Routine Prenatal cfDNA Screening for Autosomal Dominant Single-Gene Conditions

Area of Science:

• Genetics
• Reproductive Medicine
• Molecular Diagnostics

Background:

• Genetic screening has evolved from aneuploidy detection to single-gene disorders (cfDNA-SGD).
• Clinical validation of cfDNA-SGD is promising in high-risk pregnancies but less studied in the general population.

Purpose of the Study:

• To evaluate the utility and outcomes of routine cell-free DNA screening for single-gene disorders (cfDNA-SGD) in a general pregnant population.
• To assess the concordance and clinical significance of cfDNA-SGD results.

Main Methods:

• Retrospective chart review of pregnancies undergoing cfDNA-SGD screening for 25 autosomal dominant conditions.
• Exclusion of pregnancies with ultrasound anomalies or known family history.
• Analysis of screening concordance, pregnancy outcomes, and phenotypes.

Main Results:

• 9.4% of pregnancies underwent cfDNA-SGD screening, with 78.9% being routine.
• 0.51% of routine screenings yielded high-risk results (pathogenic/likely pathogenic variants).
• Diagnostic testing confirmed variants in 11/14 affected pregnancies/newborns, with no false positives but two discrepant classifications.

Conclusions:

• Routine cfDNA-SGD screening identifies 0.51% of pregnancies as high-risk, necessitating further evaluation.
• Early identification through cfDNA-SGD allows for timely intervention.
• Challenges include counseling due to variable expressivity, limited genotype-phenotype correlations, and classification discrepancies.