Clinically Irrelevant Terminal 16q21 Deletion Detected by NIPT Is Attributable to Inherited Fragility at FRA16B

Area of Science:

• Genetics
• Genomics
• Prenatal Diagnostics

Background:

• Genome-wide non-invasive prenatal testing (NIPT) screens for common aneuploidies and structural chromosomal abnormalities.
• Terminal deletions detected by NIPT require careful interpretation, as they may not always indicate a pathogenic condition.

Purpose of the Study:

• To investigate a case where NIPT detected a ~25 Mb terminal deletion on chromosome 16.
• To determine the origin and mechanism of the observed deletion.
• To characterize the molecular structure of the involved rare autosomal fragile site (RFS).

Main Methods:

• Non-invasive prenatal testing (NIPT) for chromosomal abnormalities.
• Bromodeoxyuridine (BrdU)-induced cultures to assess chromosomal fragility.
• Long-read sequencing (LRS) for molecular characterization of fragile sites.

Main Results:

• NIPT identified a mosaic deletion on chromosome 16 in both mother and child.
• The deletion was linked to the rare autosomal fragile site FRA16B, causing instability at 16q21.
• FRA16B is an expanded repeat region (>20 kb) with over 700 AT-rich minisatellite repeats.

Conclusions:

• Terminal 16q21 deletions detected by NIPT can result from fragile site instability (FRA16B) rather than pathogenic chromosomal abnormalities.
• The child inherited the fragile site, not the deletion, leading to instability in both mother and child.
• Cautious interpretation of NIPT findings for 16q21 deletions is crucial to prevent unnecessary invasive prenatal testing.