Optical genome mapping enables constitutional chromosomal aberration detection

Am J Hum Genet. 2021 Aug 5;108(8):1409-1422. doi: 10.1016/j.ajhg.2021.05.012. Epub 2021 Jul 7.

Abstract

Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard cytogenetics. Drawbacks of these tests are a very low resolution (karyotyping) and the inability to detect balanced SVs or indicate the genomic localization and orientation of duplicated segments or insertions (copy number variant [CNV] microarrays). Here, we investigated the ability of optical genome mapping (OGM) to detect known constitutional chromosomal aberrations. Ultra-high-molecular-weight DNA was isolated from 85 blood or cultured cells and processed via OGM. A de novo genome assembly was performed followed by structural variant and CNV calling and annotation, and results were compared to known aberrations from standard-of-care tests (karyotype, FISH, and/or CNV microarray). In total, we analyzed 99 chromosomal aberrations, including seven aneuploidies, 19 deletions, 20 duplications, 34 translocations, six inversions, two insertions, six isochromosomes, one ring chromosome, and four complex rearrangements. Several of these variants encompass complex regions of the human genome involved in repeat-mediated microdeletion/microduplication syndromes. High-resolution OGM reached 100% concordance compared to standard assays for all aberrations with non-centromeric breakpoints. This proof-of-principle study demonstrates the ability of OGM to detect nearly all types of chromosomal aberrations. We also suggest suited filtering strategies to prioritize clinically relevant aberrations and discuss future improvements. These results highlight the potential for OGM to provide a cost-effective and easy-to-use alternative that would allow comprehensive detection of chromosomal aberrations and structural variants, which could give rise to an era of "next-generation cytogenetics."

Keywords: CNV microarray; FISH; OGM; breakpoint characterization; chromosomal aberration; constitutional aberrations; cytogenetics; karyotyping; optical genome mapping; structural variants.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Aberrations*
  • Chromosome Disorders / diagnosis*
  • Chromosome Disorders / genetics
  • Chromosome Mapping / methods*
  • Cytogenetic Analysis / methods*
  • DNA Copy Number Variations*
  • Genome, Human*
  • Humans
  • Karyotyping
  • Microarray Analysis / methods*