Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA

Area of Science:

• Genetics
• Molecular Biology
• Prenatal Diagnostics

Background:

• Current non-invasive prenatal screening focuses on fetal chromosomal abnormalities.
• Screening for dominant monogenic disorders, often caused by de novo mutations, is lacking despite their prevalence.

Purpose of the Study:

• To develop and validate a novel non-invasive prenatal sequencing approach for common dominant monogenic diseases.
• To assess the early clinical performance of this new screening method.

Main Methods:

• Utilized cell-free DNA (cfDNA) from maternal plasma for targeted next-generation sequencing (NGS).
• Employed statistical analysis to detect low-level fetal variants, considering NGS read count and fetal fraction.
• Confirmed pathogenic variants using a secondary amplicon-based cfDNA test.

Main Results:

• The study included 422 pregnancies, with or without relevant clinical indications.
• Follow-up confirmed 20 true-positive and 127 true-negative results.
• Achieved zero false-positive and zero false-negative results, demonstrating high accuracy.

Conclusions:

• The developed non-invasive test effectively detects a broad range of dominant monogenic diseases.
• This approach complements existing prenatal screening for aneuploidies and carrier screening for recessive disorders.