Evidence for a dual-pathway, 2-hit genetic model for focal cortical dysplasia and epilepsy

Files

hdl_134592.pdf (863.09 KB)
  (Published version)

Date

2022

Authors

Bennett, M.F.
Hildebrand, M.S.
Kayumi, S.
Corbett, M.A.
Gupta, S.
Ye, Z.
Krivanek, M.
Burgess, R.
Henry, O.J.
Damiano, J.A.

Editors

Advisors

Journal Title

Journal ISSN

Volume Title

Type:

Journal article

Citation

Neurology: Genetics, 2022; 8(1):e0652-1-e0652-11

Statement of Responsibility

Mark F. Bennett, Michael S. Hildebrand, Sayaka Kayumi, Mark A. Corbett, Sachin Gupta, Zimeng Ye, Michael Krivanek, Rosemary Burgess, Olivia J. Henry, John A. Damiano, Amber Boys, Jozef Gécz, Melanie Bahlo, Ingrid E. Scheffer, and Samuel F. Berkovic

Conference Name

DOI

10.1212/NXG.0000000000000652

Abstract

Background and Objectives: The 2-hit model of genetic disease is well established in cancer, yet has only recently been reported to cause brain malformations associated with epilepsy. Pathogenic germline and somatic variants in genes in the mechanistic target of rapamycin (mTOR) pathway have been implicated in several malformations of cortical development. We investigated the 2-hit model by performing genetic analysis and searching for germline and somatic variants in genes in the mTOR and related pathways. Methods: We searched for germline and somatic pathogenic variants in 2 brothers with drug-resistant focal epilepsy and surgically resected focal cortical dysplasia (FCD) type IIA. Exome sequencing was performed on blood- and brain-derived DNA to identify pathogenic variants, which were validated by droplet digital PCR. In vitro functional assays of a somatic variant were performed. Results: Exome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG; p.Ser17Alafs*70) in NPRL3 in both brothers. NPRL3 is a known FCD gene that encodes a negative regulator of the mTOR pathway. Somatic variant calling in brain-derived DNA from both brothers revealed a low allele fraction somatic variant (c.338C>T; p.Ala113Val) in the WNT2 gene in 1 brother, confirmed by droplet digital PCR. In vitro functional studies suggested a loss of WNT2 function as a consequence of this variant. A second somatic variant has not yet been found in the other brother. Discussion: We identify a pathogenic germline mTOR pathway variant (NPRL3) and a somatic variant (WNT2) in the intersecting WNT signaling pathway, potentially implicating the WNT2 gene in FCD and supporting a dual-pathway 2-hit model. If confirmed in other cases, this would extend the 2-hit model to pathogenic variants in different genes in critical, intersecting pathways in a malformation of cortical development. Detection of low allele fraction somatic second hits is challenging but promises to unravel the molecular architecture of FCDs.

School/Discipline

Dissertation Note

Provenance

Description

Access Status

Rights

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

License

Grant ID

http://purl.org/au-research/grants/nhmrc/1054618
 http://purl.org/au-research/grants/nhmrc/1091593
 http://purl.org/au-research/grants/nhmrc/1079058
 http://purl.org/au-research/grants/nhmrc/1129054
 http://purl.org/au-research/grants/nhmrc/1102971
 http://purl.org/au-research/grants/nhmrc/1104831
 http://purl.org/au-research/grants/nhmrc/GNT1155224
 http://purl.org/au-research/grants/nhmrc/1063799

Published Version

https://doi.org/10.1212/nxg.0000000000000652

Call number

Persistent link to this record

https://hdl.handle.net/2440/134592