The packet lists TBX1 as the known gene, located on chromosome 22, and does not supply ClinGen validity classifications for it. According to GeneReviews, 22q11.2DS is a contiguous gene deletion syndrome. The diagnosis is established by identification of a heterozygous deletion at chromosome 22q11.2. About 85% of affected individuals have a heterozygous 2.54-Mb deletion, extending from flanking low copy number repeats A through D and including TBX1. The packet lists autosomal dominant as the inheritance pattern. GeneReviews reports that, for the 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%. For nested deletions, an inherited deletion is reported in 60%. GeneReviews notes that parental germline mosaicism has been reported, and that an apparently negative family history may reflect clinical variability or reduced penetrance. It reports a 50% risk to siblings when a parent is known to have the deletion, with significant intrafamilial variability in the resulting phenotype.

GeneReviews describes suggestive findings that include congenital heart disease, palatal abnormalities, laryngotracheoesophageal and gastrointestinal anomalies, immune deficiency, autoimmune disorders, ophthalmologic findings, craniofacial features, hearing loss, central nervous system abnormalities, developmental delay or learning difficulties, psychiatric illness, skeletal anomalies and genitourinary anomalies. Laboratory features listed include hypoparathyroidism and hypocalcemia, growth hormone deficiency, hypothyroidism and cytopenias. GeneReviews states that the diagnosis is established in a proband by identification of a heterozygous deletion at chromosome 22q11.2, and describes chromosomal microarray designs in connection with the typical 2.54-Mb deletion. GeneReviews also describes genomic testing capable of identifying the proband's deletion as the means of determining whether a parent carries it. Newborn screening information is not certified in this packet.

The packet records no FDA-approved treatments and no certified foundational therapies. GeneReviews describes management as multisystem, with evaluations following initial diagnosis across cardiology, otolaryngology, gastroenterology, immunology, hematology, endocrinology (calcium, parathyroid hormone, thyroid function and growth), ophthalmology, audiology, neurology, development and speech, psychiatry, musculoskeletal and nephrology, along with evaluation by a clinical geneticist or genetic counselor. For manifestations, GeneReviews describes surgery for cardiac anomalies, with multiple surgeries sometimes needed over a lifetime, surgical treatment of palatal anomalies, standard measures for feeding difficulties and gastrointestinal dysmotility, calcium supplementation for hypocalcemia, standard treatment for growth hormone deficiency, ocular treatment, and hearing aids for hearing loss. For immune deficiency, it notes that prophylactic antibiotics, immunoglobulin therapy or thymus tissue implantation are rarely required. Three orphan drug designations are listed for 22q11.2 deletion syndrome or related psychosis (cannabidiol, fasoracetam monohydrate and metyrosine); designation is not approval.

GeneReviews reports that congenital heart defects are the major cause of mortality in children with 22q11.2DS, accounting for about 87% of deaths, and that adults with 22q11.2DS die prematurely, with sudden death and heart failure the most common causes, including in individuals without congenital heart defects. A subset of individuals is found to have a dilated aortic root, and GeneReviews states that the natural history of aortic root dilatation is unknown. On penetrance, GeneReviews states that penetrance is complete in the majority of individuals but variability is marked, and that nested deletions are often familial with reduced penetrance or milder expression.

ClinicalTrials.gov records in the packet include several recruiting studies. Examples include a study titled Examining Genetic Factors That Affect the Severity of 22q11.2 Deletion Syndrome (NCT00556530, Albert Einstein College of Medicine), a study titled The Psychiatric and Cognitive Phenotypes in Velocardiofacial Syndrome (NCT00768820, Chaim Sheba Medical Center, Phase 4), a study titled Using Transcranial Alternating Current Stimulation to Improve Executive Function in 22q11.2 Deletion Syndrome (NCT05664412, Stephan Eliez), and a study titled Understanding of Psychotic Disorders in Children With 22q11.2DS (NCT04639388, Hopital le Vinatier). Active clinical trials for this condition are listed on ClinicalTrials.gov.