Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders

: Schrauwen Isabelle, Rajendran Yasmin, Acharya Anushree, Öhman Susanna, Arvio Maria, Paetau Ritva, Siren Auli, Avela Kristiina, Granvik Johanna, Leal Suzanne M., Määttä Tuomo, Kokkonen Hannaleena, Järvelä Irma

Publisher: Springer Nature

: 2024

: Scientific Reports

: Scientific reports

: Sci Rep

: 11239

: 14

: 1

: 2045-2322

DOI: https://doi.org/10.1038/s41598-024-62009-y

: https://www.nature.com/articles/s41598-024-62009-y

: https://research.utu.fi/converis/portal/detail/Publication/404684262

While short-read sequencing currently dominates genetic research and diagnostics, it frequently falls short of capturing certain structural variants (SVs), which are often implicated in the etiology of neurodevelopmental disorders (NDDs). Optical genome mapping (OGM) is an innovative technique capable of capturing SVs that are undetectable or challenging-to-detect via short-read methods. This study aimed to investigate NDDs using OGM, specifically focusing on cases that remained unsolved after standard exome sequencing. OGM was performed in 47 families using ultra-high molecular weight DNA. Single-molecule maps were assembled de novo, followed by SV and copy number variant calling. We identified 7 variants of interest, of which 5 (10.6%) were classified as likely pathogenic or pathogenic, located in BCL11A, OPHN1, PHF8, SON, and NFIA. We also identified an inversion disrupting NAALADL2, a gene which previously was found to harbor complex rearrangements in two NDD cases. Variants in known NDD genes or candidate variants of interest missed by exome sequencing mainly consisted of larger insertions (> 1kbp), inversions, and deletions/duplications of a low number of exons (1-4 exons). In conclusion, in addition to improving molecular diagnosis in NDDs, this technique may also reveal novel NDD genes which may harbor complex SVs often missed by standard sequencing techniques.

s41598-024-62009-y.pdf

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This research was supported by a pilot Grant from the Columbia University Sergievsky Center (Gertrude H. Sergievsky Center Award), R21 NS123325 to IS and R01 HD109342 to SML and IS.