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Flagship Program

22q11.2 Deletion Syndrome

The most common microdeletion syndrome offers a unique window into cross-system medicine. Same genetic deletion, dramatically different outcomes—the perfect test case for identifying patterns that predict disease.

1:4,000
Live births affected
Population-based studies
50-80×
Elevated lupus risk
Crowley et al., 2018
25×
Elevated psychosis risk
Schneider et al., 2014
75-80%
Immune abnormalities
Sullivan, 2019

Why 22q11.2DS Is Our Flagship Model

22q11.2 deletion syndrome presents medicine with a fundamental puzzle: every affected individual is missing the same stretch of chromosome 22, encompassing approximately 30-45 genes. Yet outcomes range from minimal clinical impact to severe multi-organ disease.

Some patients develop schizophrenia; most do not. Some develop lupus; most do not. Some have severe immune deficiency; others have nearly normal immune function. What determines the difference?

Traditional single-system approaches have failed to explain this variance. But when we analyze multiple biological systems together—immune function, cardiac status, neurodevelopment, inflammatory markers—patterns emerge that correlate with outcomes.

The Cross-System Insight

Variable expressivity becomes partially predictable when we look at cross-system signatures rather than single-system measurements. A patient's cardiac status, immune profile, and neurological development together tell a story that no single system reveals alone.

This makes 22q11.2DS the ideal proving ground for cross-system medicine: a genetically defined population with known risk factors, documented outcome variance, and existing longitudinal cohorts that can be retrospectively analyzed and prospectively studied.

Research Programs

Our 22q11.2DS research is organized into interconnected programs, each addressing a major outcome domain with cross-system perspective.

Key Finding

The TLR9 Convergence Model

We propose that two independent pathways in 22q11.2DS—thymic hypoplasia and microRNA dysregulation—converge on TLR9-mediated autoimmunity. This explains the dramatically elevated lupus risk and suggests intervention points.

TBX1 Haploinsufficiency
Thymic hypoplasia → Tolerance failure
↘
TLR9
Central node
↙
DGCR8 Haploinsufficiency
miRNA dysregulation → IFN hyperactivation
Explore TLR9 Model View Literature

Brain-Immune Axis in Psychosis

Framework connecting complement activation, microglial function, and synaptic pruning to the 25x elevated schizophrenia risk. Identifies potential prevention windows.

In Development

IBD-Lupus-22q Pathway Convergence

TLR9 as convergence node: Evidence that IBD, lupus, and 22q share innate immune pathways. Suggests expanded screening and therapeutic opportunities.

Hypothesis

Clinical Screening Protocols

Evidence-based screening recommendations for autoimmune, psychiatric, and multi-organ manifestations. Ready for clinical implementation.

Clinical Ready

Comprehensive Literature Review

Systematic synthesis of epidemiological, mechanistic, and clinical evidence. GRADE-rated evidence summaries and complete bibliography.

Complete

What We Know with Confidence

Epidemiology

High
  • 1:4,000 live births affected
  • 50-80× elevated SLE risk
  • 25× elevated schizophrenia risk
  • 75-80% with immune abnormalities

Mechanistic Certainties

High
  • TBX1 → thymic hypoplasia
  • DGCR8 → miRNA dysregulation
  • TLR9 central in SLE pathogenesis
  • C4 linked to schizophrenia risk

What We Propose (Requires Validation)

Hypothesis 1
TLR9 pathway convergence explains the 50-80× SLE risk elevation in 22q11.2DS.
Status: Literature-supported, awaiting prospective validation
Hypothesis 2
Brain-immune axis dysregulation predicts psychosis conversion years before clinical onset.
Status: Literature-supported, requires longitudinal testing
Hypothesis 3
SNAP29-mediated autophagy defects elevate IBD risk in 22q11.2DS.
Status: Mechanistically plausible, epidemiological data needed
Hypothesis 4
Early intervention (HCQ, CBT, omega-3) can prevent autoimmune and psychiatric outcomes.
Status: No RCTs conducted, prevention potential unknown

Clinical Implications

Our cross-system analysis suggests actionable approaches for clinicians caring for 22q11.2DS patients—while acknowledging that many recommendations require validation.

Recommended Screening Protocol
  1. Baseline autoimmune panel: ANA, anti-dsDNA, CBC with differential at diagnosis and annually
  2. Thyroid function: TSH annually, thyroid antibodies if symptomatic
  3. Psychiatric surveillance: Structured assessment annually from age 10, intensified in adolescence
  4. Inflammatory markers: CRP, ESR if autoimmune symptoms
  5. GI screening: Consider if symptoms present (IBD prevalence uncertain)
Important Limitations

These screening recommendations are based on epidemiological risk and mechanistic reasoning. No RCTs have established that screening or early intervention improves outcomes in 22q11.2DS. Clinical judgment must guide individual patient care.

View Screening Protocol Clinical Resources

Join the Research

Validating these hypotheses requires collaboration. We seek partners with access to:

22q11.2DS Cohorts

Longitudinal patient populations with multi-system data for hypothesis testing

Biobank Samples

Stored samples from 22q patients for TLR9 and inflammatory marker analysis

Clinical Expertise

Immunologists, rheumatologists, psychiatrists with 22q experience

Learn More Publications