Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders

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

Research output: Contribution to journalArticleScientificpeer-review


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.
Original languageEnglish
Article number11239
JournalScientific Reports
Issue number1
Number of pages7
Publication statusPublished - 2024
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3112 Neurosciences

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