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Long‐read sequencing of recurrent FGF12 duplications in epilepsy: Insights into structural mechanisms and aberrant isoforms.

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Title: Long‐read sequencing of recurrent FGF12 duplications in epilepsy: Insights into structural mechanisms and aberrant isoforms.
Authors: Fauqueux, Jade (AUTHOR), Chaton, Laurence (AUTHOR), Cleuziou, Pierre (AUTHOR), Diependaële, Anne‐Sophie (AUTHOR), Bach, Nathalie (AUTHOR), Gruchy, Nicolas (AUTHOR), Gerard, Marion (AUTHOR), Meneboo, Jean‐Pascal (AUTHOR), Villenet, Céline (AUTHOR), Figeac, Martin (AUTHOR), Ait‐Yahya, Emilie (AUTHOR), Thuillier, Caroline (AUTHOR), Boudry, Elise (AUTHOR), Trauffler, Adeline (AUTHOR), Nguyen‐The‐Tich, Sylvie (AUTHOR), Boussion, Simon (AUTHOR), Caumes, Roseline (AUTHOR), Ghoumid, Jamal (AUTHOR), Smol, Thomas (AUTHOR)
Source: Epilepsia (Series 4). Dec2025, Vol. 66 Issue 12, p5014-5032. 19p.
Subjects: Epilepsy, Sodium channels, Chromosomal rearrangement, Fibroblast growth factors, Brain diseases, Nucleotide sequencing, Electroencephalography
Abstract: Objective: Fibroblast growth factor 12 (FGF12), a member of the fibroblast homologous factor family, plays a key role in the modulation of voltage‐gated sodium (Nav) channels. Pathogenic variants in the FGF12 gene leading to a gain‐of‐function mechanism and partial duplication encompassing the FGF12 gene leading to a loss‐of‐function mechanism are associated with developmental and epileptic encephalopathy (DEE), characterized by developmental delay, intellectual disability, ataxia, and drug‐resistant epilepsy. We report two patients with DEE harboring de novo recurrent intragenic duplications of FGF12 identified by long‐read sequencing (LRS). Methods: We applied LRS to the DNA and cDNA of patients with FGF12 duplication to fully characterize the DNA's structural organization and its transcriptional consequences. Additionally, we reanalyzed electroencephalographic (EEG) data from patients at different timepoints to identify phenotypical specificities and refine the electroclinical spectrum. Results: These duplications, spanning approximately 536 kbp, were mediated by nonallelic homologous recombination between L1PA2 elements (LINE‐1 Primate‐specific subfamily A, number 2). cDNA analysis revealed aberrant transcripts, one predicted to encode an elongated FGF12 protein and another leading to premature termination. Both patients shared overlapping clinical features, including postepilepsy onset regression, global developmental delay, and ataxia. EEG studies revealed a marked early encephalopathic pattern with disorganized and high‐voltage slow background activity with multifocal spikes at onset evolving later into subcontinuous generalized spike and wave activation. Significance: Our findings are consistent with previous reports linking structural variants to functional disruption, suggesting impaired Nav channel activity due to a shift in inactivation to hyperpolarized potential, leading to a loss‐of‐function effect. These findings underscore the utility of LRS for DNA and cDNA analysis in resolving structural variants and expanding the electroclinical spectrum of patients with FGF12 duplications. [ABSTRACT FROM AUTHOR]
Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Long‐read sequencing of recurrent FGF12 duplications in epilepsy: Insights into structural mechanisms and aberrant isoforms.
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  Data: <searchLink fieldCode="AR" term="%22Fauqueux%2C+Jade%22">Fauqueux, Jade</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chaton%2C+Laurence%22">Chaton, Laurence</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cleuziou%2C+Pierre%22">Cleuziou, Pierre</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Diependaële%2C+Anne‐Sophie%22">Diependaële, Anne‐Sophie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Bach%2C+Nathalie%22">Bach, Nathalie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gruchy%2C+Nicolas%22">Gruchy, Nicolas</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gerard%2C+Marion%22">Gerard, Marion</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Meneboo%2C+Jean‐Pascal%22">Meneboo, Jean‐Pascal</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Villenet%2C+Céline%22">Villenet, Céline</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Figeac%2C+Martin%22">Figeac, Martin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ait‐Yahya%2C+Emilie%22">Ait‐Yahya, Emilie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Thuillier%2C+Caroline%22">Thuillier, Caroline</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Boudry%2C+Elise%22">Boudry, Elise</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Trauffler%2C+Adeline%22">Trauffler, Adeline</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nguyen‐The‐Tich%2C+Sylvie%22">Nguyen‐The‐Tich, Sylvie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Boussion%2C+Simon%22">Boussion, Simon</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Caumes%2C+Roseline%22">Caumes, Roseline</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ghoumid%2C+Jamal%22">Ghoumid, Jamal</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Smol%2C+Thomas%22">Smol, Thomas</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Epilepsia+%28Series+4%29%22">Epilepsia (Series 4)</searchLink>. Dec2025, Vol. 66 Issue 12, p5014-5032. 19p.
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  Data: <searchLink fieldCode="DE" term="%22Epilepsy%22">Epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22Sodium+channels%22">Sodium channels</searchLink><br /><searchLink fieldCode="DE" term="%22Chromosomal+rearrangement%22">Chromosomal rearrangement</searchLink><br /><searchLink fieldCode="DE" term="%22Fibroblast+growth+factors%22">Fibroblast growth factors</searchLink><br /><searchLink fieldCode="DE" term="%22Brain+diseases%22">Brain diseases</searchLink><br /><searchLink fieldCode="DE" term="%22Nucleotide+sequencing%22">Nucleotide sequencing</searchLink><br /><searchLink fieldCode="DE" term="%22Electroencephalography%22">Electroencephalography</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Objective: Fibroblast growth factor 12 (FGF12), a member of the fibroblast homologous factor family, plays a key role in the modulation of voltage‐gated sodium (Nav) channels. Pathogenic variants in the FGF12 gene leading to a gain‐of‐function mechanism and partial duplication encompassing the FGF12 gene leading to a loss‐of‐function mechanism are associated with developmental and epileptic encephalopathy (DEE), characterized by developmental delay, intellectual disability, ataxia, and drug‐resistant epilepsy. We report two patients with DEE harboring de novo recurrent intragenic duplications of FGF12 identified by long‐read sequencing (LRS). Methods: We applied LRS to the DNA and cDNA of patients with FGF12 duplication to fully characterize the DNA's structural organization and its transcriptional consequences. Additionally, we reanalyzed electroencephalographic (EEG) data from patients at different timepoints to identify phenotypical specificities and refine the electroclinical spectrum. Results: These duplications, spanning approximately 536 kbp, were mediated by nonallelic homologous recombination between L1PA2 elements (LINE‐1 Primate‐specific subfamily A, number 2). cDNA analysis revealed aberrant transcripts, one predicted to encode an elongated FGF12 protein and another leading to premature termination. Both patients shared overlapping clinical features, including postepilepsy onset regression, global developmental delay, and ataxia. EEG studies revealed a marked early encephalopathic pattern with disorganized and high‐voltage slow background activity with multifocal spikes at onset evolving later into subcontinuous generalized spike and wave activation. Significance: Our findings are consistent with previous reports linking structural variants to functional disruption, suggesting impaired Nav channel activity due to a shift in inactivation to hyperpolarized potential, leading to a loss‐of‐function effect. These findings underscore the utility of LRS for DNA and cDNA analysis in resolving structural variants and expanding the electroclinical spectrum of patients with FGF12 duplications. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=190718457
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        Value: 10.1111/epi.18609
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        Text: English
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      – SubjectFull: Epilepsy
        Type: general
      – SubjectFull: Sodium channels
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      – SubjectFull: Chromosomal rearrangement
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      – SubjectFull: Fibroblast growth factors
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      – SubjectFull: Brain diseases
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      – SubjectFull: Nucleotide sequencing
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      – SubjectFull: Electroencephalography
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              Text: Dec2025
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