Clinical experience with non-invasive prenatal screening for single-gene disorders

Area of Science:

• Genetics
• Prenatal diagnostics
• Molecular biology

Background:

• Dominant single-gene disorders (SGD) represent a significant portion of genetic conditions.
• Current prenatal screening methods may have limitations in detecting a broad range of SGD.
• Non-invasive prenatal screening (NIPT) offers a potential advancement in prenatal diagnostics.

Purpose of the Study:

• To evaluate the clinical performance of a non-invasive prenatal screening test (NIPT) designed for a panel of dominant single-gene disorders (SGD).
• To assess the test-positive rates of NIPT-SGD in relation to specific clinical indications.
• To determine the accuracy of NIPT-SGD in identifying pathogenic variants for a combined population incidence of 1 in 600.

Main Methods:

• Next-generation sequencing of cell-free fetal DNA from maternal plasma.
• Targeting 30 genes associated with 25 dominant conditions, including Noonan spectrum and skeletal disorders.
• Utilizing maternal and paternal genomic DNA for variant interpretation and requiring a minimum 4.5% fetal fraction.

Main Results:

• A NIPT-SGD result was obtained for 2208 women, with 125 (5.7%) testing positive.
• Elevated test-positive rates were observed in cases with a family history (15.2%) or fetal abnormalities (e.g., long-bone 33.7%, craniofacial 28.6%).
• No false-positive or false-negative cases were identified among the 67 cases with available follow-up information.

Conclusions:

• Non-invasive prenatal screening (NIPT) can aid in the early detection of dominant single-gene disorders (SGD).
• NIPT-SGD is particularly effective when abnormal ultrasound findings or a family history are present.
• NIPT-SGD provides a safe and early prenatal screening option, though further studies on panel design and target populations are needed.