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Title: Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy.
Austin Authors: Bennett, Mark F ;Hildebrand, Michael S ;Kayumi, Sayaka;Corbett, Mark A;Gupta, Sachin;Ye, Zimeng;Krivanek, Michael;Burgess, Rosemary;Henry, Olivia J;Damiano, John A;Boys, Amber;Gécz, Jozef;Bahlo, Melanie;Scheffer, Ingrid E ;Berkovic, Samuel F 
Affiliation: The Florey Institute of Neuroscience and Mental Health
Epilepsy Research Centre
Medicine (University of Melbourne)
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville
Robinson Research Institute and Adelaide Medical School, The University of Adelaide, South Australia
TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead
Department of Histopathology, The Children's Hospital at Westmead, New South Wales
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria
South Australian Health and Medical Research Institute, Adelaide, South Australia
Department of Paediatrics, The University of Melbourne, Royal Children's Hospital
Department of Medical Biology, The University of Melbourne, Parkville
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research
Issue Date: 2022
Date: 2022
Publication information: Neurology. Genetics 2022; 8(1): e652
Abstract: 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 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. 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.
DOI: 10.1212/NXG.0000000000000652
Journal: Neurology. Genetics
PubMed URL: 35097204
ISSN: 2376-7839
Type: Journal Article
Appears in Collections:Journal articles

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