A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy

Purpose: We present the case of 2 siblings with profound refractory epilepsy and neurological regression that began at the ages of 3 and 6 months. Diagnosis remained elusive despite extensive metabolic and genetic workups, including use of a targeted next-generation sequencing panel for epilepsy gen...

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Autores: Fernández-Marmiesse A, Sánchez-Iglesias S, Darling A, O'Callaghan MM, Tonda R, Jou C, Araújo-Vilar D
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p16496
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=16496
Access Level:acceso abierto
Palabra clave:Whole exome sequencing
BSCL2
Seipin
Early infantile epileptic encephalopathy
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spelling A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathyFernández-Marmiesse ASánchez-Iglesias SDarling AO'Callaghan MMTonda RJou CAraújo-Vilar DWhole exome sequencingBSCL2SeipinEarly infantile epileptic encephalopathyPurpose: We present the case of 2 siblings with profound refractory epilepsy and neurological regression that began at the ages of 3 and 6 months. Diagnosis remained elusive despite extensive metabolic and genetic workups, including use of a targeted next-generation sequencing panel for epilepsy genes. Methods: Whole-exome sequencing was performed for the 2 siblings and their unaffected parents, in addition to fibroblast cell culture, RNA extraction and reverse-transcription, and cDNA PCR. Brain tissue from one of the siblings was collected post-mortem for neuropathological examination, including histology and immunohistochemistry. Results: Ade novo nucleotide change (c.566 T > A; p.(Met189Lys)) in exon 4 of the BSCL2 gene was detected in the 2 siblings, and confirmed by Sanger sequencing. This variant was absent in the parents and in a third, unaffected sibling. Conclusion: Given thede novo nature of the variant, its absence from public and in-house databases, our in silico pathogenicity predictions, and co-segregation of the variant with the disease phenotype, we believe that this novel variant is associated with the epileptic encephalopathy phenotype of the 2 siblings. Our findings provide the first evidence of an association between a heterozygous BSCL2 variant and developmental and early infantile epileptic encephalopathy. Further functional studies will be needed to elucidate the pathophysiological mechanisms underlying this new BSCL2-associated phenotype.W B SAUNDERS CO LTD2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=16496SEIZURE-EUROPEAN JOURNAL OF EPILEPSYISSN: 10591311ISSNe: 15322688reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p164962026-05-27T12:37:41Z
dc.title.none.fl_str_mv A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy
title A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy
spellingShingle A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy
Fernández-Marmiesse A
Whole exome sequencing
BSCL2
Seipin
Early infantile epileptic encephalopathy
title_short A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy
title_full A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy
title_fullStr A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy
title_full_unstemmed A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy
title_sort A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy
dc.creator.none.fl_str_mv Fernández-Marmiesse A
Sánchez-Iglesias S
Darling A
O'Callaghan MM
Tonda R
Jou C
Araújo-Vilar D
author Fernández-Marmiesse A
author_facet Fernández-Marmiesse A
Sánchez-Iglesias S
Darling A
O'Callaghan MM
Tonda R
Jou C
Araújo-Vilar D
author_role author
author2 Sánchez-Iglesias S
Darling A
O'Callaghan MM
Tonda R
Jou C
Araújo-Vilar D
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Whole exome sequencing
BSCL2
Seipin
Early infantile epileptic encephalopathy
topic Whole exome sequencing
BSCL2
Seipin
Early infantile epileptic encephalopathy
description Purpose: We present the case of 2 siblings with profound refractory epilepsy and neurological regression that began at the ages of 3 and 6 months. Diagnosis remained elusive despite extensive metabolic and genetic workups, including use of a targeted next-generation sequencing panel for epilepsy genes. Methods: Whole-exome sequencing was performed for the 2 siblings and their unaffected parents, in addition to fibroblast cell culture, RNA extraction and reverse-transcription, and cDNA PCR. Brain tissue from one of the siblings was collected post-mortem for neuropathological examination, including histology and immunohistochemistry. Results: Ade novo nucleotide change (c.566 T > A; p.(Met189Lys)) in exon 4 of the BSCL2 gene was detected in the 2 siblings, and confirmed by Sanger sequencing. This variant was absent in the parents and in a third, unaffected sibling. Conclusion: Given thede novo nature of the variant, its absence from public and in-house databases, our in silico pathogenicity predictions, and co-segregation of the variant with the disease phenotype, we believe that this novel variant is associated with the epileptic encephalopathy phenotype of the 2 siblings. Our findings provide the first evidence of an association between a heterozygous BSCL2 variant and developmental and early infantile epileptic encephalopathy. Further functional studies will be needed to elucidate the pathophysiological mechanisms underlying this new BSCL2-associated phenotype.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=16496
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=16496
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv W B SAUNDERS CO LTD
publisher.none.fl_str_mv W B SAUNDERS CO LTD
dc.source.none.fl_str_mv SEIZURE-EUROPEAN JOURNAL OF EPILEPSY
ISSN: 10591311
ISSNe: 15322688
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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