22q11.2 deletion syndrome results from a hemizygous deletion of chromosomal region 22q11.2. The deletion arises as a new (de novo) genetic event in the majority of affected individuals; in a minority of cases, the deletion is inherited from an affected parent and follows an autosomal dominant inheritance pattern. The deletion encompasses a region containing multiple genes, and haploinsufficiency of genes within this region is responsible for the multisystemic phenotype. Because the deletion arises de novo in the majority of cases, most affected individuals are born to parents without the deletion.

Diagnosis of 22q11.2 deletion syndrome is confirmed through chromosomal microarray analysis or fluorescence in situ hybridization targeting the 22q11.2 region. Clinical suspicion may arise from the presence of characteristic features, particularly conotruncal congenital heart defects, palatal abnormalities, immune deficiency with T-cell lymphopenia, or characteristic facial features. Presentations in the newborn period often come to clinical attention through cardiac evaluation. Older individuals may come to genetic evaluation through developmental or psychiatric assessments. Clinical practice guidelines for the evaluation of affected individuals have been published and describe evaluation protocols across multiple organ systems following diagnosis.

No FDA-approved therapies are specifically indicated for 22q11.2 deletion syndrome as a condition. Management is supportive and directed toward individual organ-system manifestations. Congenital heart defects require cardiac surgical intervention in most affected individuals. Immune deficiency associated with thymic hypoplasia is addressed through immunological monitoring and, in the most severe cases of thymic aplasia, thymic tissue transplantation. Hypocalcemia due to hypoparathyroidism is managed with calcium and vitamin D supplementation. Palatal abnormalities are addressed through surgical and speech-language pathology interventions. Developmental and educational services address cognitive and speech-language needs. Psychiatric manifestations in adolescence and adulthood are managed according to standard approaches for the specific conditions present. Several investigational agents hold orphan drug designation for conditions associated with 22q11.2 deletion syndrome, including cannabidiol, fasoracetam monohydrate, L-citrulline, metyrosine, and thymalfasin, but none has received FDA marketing approval for this indication.

The natural history of 22q11.2 deletion syndrome is variable, influenced substantially by the specific combination and severity of organ-system involvement in each individual. Congenital heart defects represent the primary determinant of early mortality; cardiac complications account for approximately 87% of all disease-related deaths, making cardiac management central to early survival outcomes. Individuals who survive the neonatal and early childhood period following management of cardiac disease typically have life expectancy approaching that of the general population, though ongoing medical needs in multiple organ systems persist into adulthood. Immune function improves over time in most affected individuals as compensatory T-cell development occurs. Psychiatric morbidity, particularly schizophrenia spectrum disorders in adulthood, represents a major contributor to long-term functional outcomes.

Active clinical trial activity is documented in 22q11.2 deletion syndrome, with registered studies addressing cardiac, immunological, psychiatric, and neurodevelopmental features of the condition. Published literature covers natural history, molecular mechanisms of the deletion, long-term outcomes across age groups, and interventional approaches across multiple organ systems. Investigational agents under evaluation include those targeting psychiatric and neurological manifestations. The GeneReviews chapter documents the condition comprehensively, reflecting extensive accumulated research in this area.