The packet describes 22q11.2 deletion syndrome as resulting from a microdeletion on chromosome 22, typically a deletion of about 3 Mb that encompasses approximately 30 to 40 other genes in addition to a key gene in the region. A specific gene list is not certified in this packet, so no individual gene is named here. GeneReviews reports that about 85% of individuals have a heterozygous 2.54-Mb deletion as described by chromosomal microarray designs, extending between flanking low copy number repeats.

The packet's curated data report that approximately 90% of cases arise de novo and about 10% are inherited from an affected parent. GeneReviews similarly reports that, for the typical 3.0 (2.54)-Mb deletion, the deletion is de novo in more than 90% of individuals and inherited from a heterozygous parent in about 10%, and that a higher proportion (60%) of individuals with a smaller recurrent nested deletion inherit it from an affected parent. GeneReviews notes that parental germline mosaicism has been reported and that significant intrafamilial clinical variability occurs. It states that penetrance is complete in the majority of individuals, with marked variability, while nested deletions are often familial and have reduced penetrance and/or milder expression.

According to GeneReviews, the diagnosis of 22q11.2DS is established in a proband by identification of a heterozygous deletion at chromosome 22q11.2. The packet's diagnostic methods list chromosomal microarray (CMA) to detect the microdeletion, FISH for the 22q11.2 region, MLPA as an alternative testing method, and cardiac evaluation with echocardiogram.

GeneReviews states that the condition is suspected based on clinical features, including congenital heart disease (in 64% of individuals), palatal abnormalities (67%), immune deficiency (77%), and developmental delay and/or learning difficulties (70% to 90%), together with features of the other organ systems described above. Laboratory features listed include hypoparathyroidism and hypocalcemia (in 50%), growth hormone deficiency, hypothyroidism, and cytopenias. GeneReviews notes that all of these findings can also occur as an isolated anomaly in an otherwise healthy individual.

The packet lists foundational therapies of cardiac surgery for congenital heart defects, speech therapy for velopharyngeal insufficiency, calcium and vitamin D supplementation for hypocalcemia, immunologic follow-up and management, developmental support and educational interventions, and psychiatric care for behavioral and mental health concerns. Specialist types listed in the packet are geneticist, cardiologist, immunologist, endocrinologist, speech-language pathologist, psychiatrist, and developmental pediatrician.

GeneReviews outlines evaluations following diagnosis across cardiology, ENT, gastroenterology, immunology, hematology, endocrine, ophthalmology, audiology, neurology, development, psychiatry, musculoskeletal, and nephrology concerns. Its treatment table describes surgery or treatment for cardiac anomalies, with multiple surgeries possible over a lifetime; surgical treatment of palatal anomalies; and, for feeding difficulties, modification of spoon placement, standard treatment of gastroesophageal reflux with acid blockade, prokinetic agents, and postural therapy. For immune deficiency, GeneReviews describes aggressive treatment of infections, with prophylactic antibiotics, IVIG therapy, or thymus tissue implantation required rarely, and irradiated blood products used until normalization of the immune system can be confirmed. It also lists calcium supplementation for hypocalcemia, standard treatment for growth hormone deficiency, standard treatment for ocular anomalies, and hearing aids for hearing loss.

No FDA-approved treatment is certified in this packet. The packet lists orphan drug designations for cannabidiol, fasoracetam monohydrate, metyrosine (velocardiofacial syndrome associated psychosis), and thymalfasin (DiGeorge anomaly with immune defects). An orphan designation does not indicate approval, efficacy, or active development.

GeneReviews reports that congenital heart defects are the major cause of mortality, accounting for about 87% of all deaths in children with 22q11.2DS. It also states that adults with 22q11.2DS die prematurely, with sudden death and heart failure being the most common causes of death, even in individuals without congenital heart defects. GeneReviews describes the natural history of aortic root dilatation as unknown and describes marked clinical variability, including significant intrafamilial variability. Individual-level outcome estimates are not certified in this packet.

Trial records in the packet that name this condition include the following, listed by registry title; a title does not establish what an intervention achieves. NCT00556530 is a study examining genetic factors that affect the severity of 22q11.2 deletion syndrome (sponsor Albert Einstein College of Medicine; recruiting). NCT00768820 is a Phase 4 study of the psychiatric and cognitive phenotypes in velocardiofacial syndrome (sponsor The Chaim Sheba Medical Center; recruiting). NCT04639388 is a study on understanding psychotic disorders in children with 22q11.2DS (sponsor Hopital le Vinatier; recruiting). The packet's research directions list neurodevelopmental outcome studies, psychiatric intervention strategies, and immune reconstitution approaches. Active clinical trials for this condition are listed on ClinicalTrials.gov.