Hi-C technology for detection of chromosomal rearrangements in families with adverse pregnancy outcomes: a preliminary exploratory study

Chromosomal abnormalities are a leading cause of adverse pregnancy outcomes. Conventional methods such as karyotyping and chromosomal microarray analysis (CMA) have limited ability to detect cryptic, mosaic, or repeat-region structural variants. This preliminary exploratory study evaluated the feasibility and potential utility of Hi-C in comparison with karyotyping, CMA, optical genome mapping (OGM), and structural variant sequencing (SV-seq) in two families with unexplained or incompletely characterized recurrent adverse pregnancy outcomes. In Family 1, CMA and recurrent abnormal NIPS results suggested maternal mosaic copy number changes, and high depth karyotyping, SV-seq, and Hi-C supported a mosaic unbalanced translocation involving chromosomes 9 and 18; OGM detected the copy number changes but did not resolve the underlying cryptic rearrangement structure. In Family 2, Hi-C, together with OGM and SV-seq, refined the candidate breakpoint regions of a balanced translocation initially detected by karyotyping, and supported transmission of the same rearrangement to the daughter. These findings suggest that Hi-C may serve as a valuable complementary diagnostic tool for identifying cryptic balanced or mosaic chromosomal rearrangements in selected families with unexplained or incompletely characterized recurrent adverse pregnancy outcomes. Larger sample prospective studies are still required to verify its general clinical application in the future.