Non-Invasive Prenatal Testing (NIPT) for Microdeletions: High-Risk Result with Conflicting Follow-Up
A 35-year-old woman at 12 weeks gestation undergoes NIPT (cell-free DNA screening) that includes common microdeletions. The result is high risk for 22q11.2 deletion syndrome (positive predictive value ~50% in the general population, but higher in this case due to additional ultrasound findings). The patient is counseled and elects to have diagnostic testing via chorionic villus sampling (CVS). The CVS karyotype is normal, but the microarray (CMA) shows a 2.5 Mb deletion at 22q11.2. The laboratory uses a CMA platform with a resolution of 50 kb. The deletion is confirmed by FISH. The parents are both healthy and have no family history. The mother's NIPT was performed at a lab with a fetal fraction of 8%. The CVS was performed at 13 weeks. The patient is anxious and wants to know if the baby will be affected.
1. Explain the discordance between the normal karyotype and the abnormal CMA result. What is the most likely explanation?
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The normal karyotype (resolution ~5-10 Mb) cannot detect a 2.5 Mb microdeletion. CMA has much higher resolution (50 kb in this case) and thus detects submicroscopic deletions. The most likely explanation is that the 22q11.2 deletion is below the detection limit of karyotyping. This is a common scenario: karyotype is normal because the deletion is too small. The CMA result is confirmatory. The FISH result further confirms the deletion. Therefore, the discordance is due to differences in resolution. The deletion is real and likely pathogenic.
2. What is the probability that the fetus is affected with 22q11.2 deletion syndrome given the positive NIPT and confirmatory CMA? Discuss the factors that influence this probability.
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Given a positive NIPT and a confirmatory diagnostic test (CMA), the probability that the fetus has the deletion is essentially 100% (barring technical errors, which are minimal with confirmatory testing). However, the question of whether the fetus will be 'affected' (i.e., have clinical features) is more nuanced. 22q11.2 deletion syndrome has variable expressivity and reduced penetrance. Many individuals with the deletion have significant medical and developmental issues, but the severity varies. Factors influencing the probability of being affected include:
- Deletion size and location: The typical 3 Mb deletion (or 2.5 Mb in this case) is associated with the full syndrome. Smaller atypical deletions may have milder phenotypes.
- Inheritance: De novo deletions (as likely here, since parents are healthy) may have a different prognosis than inherited ones? Actually, the phenotype is similar regardless of inheritance.
- Family history: None, but the deletion is likely de novo.
- Genetic modifiers: Unknown.
- Environmental factors: Unknown.
- Prenatal ultrasound findings: The case mentions additional ultrasound findings that increased the PPV. These could indicate a more severe phenotype.
Overall, the fetus has a high probability (~80-90%) of having some features of 22q11.2 deletion syndrome, but the spectrum is wide. Genetic counseling should cover the range of possible outcomes, including congenital heart defects, immune deficiency, hypocalcemia, palatal anomalies, developmental delay, and psychiatric issues. The parents should be offered further evaluation (e.g., fetal echocardiogram) and support.