the duplication.
  
  Note: (1) It is not possible to size the duplication routinely using this method. (2) Routine metaphase FISH analysis often does not detect duplication of 22q11.2 because duplication or greater intensity of the signal cannot be recognized. Thus, a normal metaphase FISH study does not exclude 22q11.2 duplication.
• MLPA. Multiplex ligation-dependent probe amplification is used primarily for confirmation of the duplication after aCGH analysis and for evaluating relatives of the proband for presence of the duplication.
  
  Note: Whether or not it is possible to size the duplication depends on the number and distribution of probes in the 22q11.2 region in the MLPA test.

Table 1. Summary of Molecular Genetic Testing Used in 22q11.2 Duplication

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Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
Deletion / duplication analysis 1, 2	3-Mb or 1.5-Mb duplication	N/A	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array CGH may be used.

2. Interphase FISH and/or MLPA are often used as reflex tests by the laboratory performing the array CGH testing to confirm the presence of a duplication. Interphase FISH or MLPA can then be used to test relatives of the proband for presence of the duplication.

Testing Strategy

Establishing the diagnosis in a proband requires detection of the common 3-Mb or 1.5-Mb proximal nested 22q11.2 duplication.

Evaluating at-risk relatives. Either interphase FISH or MLPA can be used to identify relatives who also have the duplication.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the duplication in the proband. Whether prenatal diagnosis or PGD for 22q11.2 duplication is appropriate clinically is uncertain given the inherent difficulty in predicting the phenotype accurately (see Prenatal Testing).

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

22q11.2 microdeletion syndrome involves deletion of the same 3-Mb or 1.5-Mb region and the same genes that are duplicated in 22q11.2 duplication.

Natural History

Findings in individuals with 22q11.2 duplication range from apparently normal to intellectual disability/learning disability, delayed psychomotor development, growth retardation, and/or hypotonia.

The most common findings in symptomatic individuals with 22q11.2 duplication are [Wentzel et al 2008]:

• Intellectual disability/learning disability (97%), but note ascertainment bias (see below)
• Delayed psychomotor development (67%)
• Growth retardation (63%)
• Muscular hypotonia (43%)

In a recent study of nine individuals with duplication of 22q11.2, the phenotypes observed were generally mild and highly variable [Ou et al 2008].

The high frequency with which the 22q11.2 duplication is found in an apparently normal parent of a proband suggests that many individuals can harbor a duplication of 22q11.2 with no discernible phenotypic effect. Whether duplication 22q11.2 could be a non-pathogenic polymorphism or whether it is a real syndrome with a very large clinical variability and reduced penetrance is uncertain [Courtens et al 2008]. Alternatively, 22q11.2 duplication may only confer a susceptibility to developmental problems.

Determining the clinical phenotype and natural history of 22q11.2 duplication will require study of a large prospective birth cohort. All of the reports currently in the literature are subject to ascertainment bias, making it extremely difficult to discern the true nature and spectrum of this condition. Given the frequency with which the 22q11.2 duplication is found in apparently normal parents of probands, there is an urgent need to establish the frequency with which this duplication occurs in the “normal” population.

There is also a need for a detailed study of the phenotype in secondarily ascertained individuals, e.g., siblings identified on cascade testing to have the duplication. Study of secondarily ascertained individuals would help establish a less biased view of the phenotype than that which emerges from study of probands selected for chromosomal investigations and a more complete view than is possible by analysis of large data sets of “apparently normal” individuals whose phenotypes are not well delineated.

Genotype-Phenotype Correlations

Given the limited data and difficulties in establishing whether and to what extent a 22q11.2 duplication modifies phenotype, it is not possible to determine whether there is a predictable difference between the larger recurrent duplication (3 Mb) and the smaller recurrent duplication (1.5 Mb). An individual with the smaller duplication is described in the paper by Alberti et al [2007].

Penetrance

In probands in whom 22q11.2 duplication is identified, caution is needed in attributing the observed clinical features to this finding. Duplication 22q11.2 has been observed in normal people as well as in people who were studied because they had developmental delay, intellectual disability, or other clinical features suggestive of a chromosomal abnormality. If duplication 22q11.2 causes such phenotypic features, it must frequently be non-penetrant or only penetrant in the presence of other predisposing factors. With present technology and knowledge, it is not possible to reliably predict the phenotype from a laboratory finding of a 22q11.2 duplication [Wentzel et al 2008].

Prevalence

In a study of 7,000 individuals referred for genomic microarray analysis for the investigation of developmental delay/intellectual disability, 3-Mb duplications of 22q11.2 were identified in ten individuals, giving a prevalence of approximately 1:700 in this referral population [Ou et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with 22q11.2 duplication, the following are recommended:

• Clinical examination
• Developmental assessment

Treatment of Manifestations

Educational program should be tailored to individual needs.

Surveillance

Periodic developmental assessment to assure that educational needs are being met is appropriate.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

22q11.2 duplication may be inherited in an autosomal dominant manner or occur de novo.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with a 22q11.2 duplication have inherited the duplication from a parent [Ou et al 2008, Wentzel et al 2008]. The duplication may be inherited through several generations [Yu et al 2008].
• To date, 63 individuals from 35 families have been described with duplication 22q11.2 [Courtens et al 2008]. Familial transmission was seen in 18/26 families (~70%) in which it was analyzed [Wentzel et al 2008]. This is in marked contrast to the reciprocal microdeletion (22q11.2 microdeletion syndrome), roughly 90% of which occurs de novo.
• De novo mutations, in which the duplication is present in a child but not in either parent, also occur.
• A parent who has the duplication 22q11.2 may have a normal or near-normal phenotype (i.e., no physical findings of the 22q11.2 duplication), while the child with an apparently identical genomic alteration has obvious clinical features.
• Because the penetrance of 22q11.2 duplication is incomplete, both parents must be tested to distinguish inherited from de novo cases.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
• If the parents of an individual with the 22q11.2 duplication have normal interphase FISH/MLPA/array studies, the risk to sibs is low but greater than that of the general population because one parent may have germline mosaicism or low-level somatic mosaicism that also includes the gonads.
• If a parent also has the 22q11.2 duplication, the risk to each sib of inheriting the duplication is 50%. However, it is not possible to predict the phenotype reliably from a laboratory finding of the 22q11.2 duplication, and many people who have this genomic alteration are clinically normal.
• In one report [Yobb et al 2005], a parent with a 22q11 duplication had a child with a 22q11 microtriplication, suggesting that occasionally the duplication may expand between parent and offspring. This risk appears very small, but data are insufficient at present to quantify the risk accurately.

Offspring of a proband. Offspring of individuals with the 22q11.2 duplication have a 50% chance of inheriting the duplication. It is not possible to predict the phenotype of individuals who inherit the duplication. There may also be a small chance of expansion to a microtriplication (see Sibs of a proband).

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent has the 22q11 duplication, his or her family members may also have the duplication.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have the 22q11.2 duplication or are at risk of having it.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using interphase FISH in the manner described in Molecular Genetic Testing.

However, it is not possible to reliably predict the phenotype from a laboratory finding of 22q11.2 duplication.

Whether prenatal diagnosis for 22q11 duplication is clinically appropriate, given the difficulty in predicting the phenotype accurately in this nebulous disorder, is uncertain. With the current state of knowledge, such a request would merit careful thought and discussion and review of the current literature.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The low-copy repeat sequences on chromosome 22q11.2 (LCR22s) mediate chromosomal rearrangements resulting in microdeletions and microduplications. This region of the genome is highly dynamic, and in at least one family, expansion of a duplication of 22q11 to a triplication has been observed [Yobb et al 2005].

Duplications of 22q11 vary in size and thereby in gene content. They include:

• The typical common 3-Mb duplication, thought to arise by nonallelic homologous recombination (NAHR) between LCRs;
• A 1.5-Mb nested duplication consistent with NAHR between distinct LCRs [Lupski 2007].

These duplications likely represent the predicted reciprocal rearrangements to the microdeletions characterized in the 22q11.2 region [Ou et al 2008].

Smaller duplications may also occur within this highly dynamic region, with frequent rearrangements using alternative LCRs (LCR22s) as recombination substrates within and distal to the DiGeorge/velocardiofacial syndrome region.

Literature Cited

1. Alberti A, Romano C, Falco M, Calì F, Schinocca P, Galesi O, Spalletta A, Di Benedetto D, Fichera M. 1.5 Mb de novo 22q11.21 microduplication in a patient with cognitive deficits and dysmorphic facial features. Clin Genet. 2007;71:177–82. [PubMed: 17250668]
2. Courtens W, Schramme I, Laridon A. Microduplication 22q11.2: a benign polymorphism or a syndrome with a very large clinical variability and reduced penetrance?--Report of two families. Am J Med Genet A. 2008;146A:758–63. [PubMed: 18260141]
3. Ensenauer RE, Adeyinka A, Flynn HC, Michels VV, Lindor NM, Dawson DB, Thorland EC, Lorentz CP, Goldstein JL, McDonald MT, Smith WE, Simon-Fayard E, Alexander AA, Kulharya AS, Ketterling RP, Clark RD, Jalal SM. Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am J Hum Genet. 2003;73:1027–40. [PMC free article: PMC1180483] [PubMed: 14526392]
4. Hassed SJ, Hopcus-Niccum D, Zhang L, Li S, Mulvihill JJ. A new genomic duplication syndrome complementary to the velocardiofacial (22q11 deletion) syndrome. Clin Genet. 2004;65:400–4. [PubMed: 15099348]
5. Lupski JR. Structural variation in the human genome. N Engl J Med. 2007;356:1169–71. [PubMed: 17360997]
6. 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. Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genet Med. 2008;10:267–77. [PubMed: 18414210]
7. Stachon AC, Baskin B, Smith AC, Shugar A, Cytrynbaum C, Fishman L, Mendoza-Londono R, Klatt R, Teebi A, Ray PN, Weksberg R. Molecular diagnosis of 22q11.2 deletion and duplication by multiplex ligation dependent probe amplification. Am J Med Genet A. 2007;143A:2924–30. [PubMed: 18000985]
8. Wentzel C, Fernström M, Ohrner Y, Annerén G, Thuresson AC. Clinical variability of the 22q11.2 duplication syndrome. Eur J Med Genet. 2008;51:501–10. [PubMed: 18707033]
9. 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, Haase S, Elyas B, Lilley M, Bamforth S, McDermid HE. Microduplication and triplication of 22q11.2: a highly variable syndrome. Am J Hum Genet. 2005;76:865–76. [PMC free article: PMC1199375] [PubMed: 15800846]
10. Yu S, Cox K, Friend K, Smith S, Buchheim R, Bain S, Liebelt J, Thompson E, Bratkovic D. Familial 22q11.2 duplication: a three-generation family with a 3-Mb duplication and a familial 1.5-Mb duplication. Clin Genet. 2008;73:160–4. [PubMed: 18076674]

Author Notes

DECIPHER Project Web site: decipher.sanger.ac.uk

Acknowledgments

Dr Lionel Willatt, Cytogeneticist, Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge CB2 2QQ

Revision History

• 17 February 2009 (cg) Review posted live
• 5 September 2008 (hvf) Original submission