Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping

Area of Science:

• Genomics
• Human Genetics
• Medical Diagnostics

Background:

• Chromosomal rearrangements significantly impact human genetic diseases.
• Standard karyotyping often fails to detect cryptic balanced chromosomal rearrangements (BCRs).
• Undetected cryptic BCRs increase risks of miscarriage and congenital abnormalities.

Purpose of the Study:

• To evaluate the utility of optical genome mapping (OGM) for detecting cryptic chromosomal rearrangements.
• To assess OGM's potential as a clinical diagnostic tool for identifying complex genetic variations.

Main Methods:

• Ultra-high-molecular-weight DNA from eleven couples with unexplained reproductive issues was analyzed using OGM.
• OGM data underwent genome assembly, variant calling, and annotation.
• Results were validated using fluorescence in situ hybridization (FISH), next-generation sequencing, and Sanger sequencing.

Main Results:

• High-resolution OGM accurately identified cryptic reciprocal translocations in all participating couples.
• OGM findings were consistently confirmed by FISH and sequencing analyses of breakpoint regions.
• OGM also detected complex rearrangements, including inverted aberrations, enhancing genetic interpretation.

Conclusions:

• This study demonstrates OGM's capability for rapid and reliable detection of cryptic chromosomal reciprocal translocations in a clinical setting.
• OGM proves to be an accurate, comprehensive, and suitable first-line method for routine clinical testing of cryptic BCRs.