Analysis of complex chromosomal structural variants through optical genome mapping integrated with karyotyping

Area of Science:

• Genetics
• Genomics
• Reproductive Medicine

Background:

• Parental chromosomal structural variations (SVs) are a key cause of recurrent spontaneous abortion (RSA).
• Complex chromosomal rearrangements (CCRs) in carriers often lead to miscarriage despite normal phenotypes.
• Standard clinical methods struggle to detect all SV types, complicating genetic counseling for RSA couples.

Purpose of the Study:

• To utilize optical genome mapping (OGM) for rapid and accurate identification of complex SVs in RSA couples.
• To analyze genetic information within breakpoint regions for enhanced cellular and genetic counseling.
• To provide a comprehensive scientific basis for genetic counseling in RSA.

Main Methods:

• Selected nine subjects from two families undergoing genetic counseling for RSA.
• Performed chromosomal karyotype analysis and optical genome mapping (OGM).
• Used Sanger sequencing to validate OGM findings for SV carriers.

Main Results:

• OGM precisely identified complex SVs, including a novel translocation variant of the KIF7 gene associated with miscarriage in Family 1.
• OGM determined accurate karyotypes for SV carriers in Family 2, resolving ambiguities from initial analysis.
• OGM technology effectively detected intricate and cryptic SVs missed by traditional karyotyping.

Conclusions:

• OGM significantly enhances diagnostic rates for the genetic causes of RSA by precisely identifying complex SVs.
• The study provides a robust method for breakpoint mapping and gene interpretation, aiding RSA disease assessment and counseling.
• Further large-scale studies are needed to validate findings, and the role of KIF7 in RSA requires experimental verification.