Velocardiofacial syndrome results from a deletion at chromosome location 22q11, as specified in the disease definition. The TBX1 gene, located within this deleted chromosomal segment, has been identified in association with this condition. The 22q11 deletion is inherited in an autosomal dominant pattern: one copy of the deletion is sufficient to cause the condition, and each child of an affected individual has a 50% chance of inheriting the deletion. Penetrance is complete in the majority of individuals carrying the deletion, while the expression of features is markedly variable—individuals carrying the same deletion may differ substantially in which features are present and in their severity, as documented in the GeneReviews chapter for 22q11.2 deletion syndrome. Nested deletions within 22q11.2 have been associated with reduced penetrance and milder expression, as noted in the penetrance section of that chapter.

The diagnosis of velocardiofacial syndrome is suspected based on characteristic clinical findings including congenital heart disease, palatal anomalies, immunological abnormalities, and neurodevelopmental features, as described in the suggestive findings section of the GeneReviews chapter for 22q11.2 deletion syndrome. Molecular genetic testing to identify the 22q11.2 deletion is used to confirm the diagnosis. Comprehensive evaluations following diagnosis are described in the GeneReviews management guidelines, addressing cardiac function, palatal anatomy, immunological status, calcium and parathyroid hormone levels, and neurodevelopmental assessment across the affected systems.

No FDA-approved treatments are specifically indicated for velocardiofacial syndrome in this packet. Management is directed at the specific features present in each individual and requires coordination across multiple medical specialties. The GeneReviews management chapter describes evaluations and interventions across the affected organ systems: cardiac defects may require surgical or interventional assessment by cardiology; palatal insufficiency is addressed through specialist evaluation and appropriate intervention; monitoring of calcium levels is described as a component of endocrine management where hypoparathyroidism is present, with the GeneReviews surveillance chapter specifying calcium monitoring at intervals across infancy and childhood; immunological status is assessed and monitored given the documented frequency of T cell abnormalities; and neurodevelopmental and educational support is directly relevant given the high frequency of intellectual disability and hypotonia in this condition. Long-term, multisystem surveillance is a central component of ongoing management as described in the GeneReviews chapter, reflecting the range of organ systems affected. Additional therapies have received orphan drug designation for this condition and are under active clinical evaluation; these are not yet approved treatments.

Specific natural history data are not certified in the structured fields of this packet. The GeneReviews clinical description indicates that congenital heart disease is the major cause of mortality in 22q11.2 deletion syndrome, representing approximately 87% of deaths. Beyond cardiac outcomes, the overall trajectory varies considerably given the marked variability in clinical expression: some individuals experience significant cardiac, neurological, and immunological involvement, while others manifest a milder profile of features. The GeneReviews penetrance chapter notes that penetrance is complete in the majority of individuals with the 22q11 deletion, while the type and severity of features that emerge differ substantially among those affected.

Several certified active trial records are present for velocardiofacial syndrome. Active clinical trials for this condition are listed on ClinicalTrials.gov.