ArticleNeurology. Genetics2022
Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy.
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Article in Neurology. Genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14citing papers in PubMed
3.0field-weighted citation impact, top 8% of its field
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.Progress in neuro-psychopharmacology & biological psychiatry · 2026Article
- The genetic architecture of epilepsy across molecular mechanisms and clinical heterogeneity.Epilepsia open · 2026Review
- Beyond mTOR: Unraveling the Complex Pathophysiology and Signaling Pathways in Focal Cortical Dysplasia.Molecular neurobiology · 2025Review
- Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.medRxiv : the preprint server for health sciences · 2025Article
- ILAE genetic literacy series: Focal cortical dysplasia.Epileptic disorders : international epilepsy journal with videotape · 2025Review
- From Alpha-Thalassemia Trait toGenes · 2024Article
- Review
- Phenotypic and genotypic characterization of NPRL3-related epilepsy: Two case reports and literature review.Epilepsia open · 2024Review
- Refining the electroclinical spectrum of NPRL3-related epilepsy: A novel multiplex family and literature review.Epilepsia open · 2023Review
- Individualised human phenotype ontology gene panels improve clinical whole exome and genome sequencing analytical efficacy in a cohort of developmental and epileptic encephalopathies.Molecular genetics & genomic medicine · 2023Article
- The Power of Clinical Diagnosis for Deciphering Complex Genetic Mechanisms in Rare Diseases.Genes · 2023Review
- Identification of genetic characteristics in pediatric epilepsy with focal cortical dysplasia type 2 using deep whole-exome sequencing.Molecular genetics & genomic medicine · 2022Article
- Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- Identification of two rareFrontiers in genetics · 2022Article
Corrections and comments
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Authors and funding
15 authors at 1 institution in 1 country.
Mark F BennettPopulation 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 https://orcid.org/0000-0002-3561-6804
Michael S HildebrandPopulation 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 KayumiPopulation 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 CorbettPopulation 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 https://orcid.org/0000-0001-9298-3072
Sachin GuptaPopulation 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 YePopulation 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 KrivanekPopulation 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 BurgessPopulation 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 HenryPopulation 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 DamianoPopulation 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 BoysPopulation 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 GéczPopulation 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 https://orcid.org/0000-0002-7884-6861
Melanie BahloPopulation 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 https://orcid.org/0000-0001-5132-0774
Ingrid E SchefferPopulation 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 https://orcid.org/0000-0002-2311-2174
Samuel F BerkovicPopulation 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 https://orcid.org/0000-0003-4580-841X
Walter and Eliza Hall Institute of Medical Research · AU
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
objectivesThe 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.
methodsWe 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.
resultsExome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG; p.Ser17Alafs*70) in DISCUSSION: We identify a pathogenic germline mTOR pathway variant (
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