Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome
Pathogenic variants in the SCN1A gene are associated with a spectrum of epileptic disorders ranging in severity from familial febrile seizures to Dravet syndrome. Large proportions of reported pathogenic variants in SCN1A are annotated as missense variants and are often classified as variants of unc...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2021.761892/full |
| _version_ | 1818402375465959424 |
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| author | Peter Sparber Svetlana Mikhaylova Varvara Galkina Yulia Itkis Mikhail Skoblov |
| author_facet | Peter Sparber Svetlana Mikhaylova Varvara Galkina Yulia Itkis Mikhail Skoblov |
| author_sort | Peter Sparber |
| collection | DOAJ |
| description | Pathogenic variants in the SCN1A gene are associated with a spectrum of epileptic disorders ranging in severity from familial febrile seizures to Dravet syndrome. Large proportions of reported pathogenic variants in SCN1A are annotated as missense variants and are often classified as variants of uncertain significance when no functional data are available. Although loss-of-function variants are associated with a more severe phenotype in SCN1A, the molecular mechanism of single nucleotide variants is often not clear, and genotype-phenotype correlations in SCN1A-related epilepsy remain uncertain. Coding variants can affect splicing by creating novel cryptic splicing sites in exons or by disrupting exonic cis-regulation elements crucial for proper pre-mRNA splicing. Here, we report a novel case of Dravet syndrome caused by an undescribed missense variant, c.4852G>A (p.(Gly1618Ser)). By midigene splicing assay, we demonstrated that the identified variant is in fact splice-affecting. To our knowledge, this is the first report on the functional investigation of a missense variant affecting splicing in Dravet syndrome. |
| first_indexed | 2024-12-14T08:07:22Z |
| format | Article |
| id | doaj.art-df0dac34c2984be0a0c26e318400ea2b |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-14T08:07:22Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-df0dac34c2984be0a0c26e318400ea2b2022-12-21T23:10:08ZengFrontiers Media S.A.Frontiers in Neurology1664-22952021-12-011210.3389/fneur.2021.761892761892Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet SyndromePeter Sparber0Svetlana Mikhaylova1Varvara Galkina2Yulia Itkis3Mikhail Skoblov4Laboratory of Functional Genomics, Research Centre for Medical Genetics, Moscow, RussiaMedical Genetics Department, Russian Children's Clinical Hospital, Moscow, RussiaClinical Department, Research Centre for Medical Genetics, Moscow, RussiaLaboratory of Inherited Metabolic Disorders, Research Centre for Medical Genetics, Moscow, RussiaLaboratory of Functional Genomics, Research Centre for Medical Genetics, Moscow, RussiaPathogenic variants in the SCN1A gene are associated with a spectrum of epileptic disorders ranging in severity from familial febrile seizures to Dravet syndrome. Large proportions of reported pathogenic variants in SCN1A are annotated as missense variants and are often classified as variants of uncertain significance when no functional data are available. Although loss-of-function variants are associated with a more severe phenotype in SCN1A, the molecular mechanism of single nucleotide variants is often not clear, and genotype-phenotype correlations in SCN1A-related epilepsy remain uncertain. Coding variants can affect splicing by creating novel cryptic splicing sites in exons or by disrupting exonic cis-regulation elements crucial for proper pre-mRNA splicing. Here, we report a novel case of Dravet syndrome caused by an undescribed missense variant, c.4852G>A (p.(Gly1618Ser)). By midigene splicing assay, we demonstrated that the identified variant is in fact splice-affecting. To our knowledge, this is the first report on the functional investigation of a missense variant affecting splicing in Dravet syndrome.https://www.frontiersin.org/articles/10.3389/fneur.2021.761892/fullepilepsyDravet syndromemedical geneticsfunctional analysissplicingmolecular pathogenesis |
| spellingShingle | Peter Sparber Svetlana Mikhaylova Varvara Galkina Yulia Itkis Mikhail Skoblov Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome Frontiers in Neurology epilepsy Dravet syndrome medical genetics functional analysis splicing molecular pathogenesis |
| title | Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome |
| title_full | Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome |
| title_fullStr | Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome |
| title_full_unstemmed | Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome |
| title_short | Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome |
| title_sort | case report functional investigation of an undescribed missense variant affecting splicing in a patient with dravet syndrome |
| topic | epilepsy Dravet syndrome medical genetics functional analysis splicing molecular pathogenesis |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2021.761892/full |
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