22q11.2 Duplication Syndrome

Genetic MONDO:0012020 Pathograph 19 Show in embeddings browser hereditary disease chromosomal disorder

22q11.2 duplication syndrome is a variably penetrant genomic disorder caused by a proximal copy-number gain at 22q11.2, commonly involving the reciprocal interval of the 22q11.2 deletion syndrome. Recurrent rearrangements arise through nonallelic homologous recombination between low-copy repeats. Carriers range from apparently unaffected to individuals with developmental or learning difficulties, autism, hypotonia, and congenital anomalies. Cardiac, palatal, endocrine, hearing, immune, and other medical findings can be clinically important even when developmental concerns prompted testing. Specific gene-to-phenotype mechanisms remain incompletely resolved, and an apparently unaffected transmitting parent does not predict a mild outcome in a child.

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1
Inheritance
3
Pathophys.
25
Phenotypes
1
Gaps
19
Pathograph
1
Genes
5
Medical Actions
6
References
👪

Inheritance

1
Autosomal dominant duplication with markedly reduced penetrance HP:0000006
The duplication can arise de novo or be inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity. A carrier has a 50% chance of transmitting the duplication to each offspring; this is a transmission probability, not a probability of clinical impairment. Prenatal detection establishes the copy-number gain but cannot reliably predict the phenotype.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE De novo rate: Both de novo and inherited duplications are reported; unlike the reciprocal deletion, most tested cases are inherited.
Show evidence (4 references)
PMID:18707033 SUPPORT Human Clinical
"Both patients with a de novo 22q11.2 duplication and patients in whom the duplication has been inherited from a phenotypically normal parent have been reported."
Documents that both de novo and inherited duplications occur.
PMID:18707033 SUPPORT Human Clinical
"In a majority of the reported cases where parents have been tested, the duplication seems to have been inherited from a normal parent with minor abnormalities."
Establishes that inheritance from a minimally affected parent predominates, the basis for the reduced-penetrance classification.
PMID:20301749 SUPPORT REVIEW SYNTHESIS Human Clinical
"Offspring of individuals with the 22q11.2 duplication have a 50% chance of inheriting the duplication."
Historical GeneReviews states the Mendelian transmission risk; this does not quantify penetrance.
+ 1 more reference
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Discussions and Knowledge Gaps

1
Which duplicated genes and modifying factors account for the different neurodevelopmental and congenital outcomes among carriers?
KNOWLEDGE GAP individual_gene_contributions
Attached to
pathophysiology#Increased Dosage of 22q11.2 Genes
TBX1 is a candidate contributor to cardiac findings, but this does not establish a hypermorphic allele or a complete mechanism for proximal duplication syndrome. Comparative central-duplication studies nominate other candidates such as PI4KA and explicitly leave functional effects and additional diagnoses unresolved.
Show evidence (2 references)
PMID:30614210 SUPPORT PRIMARY RESULT Human Clinical
"The functional effect of this duplication and the clinical significance is currently unclear."
The discussion of a partial PI4KA duplication cautions against equating genomic gain with established functional gain.
PMID:30614210 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"We therefore postulate that the responsible genes for cardiac defects are likely to lie beyond the LCR22B to LCR22D interval."
The cardiac localization argument is explicitly a hypothesis based on central-duplication comparisons.
⚙

Pathophysiology

3
Nonallelic Homologous Recombination at LCR22
Homologous low-copy repeats at chromosome 22q11.2 provide substrates for recurrent nonallelic recombination.
Downstream
22q11.2 Microduplication Recombination between these repeats can generate the reciprocal copy-number gain.
Show evidence (1 reference)
PMID:30614210 SUPPORT BACKGROUND Human Clinical
"Chromosome 22q11.2 contains eight highly homologous low copy repeat (LCR) sequences that are named LCR22A to LCR22H and that predispose the region to recurrent deletions and duplications by nonallelic homologous recombination (NAHR)"
The introduction describes the established rearrangement mechanism of the proximal 22q11.2 region.
22q11.2 Microduplication
A proximal tandem duplication adds a copy of the affected chromosome 22q11.2 interval. Common duplications are approximately 3 Mb or 1.5 Mb; the larger recurrent interval extends from LCR22A to LCR22D.
Downstream
Increased Dosage of 22q11.2 Genes The additional interval increases genomic copy number for genes contained within it.
Show evidence (2 references)
PMID:20301749 SUPPORT REVIEW SYNTHESIS Human Clinical
"22q11.2 duplication is defined for this GeneReview as the presence of a common 3-Mb or 1.5-Mb proximal tandem duplication."
Defines the common proximal tandem duplications.
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"All participants in the 22q11.2DupS and 22q11.2DS groups had a typical (LCR-A to LCR-D) duplication or deletion as confirmed with clinical or research testing via SNP microarray or multiplex ligation probe amplification."
The typical duplication cohort was confirmed to carry LCR-A to LCR-D gains.
Increased Dosage of 22q11.2 Genes
Genes within the duplicated interval have increased genomic copy number. This does not establish proportional RNA or protein overexpression for every gene, or a hypermorphic TBX1 allele. The contribution of individual genes and intervening developmental processes to the variable clinical phenotype remains incompletely resolved.
Downstream
Learning Disability A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Congenital Heart Defects A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Palatal Anomalies A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Velopharyngeal Insufficiency A reported palatal manifestation of the proximal duplication; the individual gene and developmental intermediates remain unresolved.
Bifid Uvula A reported palatal manifestation of the proximal duplication; the individual gene and developmental intermediates remain unresolved.
Intellectual Disability A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Global Developmental Delay A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Growth Delay A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Autism Spectrum Disorder A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Hypotonia A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Seizures A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Hearing Impairment A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Hypothyroidism A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Hypocalcemia A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Strabismus A variably expressed clinical consequence of the proximal duplication; the responsible gene-specific intermediates are not established.
Show evidence (1 reference)
PMID:20301749 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"22q11.2 duplication is defined for this GeneReview as the presence of a common 3-Mb or 1.5-Mb proximal tandem duplication."
A tandem duplication increases the genomic dosage of its included loci.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 22q11.2 Duplication Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

25
Blood 4
Abnormal Immunoglobulin Levels Abnormal circulating immunoglobulin concentration HP:0010701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal circulating immunoglobulin concentration (HP:0010701). HP:0010701 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Immunologic | Immunology visit: n = 31 | 39 % (12/31) • Abnormal immunoglobulin levels n = 7 • Inappropriate vaccine response n = 3"
The cohort distinguishes abnormal immunoglobulin levels from vaccine-response and cellular abnormalities.
Anemia OCCASIONAL HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Hematologic | Complete blood count: n = 37 | 16 % (6/37) • Thrombocytopenia n = 1 • Thrombocytopenia and anemia n = 1 • Neutropenia n = 2 • Anemia n = 2"
Table 4 separates the individual blood-count abnormalities and includes one child in both the anemia and thrombocytopenia counts.
Thrombocytopenia OCCASIONAL HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Hematologic | Complete blood count: n = 37 | 16 % (6/37) • Thrombocytopenia n = 1 • Thrombocytopenia and anemia n = 1 • Neutropenia n = 2 • Anemia n = 2"
Table 4 separates the individual blood-count abnormalities and includes one child in both the anemia and thrombocytopenia counts.
Neutropenia OCCASIONAL Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Hematologic | Complete blood count: n = 37 | 16 % (6/37) • Thrombocytopenia n = 1 • Thrombocytopenia and anemia n = 1 • Neutropenia n = 2 • Anemia n = 2"
Table 4 reports two individuals with neutropenia among 37 with a complete blood count.
Cardiovascular 1
Congenital Heart Defects OCCASIONAL Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Cardiac | Clinical evaluation: n = 37 | 24 % (9/37) | VSD, PVS, PDA, ASD/PFO, TOF, HLHS"
Table 4 reports cardiac findings in the duplication cohort, supporting the occasional frequency band.
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"Ankyloglossia, dysphagia, laryngomalacia, Eustachian tube dysfunction."
The duplication cohort explicitly lists dysphagia.
Ear 1
Hearing Impairment OCCASIONAL HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Hearing loss | Audiogram: n = 37 | 16 % (6/37) • Conductive n = 3 • Mixed n = 2 • Sensorineural n = 1"
Table 4 supplies both the overall rate and the heterogeneous hearing-loss types.
Endocrine 1
Hypothyroidism OCCASIONAL HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Endocrine | Endocrine evaluation: n = 31 | Hypothyroidism 19 % (6/31) Hypocalcemia 10 % (3/31)"
Table 4 distinguishes hypothyroidism from hypocalcemia in the evaluated endocrine subset.
Eye 1
Strabismus OCCASIONAL HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Ophthalmologic | Ophthalmology evaluation: n = 37 | 22 % (8/37) • Strabismus n = 5"
The full-text table supplies a specific ocular phenotype rather than only an organ-system category.
Genitourinary 1
Vesicoureteral Reflux HP:0000076 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vesicoureteral reflux (HP:0000076). HP:0000076 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Renal | Renal ultrasound: n = 25 | 24 % (6/25) | VUR; Pelviectasis ( n = 2); Lithiasis; Nephromegaly; Megaureter"
Table 4 lists VUR in the duplication cohort; its legend expands VUR as vesicoureteral reflux.
Head and Neck 4
Palatal Anomalies Abnormal palate morphology HP:0000174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palatal anomaly, annotated with Abnormal palate morphology (HP:0000174). HP:0000174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34845825 SUPPORT Human Clinical
"Affected individuals are at increased risk for a variety of problems including gastrointestinal complications, endocrine dysfunction, ophthalmologic abnormalities, palatal anomalies, congenital heart disease, musculoskeletal differences, and neurologic abnormalities."
Palatal anomalies are among the increased-risk problems in 22q11.2 duplication.
Velopharyngeal Insufficiency HP:0000220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Velopharyngeal insufficiency (HP:0000220). HP:0000220 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Palate | 2/12 | Velopharyngeal insufficiency n = 1 |"
Table 5 lists one affected child; the aggregate 2/12 palate count also includes a child with bifid uvula and is not the frequency of velopharyngeal insufficiency.
Bifid Uvula HP:0000193 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bifid uvula (HP:0000193). HP:0000193 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Palate | 2/12 | Velopharyngeal insufficiency n = 1 | | Bifid uvula a n = 1 |"
Table 5 reports bifid uvula in one child, separate from the child with velopharyngeal insufficiency; the aggregate palate count is not assigned to either finding.
Facial Dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Facial findings are variable; a recognizable facial phenotype is not required for diagnosis.
Show evidence (1 reference)
PMID:36648576 SUPPORT REVIEW SYNTHESIS Human Clinical
"It has, however, also been associated with some manifestations similar to 22q11.2del, including cardiac defects, velopharyngeal insuf- ficiency, intellectual and learning disabilities, short stature, and facial dysmorphism [ 76–78]."
The duplication-specific section describes facial dysmorphism among reported manifestations.
Metabolism 1
Hypocalcemia OCCASIONAL HP:0002901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocalcemia (HP:0002901). HP:0002901 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Endocrine | Endocrine evaluation: n = 31 | Hypothyroidism 19 % (6/31) Hypocalcemia 10 % (3/31)"
Table 4 documents hypocalcemia in the duplication group.
Musculoskeletal 2
Hypotonia OCCASIONAL HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| EEG: n = 5 | Hypotonia 27 % (10/37) | | Seizure activity 19 % (7/37) |"
Table 4 gives the count for hypotonia.
Cervical Spine Anomalies Abnormality of the cervical spine HP:0003319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the cervical spine (HP:0003319). HP:0003319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Skeletal | C-Spine x-rays: n = 11 | C-spine anomaly 45 % (5/11) | Slightly large atlantodens interval; Hypoplastic PE of C1 and elongated PE of C2; Exaggerated kyphosis, lordosis; Incomplete arch C1; Lack of bony fusion of C1 and dysmorphic C2"
Table 4 describes the cervical findings and restricted imaging denominator.
Nervous System 5
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301749 SUPPORT REVIEW SYNTHESIS Human Clinical
"The 22q11.2 duplication phenotype appears to be generally mild and highly variable; findings range from apparently normal to intellectual disability / learning disability, delayed psychomotor development, growth retardation, and/or hypotonia."
Historical GeneReviews lists this feature within the variable proximal-duplication phenotype.
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301749 SUPPORT REVIEW SYNTHESIS Human Clinical
"The 22q11.2 duplication phenotype appears to be generally mild and highly variable; findings range from apparently normal to intellectual disability / learning disability, delayed psychomotor development, growth retardation, and/or hypotonia."
Historical GeneReviews lists this feature within the variable proximal-duplication phenotype.
Autism Spectrum Disorder OCCASIONAL HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"Overall, 38% of children aged 2-18 with 22q11.2DupS had community diagnoses of ASD, but fewer (14-25%) met on the basis of best clinical judgment that included ADI-R and ADOS data."
Distinguishes research-supported ASD diagnoses from the higher community-diagnosis rate.
Seizures OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| EEG: n = 5 | Hypotonia 27 % (10/37) | | Seizure activity 19 % (7/37) |"
Table 4 supports seizures without specifying a uniform seizure type.
Chiari Type I Malformation HP:0007099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chiari type I malformation (HP:0007099). HP:0007099 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"| Neurologic/calavarium | Brain MRI: n = 16 | Structural anomaly 24 % (5/21) | Chiari Type I;"
Table 4 explicitly identifies Chiari type I within the structural findings.
Respiratory 1
Laryngomalacia HP:0001601 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngomalacia (HP:0001601). HP:0001601 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"Ankyloglossia, dysphagia, laryngomalacia, Eustachian tube dysfunction."
The cohort directly lists laryngomalacia.
Growth 1
Growth Delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301749 SUPPORT REVIEW SYNTHESIS Human Clinical
"The 22q11.2 duplication phenotype appears to be generally mild and highly variable; findings range from apparently normal to intellectual disability / learning disability, delayed psychomotor development, growth retardation, and/or hypotonia."
Historical GeneReviews lists this feature within the variable proximal-duplication phenotype.
Other 1
Learning Disability
The source does not distinguish general learning difficulties from a specific academic-learning disorder. The clinical wording is retained without a binding to Specific learning disability.
Show evidence (1 reference)
PMID:18707033 SUPPORT Human Clinical
"The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from normal to learning disability and congenital defects."
Learning disability is at one end of the highly variable phenotype.
🧬

Genetic Associations

1
Proximal 22q11.2 duplication (Causal)
Show evidence (2 references)
PMID:20301749 SUPPORT REVIEW SYNTHESIS Human Clinical
"22q11.2 duplication is defined for this GeneReview as the presence of a common 3-Mb or 1.5-Mb proximal tandem duplication."
Defines the causal copy-number variant class.
PMID:18707033 SUPPORT Human Clinical
"In a majority of the reported cases where parents have been tested, the duplication seems to have been inherited from a normal parent with minor abnormalities."
Establishes that inheritance from a minimally affected parent predominates, the basis for the reduced-penetrance classification.
💊

Medical Actions

5
Multidisciplinary Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Coordinate multidisciplinary care for the manifestations present. Duplication cohorts support adapting the 22q11.2 deletion syndrome screening framework; this is not evidence that every deletion-specific treatment or precaution applies to every duplication carrier.
Show evidence (1 reference)
PMID:34845825 SUPPORT Human Clinical
"Individuals with 22q11.2 duplication syndrome would benefit from care coordinated by a multidisciplinary team and managed according to the 22q11.2 deletion syndrome guidelines."
Supports multidisciplinary care coordinated per 22q11.2 deletion guidelines.
Individualized Educational Support
Action: Educational InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Educational Intervention (NCIT:C17874). NCIT:C17874 is a clinical intervention from the NCI Thesaurus. NCIT:C17874
Platform: Behavioral / lifestyle
Tailor educational support to the developmental and learning profile and reassess periodically as needs change.
Mechanism Target:
Learning Disability
Global Developmental Delay
Show evidence (1 reference)
PMID:20301749 SUPPORT REVIEW SYNTHESIS Human Clinical
"Treatment of manifestations: Educational program tailored to individual needs. Surveillance: Periodic developmental assessments to assure that educational needs are being met."
Historical GeneReviews supports individualized education and periodic developmental assessment.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Explain incomplete penetrance, variable expressivity, the 50% transmission risk, and the inability of a parental or prenatal result to predict clinical severity.
Show evidence (1 reference)
PMID:20301749 SUPPORT REVIEW SYNTHESIS Human Clinical
"Offspring of individuals with the 22q11.2 duplication have a 50% chance of inheriting the duplication. Prenatal testing is technically feasible; however, it is not possible to predict the phenotype from a laboratory finding of 22q11.2 duplication."
Historical GeneReviews distinguishes transmission risk from phenotype prediction.
Myringotomy with Ear Tube Placement
Action: Myringotomy with Ear Tube PlacementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Myringotomy with Ear Tube Placement (NCIT:C70906). NCIT:C70906 is a clinical intervention from the NCI Thesaurus. NCIT:C70906
Platform: Surgery
Bilateral myringotomy tube placement was recorded in nine individuals in the cohort. This documents use for selected otologic manifestations; it does not establish universal need or treatment efficacy in duplication syndrome.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"Ankyloglossia, dysphagia, laryngomalacia, Eustachian tube dysfunction. Surgical interventions: BMT ( n = 9), T&A ( n = 9)"
Table 4 reports BMT use; its legend defines BMT as bilateral myringotomy tubes.
Tonsillectomy with Adenoidectomy
Action: Tonsillectomy with adenoidectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Tonsillectomy with adenoidectomy (NCIT:C51684). NCIT:C51684 is a clinical intervention from the NCI Thesaurus. Ontology label: Tonsillectomy with Adenoidectomy NCIT:C51684
Platform: Surgery
Tonsillectomy with adenoidectomy was recorded in nine individuals in the cohort. The report documents an intervention used in selected patients without establishing syndrome-specific efficacy or a universal indication.
Show evidence (1 reference)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"Ankyloglossia, dysphagia, laryngomalacia, Eustachian tube dysfunction. Surgical interventions: BMT ( n = 9), T&A ( n = 9)"
Table 4 reports T&A use; its legend defines T&A as tonsillectomy with adenoidectomy.
🔬

Diagnosis

3
Chromosomal Microarray (Proximal 22q11.2 copy-number gain)
Chromosomal microarray identifies the duplication and its extent. Clinical appearance alone is insufficiently distinctive, and routine G-banded karyotyping does not reliably detect the common microduplication.
Show evidence (2 references)
PMID:20301749 SUPPORT REVIEW SYNTHESIS Human Clinical
"The phenotype is not sufficiently distinct to be specifically suspected on clinical grounds alone. 22q11.2 duplication is not detectable by routine G-banded karyotyping. Most individuals with 22q11.2 duplication are identified by a chromosomal microarray."
Historical GeneReviews states the diagnostic limitations and principal test.
PMID:18707033 SUPPORT PRIMARY RESULT Human Clinical
"In this study we present two familial cases with a 3Mb 22q11.2 duplication detected by array-CGH."
The familial case series directly demonstrates microarray detection.
Family Testing
Offer testing to relatives, including parents with few or no clinical findings, to establish inheritance and support counseling.
Show evidence (1 reference)
PMID:18707033 SUPPORT PRIMARY RESULT Human Clinical
"With this in mind we recommend that family members of patients with a 22q11.2 duplication to be tested for this genetic defect."
The familial series recommends testing relatives.
Baseline Medical Screening
Duplication-specific cohort evidence supports baseline cardiac, renal, cervical spine, immune, calcium, thyroid, hearing, and ophthalmologic evaluation in children, including those identified because of developmental concerns alone. Screening selection and subsequent follow-up should be individualized to clinical findings.
Show evidence (2 references)
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"These practitioners should be aware of the need for children with 22q11.2DupS to undergo medical screening including echocardiogram, renal ultrasound, cervical spine x-rays, immunologic testing (or referral to immunologist for evaluation), ionized calcium levels, thyroid functioning, and..."
The full-text discussion specifies the screening investigations supported by the cohort.
PMID:27158440 SUPPORT PRIMARY RESULT Human Clinical
"Given the elevated rate of ophthalmologic abnormalities in our cohort, an ophthalmologist should also evaluate them."
The cohort also supports ophthalmologic assessment.
📊

Prevalence

1
Intellectual disability population
Point Prevalence 143.0 per 100,000 >1 in 1,000
Reported at ~1 in 700 within the intellectual-disability population (a condition-specific base, not a general-population birth prevalence). True population prevalence is uncertain because of markedly reduced penetrance and frequent ascertainment through affected relatives.
Show evidence (1 reference)
PMID:34845825 SUPPORT BACKGROUND Human Clinical
"22q11.2 duplication syndrome has a frequency of ~1/700 in the intellectual disability population."
Provides the ~1 in 700 frequency within the intellectual-disability population.
{ }

Source YAML

click to show 
name: 22q11.2 Duplication Syndrome
creation_date: "2026-08-22T00:00:00Z"
description: >-
  22q11.2 duplication syndrome is a variably penetrant genomic disorder caused by a proximal
  copy-number gain at 22q11.2, commonly involving the reciprocal interval of the 22q11.2 deletion
  syndrome. Recurrent rearrangements arise through nonallelic homologous recombination between
  low-copy repeats. Carriers range from apparently unaffected to individuals with developmental
  or learning difficulties, autism, hypotonia, and congenital anomalies. Cardiac, palatal, endocrine,
  hearing, immune, and other medical findings can be clinically important even when developmental
  concerns prompted testing. Specific gene-to-phenotype mechanisms remain incompletely resolved,
  and an apparently unaffected transmitting parent does not predict a mild outcome in a child.
category: Genetic
synonyms:
- chromosome 22q11.2 microduplication syndrome
- dup22q11 syndrome
- 22q11.2 microduplication syndrome
parents:
- hereditary disease
- chromosomal disorder
disease_term:
  preferred_term: chromosome 22q11.2 microduplication syndrome
  term:
    id: MONDO:0012020
    label: chromosome 22q11.2 microduplication syndrome
inheritance:
- name: Autosomal dominant duplication with markedly reduced penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  de_novo_rate: >-
    Both de novo and inherited duplications are reported; unlike the reciprocal
    deletion, most tested cases are inherited.
  description: >-
    The duplication can arise de novo or be inherited in an autosomal dominant manner with incomplete
    penetrance and variable expressivity. A carrier has a 50% chance of transmitting the duplication
    to each offspring; this is a transmission probability, not a probability of clinical impairment.
    Prenatal detection establishes the copy-number gain but cannot reliably predict the phenotype.
  evidence:
  - reference: PMID:18707033
    reference_title: "Clinical variability of the 22q11.2 duplication syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients with a de novo 22q11.2 duplication and patients in whom the
      duplication has been inherited from a phenotypically normal parent have
      been reported.
    explanation: Documents that both de novo and inherited duplications occur.
  - reference: PMID:18707033
    reference_title: "Clinical variability of the 22q11.2 duplication syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a majority of the reported cases where parents have been tested, the
      duplication seems to have been inherited from a normal parent with minor
      abnormalities.
    explanation: >-
      Establishes that inheritance from a minimally affected parent predominates, the basis
      for the reduced-penetrance classification.
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Offspring of individuals with the 22q11.2 duplication have a 50% chance of inheriting
      the duplication.
    explanation: >-
      Historical GeneReviews states the Mendelian transmission risk; this does not quantify
      penetrance.
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Prenatal testing is technically feasible; however, it is not possible to predict the phenotype
      from a laboratory finding of 22q11.2 duplication.
    explanation: >-
      A prenatal result cannot predict clinical severity.
prevalence:
- population: Intellectual disability population
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 143.0
  notes: >-
    Reported at ~1 in 700 within the intellectual-disability population (a condition-specific
    base, not a general-population birth prevalence). True population prevalence is uncertain
    because of markedly reduced penetrance and frequent ascertainment through affected relatives.
  evidence:
  - reference: PMID:34845825
    reference_title: "22q11.2 duplications: Expanding the clinical presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "22q11.2 duplication syndrome has a frequency of ~1/700 in the intellectual disability population."
    explanation: Provides the ~1 in 700 frequency within the intellectual-disability population.
    quote_role: BACKGROUND
pathophysiology:
- name: Nonallelic Homologous Recombination at LCR22
  biological_scale: MOLECULAR
  description: >-
    Homologous low-copy repeats at chromosome 22q11.2 provide substrates for recurrent nonallelic
    recombination.
  evidence:
  - reference: PMID:30614210
    reference_title: >-
      Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental
      phenotypes including autism spectrum disorder with incomplete penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Chromosome 22q11.2 contains eight highly homologous low copy repeat (LCR) sequences that
      are
      named LCR22A to LCR22H and that predispose the region to recurrent deletions and duplications
      by nonallelic homologous recombination (NAHR)
    explanation: >-
      The introduction describes the established rearrangement mechanism of the proximal 22q11.2
      region.
  downstream:
  - target: 22q11.2 Microduplication
    causal_link_type: DIRECT
    description: Recombination between these repeats can generate the reciprocal copy-number gain.
    evidence:
    - reference: PMID:30614210
      reference_title: >-
        Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental
        phenotypes including autism spectrum disorder with incomplete penetrance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Chromosome 22q11.2 contains eight highly homologous low copy repeat (LCR) sequences
        that are
        named LCR22A to LCR22H and that predispose the region to recurrent deletions and duplications
        by nonallelic homologous recombination (NAHR)
      explanation: >-
        Supports the recurrent duplication as a product of LCR-mediated recombination.
- name: 22q11.2 Microduplication
  biological_scale: MOLECULAR
  description: >-
    A proximal tandem duplication adds a copy of the affected chromosome 22q11.2 interval. Common
    duplications are approximately 3 Mb or 1.5 Mb; the larger recurrent interval extends from
    LCR22A to LCR22D.
  evidence:
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      22q11.2 duplication is defined for this GeneReview as the presence of a common 3-Mb or
      1.5-Mb
      proximal tandem duplication.
    explanation: >-
      Defines the common proximal tandem duplications.
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      All participants in the 22q11.2DupS and 22q11.2DS groups had a typical (LCR-A to LCR-D)
      duplication
      or deletion as confirmed with clinical or research testing via SNP microarray or multiplex
      ligation
      probe amplification.
    explanation: >-
      The typical duplication cohort was confirmed to carry LCR-A to LCR-D gains.
  downstream:
  - target: Increased Dosage of 22q11.2 Genes
    causal_link_type: DIRECT
    description: The additional interval increases genomic copy number for genes contained within it.
- name: Increased Dosage of 22q11.2 Genes
  biological_scale: MOLECULAR
  description: >-
    Genes within the duplicated interval have increased genomic copy number. This does not establish
    proportional RNA or protein overexpression for every gene, or a hypermorphic TBX1 allele.
    The contribution of individual genes and intervening developmental processes to the variable
    clinical phenotype remains incompletely resolved.
  evidence:
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      22q11.2 duplication is defined for this GeneReview as the presence of a common 3-Mb or
      1.5-Mb
      proximal tandem duplication.
    explanation: >-
      A tandem duplication increases the genomic dosage of its included loci.
    directness: INDIRECT
  downstream:
  - target: Learning Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:18707033
      reference_title: "Clinical variability of the 22q11.2 duplication syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from normal to learning disability and congenital defects."
      explanation: Learning disability is at one end of the highly variable phenotype.
      directness: INDIRECT
  - target: Congenital Heart Defects
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:27158440
      reference_title: >-
        22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for
        medical screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        | Cardiac | Clinical evaluation: n = 37 | 24 % (9/37) | VSD, PVS, PDA, ASD/PFO, TOF,
        HLHS
      explanation: >-
        Table 4 reports cardiac findings in the duplication cohort, supporting the occasional
        frequency band.
      directness: INDIRECT
  - target: Palatal Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:34845825
      reference_title: "22q11.2 duplications: Expanding the clinical presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Affected individuals are at increased risk for a variety of problems including gastrointestinal complications, endocrine dysfunction, ophthalmologic abnormalities, palatal anomalies, congenital heart disease, musculoskeletal differences, and neurologic abnormalities."
      explanation: Palatal anomalies are among the increased-risk problems in 22q11.2 duplication.
      directness: INDIRECT
  - target: Velopharyngeal Insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A reported palatal manifestation of the proximal duplication; the individual gene and developmental intermediates remain unresolved.
    evidence:
    - reference: PMID:27158440
      reference_title: '22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: '| Palate | 2/12 | Velopharyngeal insufficiency n = 1 |'
      explanation: Table 5 reports this palate finding in the 12-person subgroup screened for developmental concerns without an indicated birth defect; the individual gene and developmental intermediates are unresolved.
      directness: INDIRECT
  - target: Bifid Uvula
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A reported palatal manifestation of the proximal duplication; the individual gene and developmental intermediates remain unresolved.
    evidence:
    - reference: PMID:27158440
      reference_title: '22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: '| Palate | 2/12 | Velopharyngeal insufficiency n = 1 | | Bifid uvula a n = 1 |'
      explanation: Table 5 reports this palate finding in the 12-person subgroup screened for developmental concerns without an indicated birth defect; the individual gene and developmental intermediates are unresolved.
      directness: INDIRECT
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:20301749
      reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The 22q11.2 duplication phenotype appears to be generally mild and highly variable;
        findings
        range from apparently normal to intellectual disability / learning disability, delayed
        psychomotor
        development, growth retardation, and/or hypotonia.
      explanation: >-
        Historical GeneReviews lists this feature within the variable proximal-duplication phenotype.
      directness: INDIRECT
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:20301749
      reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The 22q11.2 duplication phenotype appears to be generally mild and highly variable;
        findings
        range from apparently normal to intellectual disability / learning disability, delayed
        psychomotor
        development, growth retardation, and/or hypotonia.
      explanation: >-
        Historical GeneReviews lists this feature within the variable proximal-duplication phenotype.
      directness: INDIRECT
  - target: Growth Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:20301749
      reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The 22q11.2 duplication phenotype appears to be generally mild and highly variable;
        findings
        range from apparently normal to intellectual disability / learning disability, delayed
        psychomotor
        development, growth retardation, and/or hypotonia.
      explanation: >-
        Historical GeneReviews lists this feature within the variable proximal-duplication phenotype.
      directness: INDIRECT
  - target: Autism Spectrum Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:27158440
      reference_title: >-
        22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for
        medical screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Overall, 38% of children aged 2-18 with 22q11.2DupS had community diagnoses of ASD,
        but fewer
        (14-25%) met on the basis of best clinical judgment that included ADI-R and ADOS data.
      explanation: >-
        Distinguishes research-supported ASD diagnoses from the higher community-diagnosis rate.
      directness: INDIRECT
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:27158440
      reference_title: >-
        22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for
        medical screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        | EEG: n = 5 | Hypotonia 27 % (10/37) | | Seizure activity 19 % (7/37) |
      explanation: >-
        Table 4 gives the count for hypotonia.
      directness: INDIRECT
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:27158440
      reference_title: >-
        22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for
        medical screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        | EEG: n = 5 | Hypotonia 27 % (10/37) | | Seizure activity 19 % (7/37) |
      explanation: >-
        Table 4 supports seizures without specifying a uniform seizure type.
      directness: INDIRECT
  - target: Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:27158440
      reference_title: >-
        22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for
        medical screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        | Hearing loss | Audiogram: n = 37 | 16 % (6/37) • Conductive n = 3 • Mixed n = 2 •
        Sensorineural
        n = 1
      explanation: >-
        Table 4 supplies both the overall rate and the heterogeneous hearing-loss types.
      directness: INDIRECT
  - target: Hypothyroidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:27158440
      reference_title: >-
        22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for
        medical screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        | Endocrine | Endocrine evaluation: n = 31 | Hypothyroidism 19 % (6/31) Hypocalcemia
        10 % (3/31)
      explanation: >-
        Table 4 distinguishes hypothyroidism from hypocalcemia in the evaluated endocrine subset.
      directness: INDIRECT
  - target: Hypocalcemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:27158440
      reference_title: >-
        22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for
        medical screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        | Endocrine | Endocrine evaluation: n = 31 | Hypothyroidism 19 % (6/31) Hypocalcemia
        10 % (3/31)
      explanation: >-
        Table 4 documents hypocalcemia in the duplication group.
      directness: INDIRECT
  - target: Strabismus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A variably expressed clinical consequence of the proximal duplication; the responsible
      gene-specific intermediates are not established.
    evidence:
    - reference: PMID:27158440
      reference_title: >-
        22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for
        medical screening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        | Ophthalmologic | Ophthalmology evaluation: n = 37 | 22 % (8/37) • Strabismus n = 5
      explanation: >-
        The full-text table supplies a specific ocular phenotype rather than only an organ-system
        category.
      directness: INDIRECT
phenotypes:
- category: Cognitive
  name: Learning Disability
  notes: >-
    The source does not distinguish general learning difficulties from a specific academic-learning
    disorder. The clinical wording is retained without a binding to Specific learning disability.
  phenotype_term:
    preferred_term: Learning disability
  evidence:
  - reference: PMID:18707033
    reference_title: "Clinical variability of the 22q11.2 duplication syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from normal to learning disability and congenital defects."
    explanation: Learning disability is at one end of the highly variable phenotype.
- category: Cardiac
  name: Congenital Heart Defects
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Cardiac | Clinical evaluation: n = 37 | 24 % (9/37) | VSD, PVS, PDA, ASD/PFO, TOF, HLHS
    explanation: >-
      Table 4 reports cardiac findings in the duplication cohort, supporting the occasional
      frequency band.
  description: >-
    Cardiac defects were recorded in 9/37 (24%) individuals in the typical-duplication cohort.
    Counts describe a clinically ascertained cohort with typical LCR22A-D duplications; they
    are not population penetrance estimates.
- category: Craniofacial
  name: Palatal Anomalies
  phenotype_term:
    preferred_term: Palatal anomaly
    term:
      id: HP:0000174
      label: Abnormal palate morphology
  evidence:
  - reference: PMID:34845825
    reference_title: "22q11.2 duplications: Expanding the clinical presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals are at increased risk for a variety of problems including gastrointestinal complications, endocrine dysfunction, ophthalmologic abnormalities, palatal anomalies, congenital heart disease, musculoskeletal differences, and neurologic abnormalities."
    explanation: Palatal anomalies are among the increased-risk problems in 22q11.2 duplication.
- category: Craniofacial
  name: Velopharyngeal Insufficiency
  description: >-
    Velopharyngeal insufficiency was identified in one child in the 12-person subgroup tested
    for developmental concerns without an indicated birth defect. This subgroup count is not
    a population frequency estimate.
  phenotype_term:
    preferred_term: Velopharyngeal insufficiency
    term:
      id: HP:0000220
      label: Velopharyngeal insufficiency
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Palate | 2/12 | Velopharyngeal insufficiency n = 1 |
    explanation: >-
      Table 5 lists one affected child; the aggregate 2/12 palate count also includes a child
      with bifid uvula and is not the frequency of velopharyngeal insufficiency.
- category: Craniofacial
  name: Bifid Uvula
  description: >-
    Bifid uvula was identified in one child in the 12-person subgroup tested for developmental
    concerns without an indicated birth defect. The table notes that this anomaly alone does
    not establish palatal dysfunction.
  phenotype_term:
    preferred_term: Bifid uvula
    term:
      id: HP:0000193
      label: Bifid uvula
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Palate | 2/12 | Velopharyngeal insufficiency n = 1 | | Bifid uvula a n = 1 |
    explanation: >-
      Table 5 reports bifid uvula in one child, separate from the child with velopharyngeal
      insufficiency; the aggregate palate count is not assigned to either finding.
- category: Craniofacial
  name: Facial Dysmorphism
  notes: >-
    Facial findings are variable; a recognizable facial phenotype is not required for diagnosis.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:36648576
    reference_title: >-
      Clinical Practice Guidelines for the Immunological Management of Chromosome 22q11.2 Deletion
      Syndrome and Other Defects in Thymic Development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It has, however, also been associated with some manifestations similar to 22q11.2del,
      including
      cardiac defects, velopharyngeal insuf- ficiency, intellectual and learning disabilities,
      short
      stature, and facial dysmorphism [ 76–78].
    explanation: >-
      The duplication-specific section describes facial dysmorphism among reported manifestations.
- name: Intellectual Disability
  category: Cognitive
  description: >-
    Intellectual disability is variably present and can be absent in transmitting relatives.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The 22q11.2 duplication phenotype appears to be generally mild and highly variable; findings
      range from apparently normal to intellectual disability / learning disability, delayed
      psychomotor
      development, growth retardation, and/or hypotonia.
    explanation: >-
      Historical GeneReviews lists this feature within the variable proximal-duplication phenotype.
- name: Global Developmental Delay
  category: Neurodevelopmental
  description: >-
    Psychomotor development can be delayed; normal development also occurs.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The 22q11.2 duplication phenotype appears to be generally mild and highly variable; findings
      range from apparently normal to intellectual disability / learning disability, delayed
      psychomotor
      development, growth retardation, and/or hypotonia.
    explanation: >-
      Historical GeneReviews lists this feature within the variable proximal-duplication phenotype.
- name: Growth Delay
  category: Growth
  description: >-
    Growth retardation is a reported manifestation, with variable expression.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The 22q11.2 duplication phenotype appears to be generally mild and highly variable; findings
      range from apparently normal to intellectual disability / learning disability, delayed
      psychomotor
      development, growth retardation, and/or hypotonia.
    explanation: >-
      Historical GeneReviews lists this feature within the variable proximal-duplication phenotype.
- name: Autism Spectrum Disorder
  category: Neurodevelopmental
  description: >-
    Research assessment estimated ASD in 14-25% of clinically identified duplication carriers.
    The estimate depends on participation and diagnostic assessment and does not measure penetrance
    among all population carriers.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Overall, 38% of children aged 2-18 with 22q11.2DupS had community diagnoses of ASD, but
      fewer
      (14-25%) met on the basis of best clinical judgment that included ADI-R and ADOS data.
    explanation: >-
      Distinguishes research-supported ASD diagnoses from the higher community-diagnosis rate.
  frequency: OCCASIONAL
- name: Hypotonia
  category: Neurologic
  description: >-
    Hypotonia was recorded in 10/37 (27%) individuals. Counts describe a clinically ascertained
    cohort with typical LCR22A-D duplications; they are not population penetrance estimates.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | EEG: n = 5 | Hypotonia 27 % (10/37) | | Seizure activity 19 % (7/37) |
    explanation: >-
      Table 4 gives the count for hypotonia.
  frequency: OCCASIONAL
- name: Seizures
  category: Neurologic
  description: >-
    Seizure activity was recorded in 7/37 (19%) individuals. Counts describe a clinically ascertained
    cohort with typical LCR22A-D duplications; they are not population penetrance estimates.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | EEG: n = 5 | Hypotonia 27 % (10/37) | | Seizure activity 19 % (7/37) |
    explanation: >-
      Table 4 supports seizures without specifying a uniform seizure type.
  frequency: OCCASIONAL
- name: Hearing Impairment
  category: Auditory
  description: >-
    Hearing loss was recorded in 6/37 (16%) individuals and included conductive, mixed, and
    sensorineural types. Counts describe a clinically ascertained cohort with typical LCR22A-D
    duplications; they are not population penetrance estimates.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Hearing loss | Audiogram: n = 37 | 16 % (6/37) • Conductive n = 3 • Mixed n = 2 • Sensorineural
      n = 1
    explanation: >-
      Table 4 supplies both the overall rate and the heterogeneous hearing-loss types.
  frequency: OCCASIONAL
- name: Hypothyroidism
  category: Endocrine
  description: >-
    Hypothyroidism was recorded in 6/31 (19%) evaluated individuals. Counts describe a clinically
    ascertained cohort with typical LCR22A-D duplications; they are not population penetrance
    estimates.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Endocrine | Endocrine evaluation: n = 31 | Hypothyroidism 19 % (6/31) Hypocalcemia 10
      % (3/31)
    explanation: >-
      Table 4 distinguishes hypothyroidism from hypocalcemia in the evaluated endocrine subset.
  frequency: OCCASIONAL
- name: Hypocalcemia
  category: Endocrine
  frequency: OCCASIONAL
  description: >-
    Hypocalcemia was recorded in 3/31 evaluated individuals. Counts describe a clinically ascertained
    cohort with typical LCR22A-D duplications; they are not population penetrance estimates.
  phenotype_term:
    preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Endocrine | Endocrine evaluation: n = 31 | Hypothyroidism 19 % (6/31) Hypocalcemia 10
      % (3/31)
    explanation: >-
      Table 4 documents hypocalcemia in the duplication group.
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Strabismus was recorded in 5/37 individuals. Counts describe a clinically ascertained cohort
    with typical LCR22A-D duplications; they are not population penetrance estimates.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Ophthalmologic | Ophthalmology evaluation: n = 37 | 22 % (8/37) • Strabismus n = 5
    explanation: >-
      The full-text table supplies a specific ocular phenotype rather than only an organ-system
      category.
  frequency: OCCASIONAL
- name: Abnormal Immunoglobulin Levels
  category: Immunologic
  description: >-
    Abnormal immunoglobulin levels and inadequate vaccine responses occur in a subset. The reported
    39% aggregate immunology rate includes several distinct abnormalities and is not assigned
    to this individual phenotype.
  phenotype_term:
    preferred_term: Abnormal circulating immunoglobulin concentration
    term:
      id: HP:0010701
      label: Abnormal circulating immunoglobulin concentration
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Immunologic | Immunology visit: n = 31 | 39 % (12/31) • Abnormal immunoglobulin levels
      n =
      7 • Inappropriate vaccine response n = 3
    explanation: >-
      The cohort distinguishes abnormal immunoglobulin levels from vaccine-response and cellular
      abnormalities.
- name: Cervical Spine Anomalies
  category: Skeletal
  description: >-
    Cervical spine anomalies included abnormal vertebral arches and posterior elements and an
    enlarged atlantodens interval. Only 11 individuals had documented cervical radiographs;
    the evaluated-subset count is not extrapolated to all carriers.
  phenotype_term:
    preferred_term: Abnormality of the cervical spine
    term:
      id: HP:0003319
      label: Abnormality of the cervical spine
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Skeletal | C-Spine x-rays: n = 11 | C-spine anomaly 45 % (5/11) | Slightly large atlantodens
      interval; Hypoplastic PE of C1 and elongated PE of C2; Exaggerated kyphosis, lordosis;
      Incomplete
      arch C1; Lack of bony fusion of C1 and dysmorphic C2
    explanation: >-
      Table 4 describes the cervical findings and restricted imaging denominator.
- name: Dysphagia
  category: Gastrointestinal
  description: >-
    Swallowing difficulty is one of the reported non-palatal otolaryngologic findings; its individual
    frequency is not provided.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Ankyloglossia, dysphagia, laryngomalacia, Eustachian tube dysfunction.
    explanation: >-
      The duplication cohort explicitly lists dysphagia.
- name: Vesicoureteral Reflux
  category: Genitourinary
  description: >-
    Vesicoureteral reflux is among the renal and urinary findings; the aggregate renal-abnormality
    rate is not applied to this specific feature.
  phenotype_term:
    preferred_term: Vesicoureteral reflux
    term:
      id: HP:0000076
      label: Vesicoureteral reflux
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Renal | Renal ultrasound: n = 25 | 24 % (6/25) | VUR; Pelviectasis ( n = 2); Lithiasis;
      Nephromegaly;
      Megaureter
    explanation: >-
      Table 4 lists VUR in the duplication cohort; its legend expands VUR as vesicoureteral
      reflux.
- name: Chiari Type I Malformation
  category: Neurologic
  description: >-
    Chiari type I malformation was among structural findings in the typical-duplication cohort.
    The aggregate imaging-abnormality percentage is not a Chiari-specific frequency.
  phenotype_term:
    preferred_term: Chiari type I malformation
    term:
      id: HP:0007099
      label: Chiari type I malformation
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Neurologic/calavarium | Brain MRI: n = 16 | Structural anomaly 24 % (5/21) | Chiari
      Type I;
    explanation: >-
      Table 4 explicitly identifies Chiari type I within the structural findings.
- name: Laryngomalacia
  category: Respiratory
  description: Laryngomalacia is a reported non-palatal otolaryngologic manifestation.
  phenotype_term:
    preferred_term: Laryngomalacia
    term:
      id: HP:0001601
      label: Laryngomalacia
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Ankyloglossia, dysphagia, laryngomalacia, Eustachian tube dysfunction.
    explanation: >-
      The cohort directly lists laryngomalacia.
- name: Anemia
  category: Hematologic
  frequency: OCCASIONAL
  description: Anemia was recorded in 3/37 individuals with a complete blood count in the typical-duplication cohort. One individual had both anemia and thrombocytopenia. These individual counts are not the aggregate 6/37 hematologic frequency and are not population penetrance estimates.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:27158440
    reference_title: '22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: '| Hematologic | Complete blood count: n = 37 | 16 % (6/37) • Thrombocytopenia n = 1 • Thrombocytopenia and anemia n = 1 • Neutropenia n = 2 • Anemia n = 2'
    explanation: Table 4 separates the individual blood-count abnormalities and includes one child in both the anemia and thrombocytopenia counts.
- name: Thrombocytopenia
  category: Hematologic
  frequency: OCCASIONAL
  description: Thrombocytopenia was recorded in 2/37 individuals with a complete blood count in the typical-duplication cohort. One individual had both anemia and thrombocytopenia. These individual counts are not the aggregate 6/37 hematologic frequency and are not population penetrance estimates.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:27158440
    reference_title: '22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: '| Hematologic | Complete blood count: n = 37 | 16 % (6/37) • Thrombocytopenia n = 1 • Thrombocytopenia and anemia n = 1 • Neutropenia n = 2 • Anemia n = 2'
    explanation: Table 4 separates the individual blood-count abnormalities and includes one child in both the anemia and thrombocytopenia counts.
- name: Neutropenia
  category: Hematologic
  frequency: OCCASIONAL
  description: Neutropenia was recorded in 2/37 individuals with a complete blood count in the typical-duplication cohort. This individual count is not the aggregate 6/37 hematologic frequency and is not a population penetrance estimate.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:27158440
    reference_title: '22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: '| Hematologic | Complete blood count: n = 37 | 16 % (6/37) • Thrombocytopenia n = 1 • Thrombocytopenia and anemia n = 1 • Neutropenia n = 2 • Anemia n = 2'
    explanation: Table 4 reports two individuals with neutropenia among 37 with a complete blood count.
genetic:
- name: Proximal 22q11.2 duplication
  association: Causal
  notes: >-
    A recurrent copy-number gain, commonly approximately 3 Mb or 1.5 Mb. This is a contiguous
    genomic interval rather than a demonstrated single-gene hypermorphic disorder. Both inherited
    and de novo events occur; the inherited genomic change can be associated with markedly different
    phenotypes within one family.
  evidence:
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      22q11.2 duplication is defined for this GeneReview as the presence of a common 3-Mb or
      1.5-Mb
      proximal tandem duplication.
    explanation: >-
      Defines the causal copy-number variant class.
  - reference: PMID:18707033
    reference_title: "Clinical variability of the 22q11.2 duplication syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a majority of the reported cases where parents have been tested, the
      duplication seems to have been inherited from a normal parent with minor
      abnormalities.
    explanation: >-
      Establishes that inheritance from a minimally affected parent predominates, the basis
      for the reduced-penetrance classification.
diagnosis:
- name: Chromosomal Microarray
  presence: Proximal 22q11.2 copy-number gain
  description: >-
    Chromosomal microarray identifies the duplication and its extent. Clinical appearance alone
    is insufficiently distinctive, and routine G-banded karyotyping does not reliably detect
    the common microduplication.
  evidence:
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The phenotype is not sufficiently distinct to be specifically suspected on clinical grounds
      alone. 22q11.2 duplication is not detectable by routine G-banded karyotyping. Most individuals
      with 22q11.2 duplication are identified by a chromosomal microarray.
    explanation: >-
      Historical GeneReviews states the diagnostic limitations and principal test.
  - reference: PMID:18707033
    reference_title: Clinical variability of the 22q11.2 duplication syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In this study we present two familial cases with a 3Mb 22q11.2 duplication detected by
      array-CGH.
    explanation: >-
      The familial case series directly demonstrates microarray detection.
- name: Family Testing
  description: >-
    Offer testing to relatives, including parents with few or no clinical findings, to establish
    inheritance and support counseling.
  evidence:
  - reference: PMID:18707033
    reference_title: Clinical variability of the 22q11.2 duplication syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      With this in mind we recommend that family members of patients with a 22q11.2 duplication
      to
      be tested for this genetic defect.
    explanation: >-
      The familial series recommends testing relatives.
- name: Baseline Medical Screening
  description: >-
    Duplication-specific cohort evidence supports baseline cardiac, renal, cervical spine, immune,
    calcium, thyroid, hearing, and ophthalmologic evaluation in children, including those identified
    because of developmental concerns alone. Screening selection and subsequent follow-up should
    be individualized to clinical findings.
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      These practitioners should be aware of the need for children with 22q11.2DupS to undergo
      medical
      screening including echocardiogram, renal ultrasound, cervical spine x-rays, immunologic
      testing
      (or referral to immunologist for evaluation), ionized calcium levels, thyroid functioning,
      and
      audiologic evaluation.
    explanation: >-
      The full-text discussion specifies the screening investigations supported by the cohort.
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Given the elevated rate of ophthalmologic abnormalities in our cohort, an ophthalmologist
      should
      also evaluate them.
    explanation: >-
      The cohort also supports ophthalmologic assessment.
treatments:
- name: Multidisciplinary Supportive Care
  description: >-
    Coordinate multidisciplinary care for the manifestations present. Duplication cohorts support
    adapting the 22q11.2 deletion syndrome screening framework; this is not evidence that every
    deletion-specific treatment or precaution applies to every duplication carrier.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:34845825
    reference_title: "22q11.2 duplications: Expanding the clinical presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with 22q11.2 duplication syndrome would benefit from care coordinated by a multidisciplinary team and managed according to the 22q11.2 deletion syndrome guidelines."
    explanation: Supports multidisciplinary care coordinated per 22q11.2 deletion guidelines.
- name: Individualized Educational Support
  therapeutic_modality: BEHAVIORAL
  description: >-
    Tailor educational support to the developmental and learning profile and reassess periodically
    as needs change.
  treatment_term:
    preferred_term: Educational Intervention
    term:
      id: NCIT:C17874
      label: Educational Intervention
  target_mechanisms:
  - target: Learning Disability
  - target: Global Developmental Delay
  evidence:
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Treatment of manifestations: Educational program tailored to individual needs. Surveillance:
      Periodic developmental assessments to assure that educational needs are being met.
    explanation: >-
      Historical GeneReviews supports individualized education and periodic developmental assessment.
- name: Genetic Counseling
  description: >-
    Explain incomplete penetrance, variable expressivity, the 50% transmission risk, and the
    inability of a parental or prenatal result to predict clinical severity.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301749
    reference_title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Offspring of individuals with the 22q11.2 duplication have a 50% chance of inheriting
      the duplication.
      Prenatal testing is technically feasible; however, it is not possible to predict the phenotype
      from a laboratory finding of 22q11.2 duplication.
    explanation: >-
      Historical GeneReviews distinguishes transmission risk from phenotype prediction.
- name: Myringotomy with Ear Tube Placement
  therapeutic_modality: SURGERY
  description: >-
    Bilateral myringotomy tube placement was recorded in nine individuals in the cohort. This
    documents use for selected otologic manifestations; it does not establish universal need
    or treatment efficacy in duplication syndrome.
  treatment_term:
    preferred_term: Myringotomy with Ear Tube Placement
    term:
      id: NCIT:C70906
      label: Myringotomy with Ear Tube Placement
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Ankyloglossia, dysphagia, laryngomalacia, Eustachian tube dysfunction. Surgical interventions:
      BMT ( n = 9), T&A ( n = 9)
    explanation: >-
      Table 4 reports BMT use; its legend defines BMT as bilateral myringotomy tubes.
- name: Tonsillectomy with Adenoidectomy
  therapeutic_modality: SURGERY
  description: >-
    Tonsillectomy with adenoidectomy was recorded in nine individuals in the cohort. The report
    documents an intervention used in selected patients without establishing syndrome-specific
    efficacy or a universal indication.
  treatment_term:
    preferred_term: Tonsillectomy with adenoidectomy
    term:
      id: NCIT:C51684
      label: Tonsillectomy with Adenoidectomy
  evidence:
  - reference: PMID:27158440
    reference_title: >-
      22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
      screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Ankyloglossia, dysphagia, laryngomalacia, Eustachian tube dysfunction. Surgical interventions:
      BMT ( n = 9), T&A ( n = 9)
    explanation: >-
      Table 4 reports T&A use; its legend defines T&A as tonsillectomy with adenoidectomy.
references:
- reference: PMID:18707033
  title: Clinical variability of the 22q11.2 duplication syndrome.
- reference: PMID:34845825
  title: '22q11.2 duplications: Expanding the clinical presentation.'
- reference: PMID:20301749
  title: 22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
  tags:
  - GeneReviews
- reference: PMID:27158440
  title: >-
    22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical
    screening.
- reference: PMID:30614210
  title: >-
    Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental
    phenotypes including autism spectrum disorder with incomplete penetrance.
- reference: PMID:36648576
  title: >-
    Clinical Practice Guidelines for the Immunological Management of Chromosome 22q11.2 Deletion
    Syndrome and Other Defects in Thymic Development.
notes: >-
  The clinical baseline here is the proximal duplication, including the common LCR22A-D and
  shorter proximal duplication. Central nested LCR22B-D duplications are considered as comparative
  evidence about candidate genes; their cohort frequencies are not pooled with typical proximal
  duplications. The GeneReviews chapter is retired and is cited as a historical baseline; later
  duplication-specific cohorts support the broader medical screening recommendations.
discussions:
- kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Increased Dosage of 22q11.2 Genes
  prompt: >-
    Which duplicated genes and modifying factors account for the different neurodevelopmental
    and congenital outcomes among carriers?
  rationale: >-
    TBX1 is a candidate contributor to cardiac findings, but this does not establish a hypermorphic
    allele or a complete mechanism for proximal duplication syndrome. Comparative central-duplication
    studies nominate other candidates such as PI4KA and explicitly leave functional effects
    and additional diagnoses unresolved.
  evidence:
  - reference: PMID:30614210
    reference_title: >-
      Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental
      phenotypes including autism spectrum disorder with incomplete penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The functional effect of this duplication and the clinical significance is currently unclear.
    explanation: >-
      The discussion of a partial PI4KA duplication cautions against equating genomic gain with
      established functional gain.
  - reference: PMID:30614210
    reference_title: >-
      Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental
      phenotypes including autism spectrum disorder with incomplete penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We therefore postulate that the responsible genes for cardiac defects are likely to lie
      beyond
      the LCR22B to LCR22D interval.
    explanation: >-
      The cardiac localization argument is explicitly a hypothesis based on central-duplication
      comparisons.
    directness: INDIRECT
  discussion_id: individual_gene_contributions
📚

References & Deep Research

References

6
PMID:18707033
Clinical variability of the 22q11.2 duplication syndrome.
No top-level findings curated for this source.
PMID:34845825
22q11.2 duplications: Expanding the clinical presentation.
No top-level findings curated for this source.
PMID:20301749
22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
No top-level findings curated for this source.
PMID:27158440
22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening.
No top-level findings curated for this source.
PMID:30614210
Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance.
No top-level findings curated for this source.
PMID:36648576
Clinical Practice Guidelines for the Immunological Management of Chromosome 22q11.2 Deletion Syndrome and Other Defects in Thymic Development.
No top-level findings curated for this source.