Detectability of 22q11.2 Deletion Syndrome (DiGeorge Syndrome) via NIPT

1. Introduction

22q11.2 deletion syndrome (DiGeorge syndrome) is a chromosomal abnormality caused by a deletion in a specific region on the long arm of human chromosome 22. It is characterized by a variety of clinical symptoms such as congenital heart defects, immune deficiency, cleft palate, developmental delay, and neuropsychiatric symptoms, making prenatal diagnosis and early detection highly important.
Traditionally, diagnosis has relied on definitive tests such as amniocentesis or chorionic villus sampling, which carry risks of miscarriage and are invasive. However, in recent years, Non‑Invasive Prenatal Testing (NIPT) has been introduced, allowing screening using cell‑free fetal DNA in maternal blood. The possibility of detecting small deletions (microdeletions) like DiGeorge syndrome via NIPT has gained attention.
In this article, based on the latest research evidence, we explain the possibility, accuracy, limitations, and clinical significance of detecting DiGeorge syndrome by NIPT.

2. What is 22q11.2 Deletion Syndrome (DiGeorge Syndrome)?

DiGeorge syndrome is a genetic disorder caused by a deletion of about 1.5 to 3 megabases (Mb) in the 22q11.2 region. Clinically, it presents with features including:

• Congenital heart defects: particularly Tetralogy of Fallot and ventricular septal defects
• Cleft palate or palate anomalies
• Immune abnormalities: hypoplasia of the thymus leading to reduced T‑cells, increased risk of infections
• Developmental delay / intellectual disability: delayed language development, learning difficulties
• Neuropsychiatric symptoms: increased risk of attention deficit/hyperactivity disorder (ADHD), autism spectrum disorders, schizophrenia

Incidence is about 1 per 4,000 to 6,000 live births, and the diagnosis is often delayed in clinical practice. Thus, prenatal diagnosis plays a crucial role in disease management and in providing information to families.

3. Overview of NIPT (Non‑Invasive Prenatal Genetic Testing)

NIPT analyzes cell‑free fetal DNA (cffDNA) present in maternal blood to evaluate risk of chromosomal abnormalities. Key features of NIPT include:

• Non‑invasive: only maternal blood draw is needed, with virtually no miscarriage risk
• High‑accuracy screening: sensitivity for Trisomy 21, 18, and 13 is about 99%
• Can be performed after ~10 weeks of gestation: enabling early screening
• Although traditionally focused on trisomies (21, 18, 13), recent advances allow detection of microdeletions and microduplications, thereby enabling prenatal screening for conditions like DiGeorge syndrome

4. Detectability of DiGeorge Syndrome by NIPT

4.1 Technical Background

Because DiGeorge syndrome involves a small deletion, standard NIPT has historically had difficulty detecting it. However, with the adoption of high‑precision sequencing technologies (e.g., Massively Parallel Sequencing, MPS) and targeted capture‑type analyses, it has become possible to infer copy number changes in the 22q11.2 region from maternal plasma. Key technical improvements include:

• Increased sequencing depth: analyzing more sequencing reads than standard NIPT to improve detection of small deletion regions
• Bioinformatics analysis: statistical evaluation of read count drops in the deletion region
• Targeted NIPT designs: assays specialized for detecting the 22q11.2 deletion to further boost accuracy

4.2 Detection Accuracy

According to recent meta‑analyses, sensitivity of NIPT for detecting DiGeorge syndrome is reported at approximately 75–95%, and specificity around 99%. The Positive Predictive Value (PPV) depends on maternal age, gestational weeks, and whether the population is high risk or the general obstetric population.

• In high‑risk pregnancies (e.g., suspected fetal heart defect), PPV tends to be higher
• In general, low‑risk populations, PPV may be lower, but NIPT remains effective as a screening tool

5. Limitations & Caveats of NIPT

When screening for DiGeorge syndrome via NIPT, several limitations and risks should be borne in mind:

• Not diagnostic
  NIPT is a screening test; if the result is positive, confirmatory diagnosis via amniocentesis or chorionic villus sampling is required.
• False positives / false negatives
  If the fetal fraction (the proportion of fetal DNA in maternal blood) is low, the risk of false negatives increases. Twin pregnancies or maternal obesity are conditions that may pose higher risk.
• Not all 22q11.2 deletions are detectable
  Depending on how large the deletion is or its precise location, some deletions may fall outside the targeted region and be missed.
• Cannot detect all microdeletions / duplications
  Microstructural abnormalities beyond those targeted or covered by the test design will not be detected.

6. Clinical Significance

6.1 For Pregnant Women / Families

Early knowledge of risk for DiGeorge syndrome allows for:

• Decision‑making about continuation or termination of pregnancy
• Preparing for postnatal medical care and early intervention
• Planning for likely complications such as heart defects or immunodeficiency

6.2 For Healthcare Providers

• Narrowing down the screening target group among high‑risk pregnancies
• Reducing psychological burden on pregnant women by offering non‑invasive methods
• Minimizing unnecessary invasive procedures and thus reducing miscarriage risk

7. International Guidelines

• United States (ACOG)
  Recommends offering NIPT for 22q11.2 deletion syndrome to high‑risk pregnancies; positive results must be followed by diagnostic confirmation.
• Europe
  In countries like the UK, microdeletion NIPT is offered under public healthcare to high‑risk pregnant women. Screening followed by confirmatory diagnostic testing is standard.
• Japan
  In Japan, NIPT for 22q11.2 deletion syndrome is generally treated as elective/private medicine, often offered to women aged 35+ or other high‑risk pregnancies. It is recommended that patients receive detailed explanation of test accuracy, limitations, and the meaning of positive/negative results.

8. What Expectant Mothers Should Know

• NIPT is voluntary
• A positive result does not equal a diagnosis
• Genetic counseling is essential for decisions based on results
• Choose a reliable medical facility for testing
• Consider gestational age, maternal age, fetal health status in decision‑making

9. Summary So Far

22q11.2 deletion syndrome (DiGeorge syndrome) is a microdeletion disorder with diverse clinical manifestations and significant prenatal diagnostic value. With NIPT, risk can be non‑invasively screened using maternal blood, which offers advantages for both pregnant women and healthcare providers.
Key points to keep in mind:

• NIPT can assess risk for DiGeorge syndrome
• Positive results require confirmatory diagnostic testing
• Genetic counseling is indispensable
• Choosing the proper testing facility and verifying test performance is critical

Looking ahead, with advances in sequencing depth and targeted assays, screening performance for microdeletions is expected to improve, and the range of detectable disorders may expand. Shared information and careful decision‑making among pregnant women, families, and providers will be central to maximizing the value of prenatal diagnosis.

10. NIPT Screening Workflow for DiGeorge Syndrome

1. Consent & Genetic Counseling
   Prior to NIPT, the healthcare provider should thoroughly explain the purpose of testing, what abnormalities can be detected, limitations, and the possibility of false positives/negatives, and obtain informed consent.
2. Maternal Blood Collection
   Usually after ~10 weeks of gestation, about 10 mL of blood is drawn. The sample contains cffDNA from the fetus in maternal plasma.
3. DNA Extraction & Analysis
   Extract cffDNA and analyze the 22q11.2 region’s copy number using NGS or targeted capture assays.
4. Result Interpretation
   • Negative (Low Risk): Deletion risk for 22q11.2 is judged low
   • Positive (High Risk): Elevated risk for 22q11.2 deletion; diagnostic confirmation via amniocentesis or CVS is recommended
5. Reporting & Follow‑Up
   The results are explained to the pregnant woman or family by medical staff or genetic counselor. If positive, plans are made for postnatal management and early interventions.

11. How to Choose a Medical Facility

Since NIPT for DiGeorge syndrome requires more advanced analysis, it is recommended to select a facility that meets these criteria:

• Experienced team in genetic counseling
• Offers NIPT tests tailored for microdeletions
• Able to promptly perform diagnostic confirmation (amniocentesis / CVS)
• Transparent publication of test accuracy and performance history
• Provides a trustworthy environment to reduce patient anxiety

Selecting a reliable facility helps support patient decisions and mental well‑being.

12. Importance of Genetic Counseling

Results from NIPT for DiGeorge syndrome only indicate risk—they do not diagnose. Knowing how to interpret them is crucial for pregnant women and families:

• Positive result: Understanding the diagnostic follow‑up path, postnatal medical/educational support, and lifestyle implications
• Negative result: Recognize that risk is reduced but not all abnormalities are excluded
• Psychological support: Screening tests can impose emotional burden; support from healthcare providers or counselors is important

13. Future Prospects

Advances in research and technology point toward:

• Improved detection of microdeletions / duplications
  With deeper sequencing and better algorithms, it may be possible to detect even smaller deletions.
• Multi‑disease screening
  Expanding beyond DiGeorge syndrome to include other microdeletion syndromes (e.g. 1p36 deletion syndrome, Cri‑du‑chat syndrome, etc.).
• Standardization & Clinical Implementation
  As screening becomes more widespread and international guidelines are refined, the balancing of detection accuracy and safety is expected to improve.
• Integration with Postnatal Care
  Coordinating prenatal diagnosis with treatment and management planning for conditions like cardiac defects or immunodeficiency after birth.

14. Conclusion

22q11.2 deletion syndrome (DiGeorge syndrome) is a microdeletion disorder for which prenatal diagnosis is highly beneficial. NIPT enables non‑invasive risk assessment via maternal blood, offering many advantages for expectant mothers and healthcare providers.
However, it must be emphasized:

• NIPT is a screening tool, not diagnostic
• Positive results always require confirmatory testing
• Genetic counseling and careful choice of testing facility are essential
• As technology advances, detection precision and the range of detectable disorders are expected to expand

NIPT can serve as a powerful tool to support decision‑making for mothers and providers and may become a new standard in prenatal care.