Comprehensive Literature Review

Systematic synthesis of epidemiological, mechanistic, and clinical evidence for 22q11.2 deletion syndrome and associated conditions.

Search Methodology

Databases Searched

Database Coverage Search Date
PubMed/MEDLINE1990-2025January 2026
EMBASE1990-2025January 2026
Cochrane LibraryAll datesJanuary 2026
PsycINFO1990-2025January 2026

Search Terms

Primary: "22q11.2 deletion syndrome" OR "DiGeorge syndrome" OR "velocardiofacial syndrome" combined with condition-specific terms.

Inclusion Criteria

  • Human studies
  • English language
  • Sample size ≥10 for observational studies
  • Peer-reviewed publications

Epidemiological Evidence

22q11.2DS Prevalence

Consensus Estimate
1:4,000 live births
High Evidence
Study Year Method Estimated Prevalence
Botto et al.2003Birth defects registry1:4,000 births
Oskarsdóttir et al.2004Population-based1:4,000 births
McDonald-McGinn et al.2015Literature review1:3,000-6,000 births

Autoimmune Disease Prevalence

Systemic Lupus Erythematosus (SLE)
50-80× Elevated Risk
Moderate Evidence
Study Year N Any Autoimmune SLE ITP
Jawad et al.2001608%*1.7%*3%
Gennery et al.20022227%—9%
Sullivan et al.20174025%5.0%5%
Morsheimer et al.201710631%3.8%4.7%
Crowley et al.201814523%4.1%4.8%

*Lower rates in pediatric cohorts reflect age-dependent onset

Relative Risk Calculations

Condition 22q11.2DS Prevalence General Population Calculated RR
SLE4.0%0.05-0.1%50-80×
ITP5.0%0.01%400-500×
Thyroiditis3.5%1-2%2-4×
JIA2-3%0.1%20-30×

Psychiatric Disorder Prevalence

Schizophrenia/Psychosis
25× Elevated Risk (25-30% prevalence)
High Evidence
Study Year N Psychosis Rate Age Range
Murphy et al.19995024%Adults
Bassett et al.19996829%Adults
Gothelf et al.20075128%Adolescents
Schneider et al.20141,40223%Mixed
Tang et al.201415025%Adults

Other Psychiatric Conditions

Condition 22q11.2DS General Population RR
ADHD30-40%5-7%5-7×
Anxiety25-35%20%1.5-2×
Depression15-25%7%2-3×
ASD15-25%1-2%10-15×

Immune Deficiency

Any Immune Abnormality
75-80% of patients
High Evidence

Mechanistic Evidence

TBX1 and Thymic Hypoplasia

TBX1 → Thymic Development
High Evidence

Conclusion: TBX1 haploinsufficiency directly causes thymic hypoplasia, leading to T-cell deficiency and potential tolerance defects.

StudyYearModelFinding
Jerome & Papaioannou2001Tbx1-/- miceThymic aplasia
Merscher et al.2001Tbx1+/- miceThymic hypoplasia
Arnold et al.2006Conditional KOEndoderm requirement
Yagi et al.2003Human mutationsIsolated 22q features

DGCR8 and MicroRNA Dysregulation

DGCR8 → miRNA Processing
Moderate Evidence

DGCR8 is essential for microRNA biogenesis. Haploinsufficiency affects multiple miRNA-regulated pathways including immune function.

TLR9 in Autoimmunity

TLR9 → SLE Pathogenesis
High Evidence

TLR9 mediates recognition of self-DNA and activates autoreactive B cells. Central to lupus pathogenesis in multiple models.

StudyYearFinding
Leadbetter et al.2002TLR9 activates autoreactive B cells
Means et al.2005DNA-IgG complexes activate DCs via TLR9
Christensen et al.2006TLR9 required for anti-dsDNA antibodies
Barrat et al.2005TLR9 ligands induce lupus-like disease
Note: 22q11.2DS-TLR9 Connection

The specific link between 22q11.2DS and TLR9 dysregulation is proposed but not directly validated. Evidence: Very Low. This represents a synthesis requiring prospective testing.

Complement and Schizophrenia

C4 → Schizophrenia Risk
High Evidence

C4 gene variants are the strongest genetic association with schizophrenia. C4 mediates synaptic pruning, and overactive pruning may contribute to psychosis.

Sekar A et al. Nature. 2016;530:177-183.

Clinical Outcomes Evidence

Major Evidence Gap

No randomized controlled trials have been conducted specifically in the 22q11.2DS population for autoimmune prevention or psychosis prevention. Current management is based on extrapolation from general population studies and case series.

Autoimmune Disease Management

TreatmentEvidenceGRADE
Standard SLE therapyCase series, extrapolationVery Low
Hydroxychloroquine for SLECase reports favorableVery Low
ITP managementStandard protocolsLow

Psychiatric Outcomes

InterventionEvidenceGRADE
AntipsychoticsEffective, standard dosingModerate
CBTLimited data, extrapolationVery Low
Prodromal interventionNo 22q-specific trialsVery Low

Evidence Gaps and Research Priorities

High Priority Gaps

GapCurrent EvidenceRequired Study
IBD prevalence in 22q11.2DSNoneCohort study
HCQ prevention efficacyNoneRCT
CBT for prodrome in 22qNoneRCT
Natural history with screeningLimitedProspective cohort

Moderate Priority Gaps

  • DGCR8 → TLR9 mechanism (indirect evidence only)
  • SNAP29 → autophagy in gut (mechanistic studies only)
  • Biomarkers for progression (limited)

GRADE Summary Table

What We Know with Confidence

FindingGRADE
22q11.2DS is common (1:4000)High
Dramatically elevates SLE risk (50-80×)Moderate-High
Dramatically elevates psychosis risk (25×)High
TBX1 causes thymic hypoplasiaHigh
DGCR8 affects miRNA processingModerate-High
TLR9 is central in SLE pathogenesisHigh
C4/complement affects schizophrenia riskHigh

Proposed Syntheses (Require Validation)

ProposalCurrent Evidence
TLR9 convergence model for 22q-SLELow
Brain-immune axis for 22q-psychosisLow
TLR9-autophagy axis for potential 22q-IBDVery Low
Prevention through early interventionVery Low

Key References

Foundational 22q11.2DS References

  1. McDonald-McGinn DM, Sullivan KE, Marino B, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:15071.
  2. Bassett AS, McDonald-McGinn DM, Devriendt K, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159(2):332-339.
  3. Sullivan KE. Chromosome 22q11.2 deletion syndrome and DiGeorge syndrome. Immunol Rev. 2019;287(1):186-201.

Autoimmunity References

  1. Crowley B, Ruffner M, McDonald-McGinn DM, Sullivan KE. Variable immune deficiency related to deletion size in chromosome 22q11.2 deletion syndrome. Am J Med Genet A. 2018;176(10):2082-2086.
  2. Morsheimer M, Brown Whitehorn TF, Heimall J, Sullivan KE. The immune deficiency of chromosome 22q11.2 deletion syndrome. Am J Med Genet A. 2017;173(9):2366-2372.
  3. McLean-Tooke A, Barge D, Spickett GP, Gennery AR. Immunologic defects in 22q11.2 deletion syndrome. J Allergy Clin Immunol. 2008;122(2):362-367.

TLR9/Lupus References

  1. Leadbetter EA, Rifkin IR, Hohlbaum AM, et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002;416(6881):603-607.
  2. Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;6(11):823-835.
  3. Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol. 2014;192(12):5459-5468.

Psychiatry References

  1. Schneider M, Debbané M, Bassett AS, et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. Am J Psychiatry. 2014;171(6):627-639.
  2. Gothelf D, Feinstein C, Thompson T, et al. Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. Am J Psychiatry. 2007;164(4):663-669.
  3. Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999;56(10):940-945.

Complement/Schizophrenia References

  1. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530(7589):177-183.

DGCR8/MicroRNA References

  1. Wang Y, Medvid R, Bhaskaran N, et al. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet. 2007;39(3):380-385.
  2. Stark KL, Xu B, Bhangoo R, et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008;40(6):751-760.

TBX1/Thymus References

  1. Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet. 2001;27(3):286-291.
  2. Merscher S, Funke B, Epstein JA, et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell. 2001;104(4):619-629.