What is the sensitivity of the MaterniT 21 (including PLUS) non‑invasive prenatal test for detecting microdeletions?

MaterniT21 PLUS Sensitivity for Microdeletion Detection

The MaterniT21 PLUS test has limited and variable sensitivity for detecting microdeletions, with the highest performance for 22q11.2 deletion syndrome (approximately 83% sensitivity) but substantially lower positive predictive values (38-53%) compared to common trisomies, making it a conditional screening option rather than a definitive diagnostic tool.

Performance Characteristics for Microdeletions

22q11.2 Deletion Syndrome (Most Common Microdeletion)

• Sensitivity: Approximately 83-100% depending on the study and algorithm used 1, 2
• Specificity: 99.95% with false-positive rate of 0.05% 1
• Positive Predictive Value (PPV): 38-53%, which is substantially lower than the 92% PPV for trisomy 21 1, 2
• The ACMG suggests (conditional recommendation) that NIPS for 22q11.2 deletion be offered to all patients based on moderate certainty of evidence 1

General Microdeletion/Microduplication Performance

The sensitivity and specificity for microdeletions overall is below that of common trisomies and sex chromosome aneuploidies 1. Recent research data shows:

• Overall sensitivity for microdeletions: 64-83% 2, 3
• PPV for microdeletion syndromes: 27-50% in unselected populations 2, 4, 5
• Fragment size matters critically: Detection sensitivity increases with larger deletions
  • CNVs ≥7 Mb: Higher detection rates 6
  • CNVs 5-7 Mb: Moderate detection 3
  • CNVs <5 Mb: High missed detection rate (36% missed in one study) 3

Key Clinical Considerations

Factors Affecting Performance

The PPV varies dramatically based on clinical context 5, 7:

• Highest PPV with abnormal ultrasound findings (57-73%) 5
• Increased nuchal translucency: PPV up to 67% 5
• Normal ultrasound findings: PPV drops to 27-38% 2, 5

Important Limitations and Pitfalls

Common causes of false results 3:

• False negatives: Confined placental mosaicism and fetal mosaicism are key factors
• False positives: Maternal chromosomal abnormalities and confined placental mosaicism
• Small fragment deletions (<5 Mb) frequently missed, with many being of maternal origin 3

The ACMG does NOT recommend genome-wide CNV screening due to limited clinical utility, uncertainties regarding PPV/NPV, and lack of clinical validation for routine use 1

Comparison to Common Trisomy Detection

For context, MaterniT21 PLUS performs far better for common aneuploidies 1:

• Trisomy 21: 98.8% sensitivity, 92% PPV
• Trisomy 18: 98.8% sensitivity, 66% PPV
• Trisomy 13: 92.9% sensitivity, 37% PPV

The microdeletion detection capability represents a significant step down in performance from these benchmarks 1, 2.

Clinical Recommendation Algorithm

When considering expanded NIPT for microdeletions:

1. Offer for 22q11.2 deletion screening with appropriate counseling about moderate PPV (50-53%) 1

2. Emphasize that positive results require confirmatory invasive testing (amniocentesis with chromosomal microarray) 1, 3

3. Counsel patients that:

   • Sensitivity is lower than for trisomies 1
   • Small deletions (<5 Mb) are frequently missed 3
   • False positives are common, leading to unnecessary invasive procedures 5

4. Ultrasound findings significantly impact interpretation: Abnormal ultrasound increases PPV substantially 5, 7

5. Do not use for genome-wide microdeletion screening in routine practice 1