Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy.

Journal

Neurology. Genetics
ISSN: 2376-7839
Titre abrégé: Neurol Genet
Pays: United States
ID NLM: 101671068

Informations de publication

Date de publication:
Feb 2022
Historique:
received: 20 08 2021
accepted: 03 12 2021
entrez: 31 1 2022
pubmed: 1 2 2022
medline: 1 2 2022
Statut: epublish

Résumé

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. 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. Exome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG; p.Ser17Alafs*70) in We identify a pathogenic germline mTOR pathway variant (

Sections du résumé

BACKGROUND AND OBJECTIVES OBJECTIVE
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 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 RESULTS
Exome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG; p.Ser17Alafs*70) in
DISCUSSION CONCLUSIONS
We identify a pathogenic germline mTOR pathway variant (

Identifiants

DOI: 10.1212/NXG.0000000000000652 PMID: 35097204 PMC: PMC8789218
pubmed: 35097204
doi: 10.1212/NXG.0000000000000652
pii: NG2021017195
pmc: PMC8789218
doi:

Types de publication

Journal Article

Langues

eng

Pagination

e652

Informations de copyright

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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Auteurs

Mark F Bennett (MF)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.
ORCID: 0000-0002-3561-6804

Michael S Hildebrand (MS)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.

Sayaka Kayumi (S)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.

Mark A Corbett (MA)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.
ORCID: 0000-0001-9298-3072

Sachin Gupta (S)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.

Zimeng Ye (Z)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.

Michael Krivanek (M)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.

Rosemary Burgess (R)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.

Olivia J Henry (OJ)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.

John A Damiano (JA)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.

Amber Boys (A)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.

Jozef Gécz (J)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.
ORCID: 0000-0002-7884-6861

Melanie Bahlo (M)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.
ORCID: 0000-0001-5132-0774

Ingrid E Scheffer (IE)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.
ORCID: 0000-0002-2311-2174

Samuel F Berkovic (SF)

Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), The University of Melbourne, Parkville; Epilepsy Research Centre (M.F.B., M.S.H., Z.Y., R.B., O.J.H., J.A.D., I.E.S., S.F.B.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Murdoch Children's Research Institute (M.S.H., I.E.S.), Royal Children's Hospital, Parkville; Robinson Research Institute and Adelaide Medical School (S.K., M.A.C., J.G.), The University of Adelaide, South Australia; TY Nelson Department of Neurology and Neurosurgery (S.G.), The Children's Hospital at Westmead; Department of Histopathology (M.K.), The Children's Hospital at Westmead, New South Wales; Victorian Clinical Genetics Services (A.B.), Murdoch Children's Research Institute, Parkville, Victoria; South Australian Health and Medical Research Institute (J.G.), Adelaide, South Australia; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital; and The Florey Institute (I.E.S.), Parkville, Victoria, Australia.
ORCID: 0000-0003-4580-841X

Classifications MeSH