IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-54911-w.html
   My bibliography  Save this article

Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR

Author

Listed:
  • Christian M. Boßelmann

    (Cleveland Clinic
    Cleveland Clinic)

  • Costin Leu

    (Cleveland Clinic
    University College London
    The University of Texas Health Science Center at Houston
    The University of Texas Health Science Center at Houston)

  • Tobias Brünger

    (The University of Texas Health Science Center at Houston
    The University of Texas Health Science Center at Houston
    University of Cologne)

  • Lucas Hoffmann

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Sara Baldassari

    (Hôpital de la Pitié Salpêtrière)

  • Mathilde Chipaux

    (Rothschild Foundation Hospital)

  • Roland Coras

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Katja Kobow

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Hajo Hamer

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Daniel Delev

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Karl Rössler

    (Vienna General Hospital)

  • Christian G. Bien

    (Bielefeld University)

  • Thilo Kalbhenn

    (Bielefeld University
    Bielefeld University)

  • Tom Pieper

    (Vogtareuth)

  • Till Hartlieb

    (Vogtareuth
    Paracelsus Medical University)

  • Kerstin Becker

    (University of Cologne)

  • Lisa Ferguson

    (Cleveland Clinic)

  • Robyn M. Busch

    (Cleveland Clinic
    Cleveland Clinic)

  • Stéphanie Baulac

    (Hôpital de la Pitié Salpêtrière)

  • Peter Nürnberg

    (University of Cologne
    Faculty of Medicine and University Hospital Cologne)

  • Imad Najm

    (Cleveland Clinic)

  • Ingmar Blümcke

    (Cleveland Clinic
    Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Dennis Lal

    (Cleveland Clinic
    Cleveland Clinic
    The University of Texas Health Science Center at Houston
    The University of Texas Health Science Center at Houston)

Abstract

Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing. Here we confirm four known associations (BRAF, SLC35A2, MTOR, PTPN11), support eight associations without prior statistical support (FGFR1, PIK3CA, AKT3, NF1, PTEN, RHEB, KRAS, NRAS), and identify novel associations for two genes, DYRK1A and EGFR. Both novel genes show specific histopathological phenotypes, interact with LFE genes and pathways, and may represent promising candidates as biomarkers and potentially druggable targets.

Suggested Citation

  • Christian M. Boßelmann & Costin Leu & Tobias Brünger & Lucas Hoffmann & Sara Baldassari & Mathilde Chipaux & Roland Coras & Katja Kobow & Hajo Hamer & Daniel Delev & Karl Rössler & Christian G. Bien &, 2024. "Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54911-w
    DOI: 10.1038/s41467-024-54911-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-54911-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-54911-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Aileen A. Ren & Daniel A. Snellings & Yourong S. Su & Courtney C. Hong & Marco Castro & Alan T. Tang & Matthew R. Detter & Nicholas Hobson & Romuald Girard & Sharbel Romanos & Rhonda Lightle & Thomas , 2021. "PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism," Nature, Nature, vol. 594(7862), pages 271-276, June.
    2. Ines H. Kaltheuner & Kanchan Anand & Jonas Moecking & Robert Düster & Jinhua Wang & Nathanael S. Gray & Matthias Geyer, 2021. "Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Jonathan Frazer & Pascal Notin & Mafalda Dias & Aidan Gomez & Joseph K. Min & Kelly Brock & Yarin Gal & Debora S. Marks, 2021. "Disease variant prediction with deep generative models of evolutionary data," Nature, Nature, vol. 599(7883), pages 91-95, November.
    4. Joanna Kaplanis & Kaitlin E. Samocha & Laurens Wiel & Zhancheng Zhang & Kevin J. Arvai & Ruth Y. Eberhardt & Giuseppe Gallone & Stefan H. Lelieveld & Hilary C. Martin & Jeremy F. McRae & Patrick J. Sh, 2020. "Evidence for 28 genetic disorders discovered by combining healthcare and research data," Nature, Nature, vol. 586(7831), pages 757-762, October.
    5. Daniel Taliun & Daniel N. Harris & Michael D. Kessler & Jedidiah Carlson & Zachary A. Szpiech & Raul Torres & Sarah A. Gagliano Taliun & André Corvelo & Stephanie M. Gogarten & Hyun Min Kang & Achille, 2021. "Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program," Nature, Nature, vol. 590(7845), pages 290-299, February.
    6. Chun Hu & Carlos A. Leche & Anatoly Kiyatkin & Zhaolong Yu & Steven E. Stayrook & Kathryn M. Ferguson & Mark A. Lemmon, 2022. "Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias," Nature, Nature, vol. 602(7897), pages 518-522, February.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Sean A. Misek & Aaron Fultineer & Jeremie Kalfon & Javad Noorbakhsh & Isabella Boyle & Priyanka Roy & Joshua Dempster & Lia Petronio & Katherine Huang & Alham Saadat & Thomas Green & Adam Brown & John, 2024. "Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Emily Olfson & Luis C. Farhat & Wenzhong Liu & Lawrence A. Vitulano & Gwyneth Zai & Monicke O. Lima & Justin Parent & Guilherme V. Polanczyk & Carolina Cappi & James L. Kennedy & Thomas V. Fernandez, 2024. "Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Yash Pershad & Taralynn Mack & Hannah Poisner & Yasminka A. Jakubek & Adrienne M. Stilp & Braxton D. Mitchell & Joshua P. Lewis & Eric Boerwinkle & Ruth J. F. Loos & Nathalie Chami & Zhe Wang & Kathle, 2024. "Determinants of mosaic chromosomal alteration fitness," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    4. Elena V. Feofanova & Michael R. Brown & Taryn Alkis & Astrid M. Manuel & Xihao Li & Usman A. Tahir & Zilin Li & Kevin M. Mendez & Rachel S. Kelly & Qibin Qi & Han Chen & Martin G. Larson & Rozenn N. L, 2023. "Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Wenkai Han & Ningning Chen & Xinzhou Xu & Adil Sahil & Juexiao Zhou & Zhongxiao Li & Huawen Zhong & Elva Gao & Ruochi Zhang & Yu Wang & Shiwei Sun & Peter Pak-Hang Cheung & Xin Gao, 2023. "Predicting the antigenic evolution of SARS-COV-2 with deep learning," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    7. Mohammad Erfan Mowlaei & Chong Li & Oveis Jamialahmadi & Raquel Dias & Junjie Chen & Benyamin Jamialahmadi & Timothy Richard Rebbeck & Vincenzo Carnevale & Sudhir Kumar & Xinghua Shi, 2025. "STICI: Split-Transformer with integrated convolutions for genotype imputation," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    8. Apeksha Shapeti & Jorge Barrasa-Fano & Abdel Rahman Abdel Fattah & Janne Jong & José Antonio Sanz-Herrera & Mylène Pezet & Said Assou & Emilie Vet & Seyed Ali Elahi & Adrian Ranga & Eva Faurobert & Ha, 2024. "Force-mediated recruitment and reprogramming of healthy endothelial cells drive vascular lesion growth," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Parsa Akbari & Olukayode A. Sosina & Jonas Bovijn & Karl Landheer & Jonas B. Nielsen & Minhee Kim & Senem Aykul & Tanima De & Mary E. Haas & George Hindy & Nan Lin & Ian R. Dinsmore & Jonathan Z. Luo , 2022. "Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Injeong Shim & Hiroyuki Kuwahara & NingNing Chen & Mais O. Hashem & Lama AlAbdi & Mohamed Abouelhoda & Hong-Hee Won & Pradeep Natarajan & Patrick T. Ellinor & Amit V. Khera & Xin Gao & Fowzan S. Alkur, 2023. "Clinical utility of polygenic scores for cardiometabolic disease in Arabs," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    11. Guoling Li & Xue Dong & Jiamin Luo & Tanglong Yuan & Tong Li & Guoli Zhao & Hainan Zhang & Jingxing Zhou & Zhenhai Zeng & Shuna Cui & Haoqiang Wang & Yin Wang & Yuyang Yu & Yuan Yuan & Erwei Zuo & Chu, 2024. "Engineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    12. Mateus H. Gouveia & Amy R. Bentley & Thiago P. Leal & Eduardo Tarazona-Santos & Carlos D. Bustamante & Adebowale A. Adeyemo & Charles N. Rotimi & Daniel Shriner, 2023. "Unappreciated subcontinental admixture in Europeans and European Americans and implications for genetic epidemiology studies," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    13. Ziyi Zhou & Liang Zhang & Yuanxi Yu & Banghao Wu & Mingchen Li & Liang Hong & Pan Tan, 2024. "Enhancing efficiency of protein language models with minimal wet-lab data through few-shot learning," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    14. Zihuai He & Linxi Liu & Michael E. Belloy & Yann Guen & Aaron Sossin & Xiaoxia Liu & Xinran Qi & Shiyang Ma & Prashnna K. Gyawali & Tony Wyss-Coray & Hua Tang & Chiara Sabatti & Emmanuel Candès & Mich, 2022. "GhostKnockoff inference empowers identification of putative causal variants in genome-wide association studies," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    15. Ada J. S. Chan & Worrawat Engchuan & Miriam S. Reuter & Zhuozhi Wang & Bhooma Thiruvahindrapuram & Brett Trost & Thomas Nalpathamkalam & Carol Negrijn & Sylvia Lamoureux & Giovanna Pellecchia & Rohan , 2022. "Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    16. Pol Solé-Navais & Julius Juodakis & Karin Ytterberg & Xiaoping Wu & Jonathan P. Bradfield & Marc Vaudel & Abigail L. LaBella & Øyvind Helgeland & Christopher Flatley & Frank Geller & Moshe Finel & Men, 2024. "Genome-wide analyses of neonatal jaundice reveal a marked departure from adult bilirubin metabolism," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    17. Lasse M. Blaabjerg & Nicolas Jonsson & Wouter Boomsma & Amelie Stein & Kresten Lindorff-Larsen, 2024. "SSEmb: A joint embedding of protein sequence and structure enables robust variant effect predictions," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    18. Yaan J. Jang & Qi-Qi Qin & Si-Yu Huang & Arun T. John Peter & Xue-Ming Ding & Benoît Kornmann, 2024. "Accurate prediction of protein function using statistics-informed graph networks," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    19. Ozvan Bocher & Cristen J. Willer & Eleftheria Zeggini, 2023. "Unravelling the genetic architecture of human complex traits through whole genome sequencing," Nature Communications, Nature, vol. 14(1), pages 1-4, December.
    20. Gareth Hawkes & Robin N. Beaumont & Zilin Li & Ravi Mandla & Xihao Li & Christine M. Albert & Donna K. Arnett & Allison E. Ashley-Koch & Aneel A. Ashrani & Kathleen C. Barnes & Eric Boerwinkle & Jenni, 2024. "Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54911-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.