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Optical genome mapping enables constitutional chromosomal aberration detection

The American Journal of Human Genetics 2021
Mantere T. et al

Tuomo Mantere,1,2,3,12 Kornelia Neveling,1,4,12 Ce line Pebrel-Richard,5 Marion Benoist,6

Guillaume van der Zande,1 Ellen Kater-Baats,1 Imane Baatout,6 Ronald van Beek,1 Tony Yammine,7,8

Michiel Oorsprong,1 Faten Hsoumi,6 Daniel Olde-Weghuis,1 Wed Majdali,6 Susan Vermeulen,1

Marc Pauper,1 Aziza Lebbar,6 Marian Stevens-Kroef,1 Damien Sanlaville,7,9 Jean Michel Dupont,6,10

Dominique Smeets,1 Alexander Hoischen,1,2,11,12,* Caroline Schluth-Bolard,7,9,12

and La ıla El Khattabi

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.’’

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