DiagnosisClinical 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 testingDuplication/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 View in own windowTest MethodMutations DetectedMutation Detection Frequency by Test MethodTest AvailabilityDeletion / duplication analysis ^{1, 23-Mb or 1.5-Mb duplicationN/AClinical1. 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).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].

Differential DiagnosisThe most common findings in duplication 22q11.2 – intellectual disability/learning disability, delayed psychomotor development, growth retardation, and muscular hypotonia – are common and relatively nonspecific indications for cytogenetic analysis; the extent to which duplication 22q11.2 is a cause for this group of findings in any individual is currently unknown.

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with 22q11.2 duplication, the following are recommended:Clinical examinationDevelopmental assessmentTreatment 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 RiskSee 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. 22q11.2 Duplication: Genes and DatabasesView in own windowCritical RegionGene SymbolChromosomal LocusProtein NameDGCRNot applicable22q11​.2Not applicableData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for 22q11.2 Duplication (View All in OMIM) View in own window 608363CHROMOSOME 22q11.2 DUPLICATION SYNDROMEMolecular 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.