Genome Sequencing Explores Complexity of Chromosomal Abnormalities in Recurrent Miscarriage

Area of Science:

• Genetics
• Reproductive Medicine
• Genomics

Background:

• Recurrent miscarriage (RM) affects millions globally, with half of cases lacking a clear cause.
• Genome sequencing (GS) is an advanced cytogenetic technique for identifying chromosomal abnormalities.
• Routine chromosome analysis has limitations in diagnosing the etiology of RM.

Purpose of the Study:

• To evaluate the utility of low-pass genome sequencing (GS) in identifying chromosomal abnormalities in couples experiencing recurrent miscarriage (RM).
• To compare the diagnostic yield of GS with traditional karyotyping methods for RM cases.
• To assess the impact of GS-detected abnormalities on subsequent pregnancy outcomes.

Main Methods:

• Retrospective analysis of 1,090 RM-affected couples using low-pass GS.
• Development of a custom pipeline for identifying chromosomal rearrangements, deletions, and duplications.
• Confirmation of GS findings using fluorescence in situ hybridization, chromosomal microarray analysis, and PCR.

Main Results:

• Low-pass GS yielded results for 98.8% of couples, detecting chromosomal abnormalities in 11.7%.
• GS identified additional abnormalities in 4.0% of couples previously diagnosed with normal karyotypes, including balanced translocations and inversions.
• Couples with GS-detected abnormalities had a significantly higher rate of miscarriage/fetal anomalies (50% vs. 22.6%).

Conclusions:

• Low-pass GS is a powerful tool for diagnosing chromosomal aberrations in recurrent miscarriage (RM) couples, with a diagnostic yield of 11.7%.
• GS identifies a subgroup of RM couples with an increased risk of pregnancy loss, enabling personalized interventions.
• This method significantly enhances the diagnostic capability compared to standard chromosome analysis.