Maternal Mosaicism Challenges in Non-Invasive Prenatal Diagnosis

Area of Science:

• Genetics
• Reproductive Medicine
• Molecular Diagnostics

Background:

• Non-invasive prenatal diagnosis for monogenic disorders (NIPD-MD) is crucial for detecting fetal genetic conditions.
• Exclusion-based NIPD-MD relies on detecting fetal-specific variants in maternal plasma.
• De novo pathogenic variants pose challenges for NIPD-MD due to the need for parental samples.

Purpose of the Study:

• To report the incidental finding of maternal somatic mosaicism during NIPD-MD development.
• To highlight the impact of maternal mosaicism on the feasibility of exclusion-based NIPD-MD.
• To emphasize the importance of pre-test evaluation for accurate genetic counseling.

Main Methods:

• Development of a droplet digital PCR (ddPCR)-based exclusion NIPD-MD assay for four couples.
• Assay design focused on detecting fetal-specific variants in maternal plasma.
• Validation involved parental and proband samples, with retrospective analysis of maternal sequencing data.

Main Results:

• Maternal somatic mosaicism (3%-9%) was detected in 4 out of 70 cases (5.7%) during assay validation.
• The identified maternal mosaicism rendered NIPD-MD infeasible due to allele interference.
• Couples were informed of elevated recurrence risks, opting for invasive testing or ultrasound follow-up.

Conclusions:

• Maternal mosaicism presents a significant limitation for exclusion-based NIPD-MD.
• Accurate identification of maternal mosaicism is essential for reliable recurrence risk estimation.
• Sensitive detection methods, pre-test evaluation, and clear communication are critical for informed reproductive decisions.