Chromosomal structural abnormalities and tissue-specific mosaicism: insights into false-negative noninvasive prenatal...

Area of Science:

• Genetics
• Prenatal Diagnostics
• Molecular Biology

Background:

• Noninvasive prenatal testing (NIPT) is a widely used screening tool for common chromosomal aneuploidies.
• False-negative NIPT results can lead to missed diagnoses and impact clinical management.
• Investigating the causes of false negatives is essential for improving NIPT accuracy and patient care.

Purpose of the Study:

• To identify the underlying genetic causes of false-negative NIPT results.
• To provide insights for technical optimization of NIPT protocols.
• To enhance genetic counseling for cases with discordant NIPT findings.

Main Methods:

• Retrospective analysis of clinical and genetic data from three cases with false-negative NIPT.
• Utilized genetic analyses including karyotyping, copy number variation sequencing (CNV-seq), trio whole-exome sequencing (WES-trio), and fluorescence in situ hybridization (FISH).
• Examined various biological samples: amniotic fluid, placental tissue, maternal peripheral blood, and buccal mucosal cells.

Main Results:

• Identified complex chromosomal abnormalities including ring chromosome 21, dicentric chromosome 18, and multiple chromosomal rearrangements.
• Demonstrated tissue-specific mosaicism and significant discrepancies in mosaic levels between different fetal and placental tissues.
• Showcased how heterogeneous genomic alterations can lead to incomplete representation in cell-free DNA (cfDNA), causing false-negative NIPT results.

Conclusions:

• Mosaicism, tissue distribution variability, and complex chromosomal abnormalities are key contributors to false-negative NIPT results.
• Highlights the importance of comprehensive genetic evaluation for discordant NIPT findings.
• Emphasizes the need for improved NIPT strategies to account for complex genomic alterations.