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

Year: 2025

Type: article

Abstract: Genome-wide non-invasive prenatal testing (NIPT) is a powerful tool for prenatal detection of the common aneuploidies causing Down-, Edwards-, and Patau syndrome. Its genome-wide reach also enables the detection of unbalanced structural chromosomal abnormalities. We report a case where NIPT indicated a ~25 Mb terminal deletion of the long arm of chromosome 16, later confirmed to be mosaic in maternal blood and buccal cells (in 35%-45% of cells). Remarkably, the same mosaic deletion was seen in the child, who was born healthy at term after an uneventful pregnancy. Further analysis using bromodeoxyuridine (BrdU)-induced cultures revealed that the deletion originated from the expression of a rare autosomal fragile site (RFS), FRA16B, resulting in enhanced chromosomal fragility at 16q21. Rather than inheriting the maternal deletion, the child had inherited the maternal RFS, causing increased fragility at 16q21 in both mother and child. Employing long-read sequencing (LRS), we characterized the molecular structure of this RFS. FRA16B is an expanded repeat region of > 20 kb in size, comprising over 700 AT-rich minisatellite repeats. We resolved both distal (35-mer) and proximal (28-mer) repeat motifs at nucleotide precision. This uncovered striking molecular parallels between FRA16B and FRA10B, an RFS that is also associated with clinically irrelevant deletions found occasionally in NIPT. Our case underscores the importance of cautious interpretation of 16q21 terminal deletions in NIPT in order to avoid unnecessary invasive prenatal testing, as their presence reflects maternal and/or fetal fragile site instability rather than a pathogenic chromosome abnormality.

Source: American Journal of Medical Genetics Part A

DOI: 10.1002/ajmg.a.64271