Noninvasive prenatal screening or advanced diagnostic testing: caveat emptor.

Area of Science:

• Prenatal Genetics
• Reproductive Medicine
• Genomic Medicine

Background:

• Recent advances include next-generation sequencing of cell-free DNA (cfDNA) for noninvasive prenatal screening (NIPS) and microarray analysis for enhanced cytogenetic resolution.
• NIPS demonstrates high sensitivity and specificity for trisomy 21, leading to reduced invasive diagnostic procedures like chorionic villus sampling (CVS) and amniocentesis.
• A decrease in patient counseling has been observed alongside the rise of NIPS.

Purpose of the Study:

• To compare karyotype with array comparative genomic hybridization (aCGH) for detecting chromosomal abnormalities.
• To evaluate the clinical relevance of copy number variants (CNVs) identified by aCGH in pregnancies with normal karyotypes.
• To advocate for comprehensive genetic counseling and diagnostic testing for all pregnant individuals.

Main Methods:

• A blinded comparison study funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
• Utilized karyotype analysis and array comparative genomic hybridization (aCGH).
• Analyzed samples from patients with normal karyotypes, ultrasound-detected anomalies, and normal scans.

Main Results:

• In patients with a normal karyotype, aCGH identified clinically relevant microdeletions or duplications in 2.5% of cases.
• Incremental findings were observed in 6% of pregnancies with ultrasound-detected structural anomalies and 1.6% of those with normal scans.
• The risk of a pathogenic CNV in patients with a normal ultrasound and karyotype is over 1%, exceeding the age-related risk for aneuploidy in a 38-year-old.

Conclusions:

• Array comparative genomic hybridization (aCGH) detects significant genetic variations missed by standard prenatal screening and karyotyping.
• The risk of pathogenic copy number variants (CNVs) warrants offering diagnostic testing to all patients, irrespective of age or ultrasound findings.
• Enhanced genetic counseling is crucial to inform patients about the risks and benefits of advanced prenatal genetic testing options.