22Q11.2 DELETION SYNDROME

22q11.2 Deletion Syndrome — the most common chromosomal microdeletion, affecting 1 in 4,000 births, where early diagnosis coordinates cardiac, immunological, endocrine, and psychiatric surveillance that changes outcomes across the lifespan.

Whole genome sequencing detects all 22q11.2 deletion sizes — typical 3Mb, nested 1.5Mb, and atypical breakpoints — providing the molecular diagnosis that standard karyotype misses and chromosomal microarray may undercharacterize.

TBX1

About this condition

22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, affecting approximately 1 in 4,000 live births. Previously described as DiGeorge syndrome, velocardiofacial syndrome (VCFS), Shprintzen syndrome, and conotruncal anomaly face syndrome, these are now understood as variable presentations of the same underlying 22q11.2 deletion. The typical deletion spans approximately 3Mb and encompasses roughly 90 genes, including TBX1 — the critical gene responsible for the conotruncal cardiac defects and pharyngeal arch developmental anomalies.

22q11.2DS produces a highly variable phenotype affecting almost every organ system: conotruncal cardiac defects (tetralogy of Fallot, interrupted aortic arch, truncus arteriosus — present in ~75%), thymic hypoplasia/aplasia with T-cell immunodeficiency (~75%), hypocalcemia from hypoparathyroidism (~50%), palatal anomalies (velopharyngeal insufficiency, cleft palate — ~70%), feeding difficulties, developmental delay and learning disabilities (~90%), and characteristic facial features. Approximately 93% of deletions are de novo; 7% are inherited from an affected parent who may have only subtle features.

The most clinically significant late-onset feature is the dramatically elevated risk of schizophrenia and psychotic disorders — approximately 25% of individuals with 22q11.2DS develop schizophrenia by adulthood, representing the strongest known genetic risk factor for this condition (30x population risk). Proactive psychiatric monitoring, early intervention for prodromal symptoms, and family education about psychiatric risk are critical components of lifelong 22q11.2DS management. Additionally, autoimmune conditions (autoimmune cytopenias, juvenile idiopathic arthritis) occur at elevated rates, particularly as the immune system matures.

25% of individuals with 22q11.2DS develop schizophrenia — the strongest known genetic risk factor. Proactive psychiatric monitoring beginning in adolescence enables early intervention during the prodromal phase, which may improve outcomes.

Gene locus: 22q11.2 (TBX1 critical region), ~3Mb typical deletion

Standard karyotype does not detect 22q11.2 deletions (they are submicroscopic). FISH detects typical deletions but misses atypical breakpoints. WGS detects all deletion sizes and identifies the specific breakpoints.

93% of 22q11.2 deletions are de novo — the first affected child in a family is usually the first clue

Because the vast majority of 22q11.2 deletions arise de novo, there is no family history to prompt genetic testing. The diagnosis depends on clinical suspicion — which is straightforward when a neonate presents with conotruncal cardiac defect plus hypocalcemia, but is much less obvious when the presentation is isolated velopharyngeal insufficiency, learning disability, or psychiatric symptoms. WGS performed for any of these indications will detect the 22q11.2 deletion, triggering the comprehensive multi-system surveillance that identifies all component features before they cause complications.

Each subsequent pregnancy after an affected child has a 50% recurrence risk — but only if the parent's deletion status is determined

7% of 22q11.2 deletions are inherited from an affected parent who may have very mild or unrecognized features. If the proband's parents are not tested, an inherited deletion is assumed de novo — and the family is counseled that recurrence risk is low (<1%). If the deletion is actually inherited, recurrence risk is 50% for each subsequent pregnancy. Parental 22q11.2 testing is mandatory after a child is diagnosed. WGS of the parents detects not only the 22q11.2 region but also identifies any other genetic findings relevant to the family.

22q11.2 Deletion Syndrome — the most common chromosomal microdeletion, affecting 1 in 4,000 births, where early diagnosis coordinates cardiac, immunological, endocrine, and psychiatric surveillance that changes outcomes across the lifespan.

22q11.2 Deletion Syndrome

Standard karyotype does not detect 22q11.2 deletions (they are submicroscopic). FISH detects typical deletions but misses atypical breakpoints. WGS detects all deletion sizes and identifies the specific breakpoints.

93% of 22q11.2 deletions are de novo — the first affected child in a family is usually the first clue

Each subsequent pregnancy after an affected child has a 50% recurrence risk — but only if the parent's deletion status is determined

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