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Related Experiment Video

Updated: May 8, 2026

A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
08:22

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Optical genome mapping identifies clinically relevant somatic structural variation in epilepsy-affected brain tissue.

Anthony R Miller1, James J Anderson1, Maria Elena Hernandez Gonzalez1

  • 1Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH.

Medrxiv : the Preprint Server for Health Sciences
|May 7, 2026
PubMed
Summary

Optical genome mapping (OGM) effectively detects mosaic structural variants in epilepsy brain tissue, improving diagnosis. This method reveals previously undetected genetic variations, advancing our understanding of neurological disorders.

Keywords:
brainoptical mappingstructural variant

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Area of Science:

  • Genomics
  • Neurology
  • Molecular Biology

Background:

  • Somatic variants contribute to epilepsy-associated cortical malformations, yet current genetic testing misses many due to detection limitations.
  • Short-read sequencing struggles to identify complex somatic structural variants, a significant factor in neurological disorders.
  • Optical Genome Mapping (OGM) shows promise for detecting structural variants but requires optimized protocols for clinical tissues.

Purpose of the Study:

  • To optimize Optical Genome Mapping (OGM) for detecting low-allele-fraction somatic variants in surgically resected human brain tissue.
  • To apply the optimized OGM protocol to brain specimens from epilepsy patients to identify novel structural variants.
  • To investigate the diagnostic utility of OGM in epilepsy and its potential to refine genotype-phenotype correlations.

Main Methods:

  • Optimized a protocol for OGM using high-quality, high-molecular-weight DNA from patient brain tissue, achieving ~450x effective coverage.
  • Applied OGM to brain specimens from four epilepsy patients, alongside short-read exome sequencing for comparison.
  • Utilized PacBio HiFi sequencing to resolve breakpoints and elucidate the mechanism of identified somatic deletions.

Main Results:

  • OGM successfully identified large, complex mosaic structural variants (7-40% variant allele fraction) in epilepsy brain tissue, missed by short-read sequencing.
  • In one patient, OGM detected a mosaic 13.2kb deletion in DEPDC5 at ~20% VAF, supporting the two-hit model for DEPDC5-associated epilepsies.
  • The mechanism of the somatic DEPDC5 deletion was identified as Alu-mediated recombination, confirmed by PacBio HiFi sequencing.

Conclusions:

  • Optimized OGM is a robust method for detecting mosaic structural variants in human brain tissue, significantly enhancing diagnostic capabilities for epilepsy.
  • OGM complements existing sequencing technologies, offering improved detection of complex variants and aiding in understanding neurological disorder mechanisms.
  • This approach holds potential for increasing diagnostic yield and refining genotype-phenotype correlations in epilepsy and other neurological conditions.