ClinGen Dosage Sensitivity Curation Page

22q11.2 recurrent (DGS/VCFS) region (proximal, A-D) (includes TBX1)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
20301696 McDonald-McGinn, Emanuel and Zackai. GeneReviews: 22q11.2 Deletion Syndrome.
27189754 McDonald-McGinn et al. (2015) reviewed clinical findings in 22q11.2 deletion syndrome. See also PMID 21200182.
Burnside (2015) reviewed the literature and clinical findings of patients with recurrent 22q11.2 deletions, including proximal (A-D) region deletions.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
20301749 Firth. GeneReviews: 22q11.2 Duplication. Review of the phenotype associated with duplication of proximal 22q11.2. Similar to the reciprocal deletion, this review combines data from reports of patients with both A-D (3 Mb) and A-B (1.5 Mb) region duplications. The phenotype is described as, ?generally mild and highly variable; findings range from apparently normal to intellectual disability/learning disability, delayed psychomotor development, growth retardation, and/or hypotonia. 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.?
19254783 Portnoi (2009) reviewed the literature and summarized findings from approximately 50 unrelated cases of duplications involving proximal 22q11.2. The author noted, ?The phenotype of patients is extremely variable, ranging from multiple defects to mild learning difficulties, sharing features with DGS/VCFS, including heart defects, urogenital abnormalities, velopharyngeal insufficiency with or without cleft palate, and with some individuals being essentially normal.?
18414210 Ou et al. (2008) reviewed clinical findings of 22q11.2 CNV carriers from a cohort of 7000 clinical aCGH cases. Three probands (Pts 1-3) and two relatives of patient 1 (sibling and mother) with A-D (3 Mb) region duplications were reported. Clinical findings in common in at least two carriers included developmental delay, speech delay, variable dysmorphic features, hypernasal speech, hearing impairment, and behavioral abnormalities. Parental samples were unavailable for patients 2 and 3.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.