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

被引：0

作者：

Bosselmann, Christian M. ^{[1
,2
]}

Leu, Costin ^{[1
,3
,4
,5
]}

Bruenger, Tobias ^{[4
,5
,6
]}

Hoffmann, Lucas ^{[7
]}

Baldassari, Sara ^{[8
]}

Chipaux, Mathilde ^{[9
]}

Coras, Roland ^{[7
]}

Kobow, Katja ^{[7
]}

Hamer, Hajo ^{[10
]}

Delev, Daniel ^{[11
]}

Roessler, Karl ^{[12
]}

Bien, Christian G. ^{[13
]}

Kalbhenn, Thilo ^{[13
,14
]}

Pieper, Tom ^{[15
]}

Hartlieb, Till ^{[15
,16
]}

Becker, Kerstin ^{[6
]}

Ferguson, Lisa ^{[2
]}

Busch, Robyn M. ^{[1
,2
]}

Baulac, Stephanie ^{[8
]}

Nuernberg, Peter ^{[6
,17
]}

Najm, Imad ^{[2
]}

Bluemcke, Ingmar ^{[2
,7
]}

Lal, Dennis ^{[1
,2
,4
,5
,6
,18
]}

机构：

[1] Cleveland Clin, Genom Med Inst, Lerner Res Inst, Cleveland, OH 44195 USA

[2] Cleveland Clin, Neurol Inst, Epilepsy Ctr, Cleveland, OH 44195 USA

[3] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, London, England

[4] Univ Texas Hlth Sci Ctr Houston, Dept Neurol, Houston, TX 77030 USA

[5] Univ Texas Hlth Sci Ctr Houston, Ctr Neurogenet, Houston, TX 77030 USA

[6] Univ Cologne, Cologne Ctr Genom CCG, Cologne, DE, Germany

[7] Friedrich Alexander Univ Erlangen Nurnberg, Dept Neuropathol, Partner European Reference Network ERN EpiCARE, Univ klin Erlangen, Erlangen, Germany

[8] Sorbonne Univ, Hop Pitie Salpetriere, Paris Brain Inst ICM, Inst Cerveau,Inserm,CNRS, F-75013 Paris, France

[9] Rothschild Fdn Hosp, Dept Pediat Neurosurg, F-75019 Paris, France

[10] Friedrich Alexander Univ Erlangen Nurnberg, Univ klin Erlangen, Epilepsy Ctr EpiCARE Partner, Erlangen, Germany

[11] Friedrich Alexander Univ Erlangen Nurnberg, Univ klin Erlangen, Dept Neurosurg, EpiCARE Partner, Erlangen, Germany

[12] Med Univ Vienna, Vienna Gen Hosp, Dept Neurosurg, EpiCARE Partner, Vienna, Austria

[13] Bielefeld Univ, Krankenhaus Mara, Bethel Epilepsy Ctr, Med Sch OWL,Dept Epileptol, Bielefeld, Germany

[14] Bielefeld Univ, Med Sch, Dept Neurosurg, Evangel Klin Bethel, Bielefeld, Germany

[15] Schoen Clin, Ctr Pediat Neurol Neurorehabil & Epileptol, Rosenheim, Germany

[16] Paracelsus Med Univ, Salzburg, Austria

[17] Univ Cologne, Univ Hosp Cologne, Fac Med, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany

[18] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR RECEPTOR; SOMATIC MUTATIONS; REFERENCE PANEL; EPILEPSY; PATHOGENICITY; FREQUENCIES; SYSTEM; CANCER;

D O I：

10.1038/s41467-024-54911-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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