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Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients
BACKGROUND: Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation. METHODS: To increase the number of validated EE gene...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023942/ https://www.ncbi.nlm.nih.gov/pubmed/27652284 http://dx.doi.org/10.1002/mgg3.235 |
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author | de Kovel, Carolien G.F. Brilstra, Eva H. van Kempen, Marjan J.A. van‘t Slot, Ruben Nijman, Isaac J. Afawi, Zaid De Jonghe, Peter Djémié, Tania Guerrini, Renzo Hardies, Katia Helbig, Ingo Hendrickx, Rik Kanaan, Moine Kramer, Uri Lehesjoki, Anna‐Elina E. Lemke, Johannes R. Marini, Carla Mei, Davide Møller, Rikke S. Pendziwiat, Manuela Stamberger, Hannah Suls, Arvid Weckhuysen, Sarah Koeleman, Bobby P.C. R, Balling N, Barisic S, Baulac HS, Caglayan DC, Craiu C, Depienne P, Gormley H, Hjalgrim D, Hoffman‐Zacharska J, Jähn KM, Klein V, Komarek E, LeGuern H, Lerche P, May H, Muhle D, Pal A, Palotie F, Rosenow K, Selmer JM, Serratosa SM, Sisodiya U, Stephani K, Sterbova P, Striano T, Talvik M, van Haelst N, Verbeek S, von Spiczak YG, Weber |
author_facet | de Kovel, Carolien G.F. Brilstra, Eva H. van Kempen, Marjan J.A. van‘t Slot, Ruben Nijman, Isaac J. Afawi, Zaid De Jonghe, Peter Djémié, Tania Guerrini, Renzo Hardies, Katia Helbig, Ingo Hendrickx, Rik Kanaan, Moine Kramer, Uri Lehesjoki, Anna‐Elina E. Lemke, Johannes R. Marini, Carla Mei, Davide Møller, Rikke S. Pendziwiat, Manuela Stamberger, Hannah Suls, Arvid Weckhuysen, Sarah Koeleman, Bobby P.C. R, Balling N, Barisic S, Baulac HS, Caglayan DC, Craiu C, Depienne P, Gormley H, Hjalgrim D, Hoffman‐Zacharska J, Jähn KM, Klein V, Komarek E, LeGuern H, Lerche P, May H, Muhle D, Pal A, Palotie F, Rosenow K, Selmer JM, Serratosa SM, Sisodiya U, Stephani K, Sterbova P, Striano T, Talvik M, van Haelst N, Verbeek S, von Spiczak YG, Weber |
author_sort | de Kovel, Carolien G.F. |
collection | PubMed |
description | BACKGROUND: Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation. METHODS: To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes. RESULTS: Twenty‐nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X‐linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X‐linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed‐up candidate genes, and the patient's phenotype was similar to a few recent publications. CONCLUSION: Mutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss‐of‐function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life. |
format | Online Article Text |
id | pubmed-5023942 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-50239422016-09-20 Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients de Kovel, Carolien G.F. Brilstra, Eva H. van Kempen, Marjan J.A. van‘t Slot, Ruben Nijman, Isaac J. Afawi, Zaid De Jonghe, Peter Djémié, Tania Guerrini, Renzo Hardies, Katia Helbig, Ingo Hendrickx, Rik Kanaan, Moine Kramer, Uri Lehesjoki, Anna‐Elina E. Lemke, Johannes R. Marini, Carla Mei, Davide Møller, Rikke S. Pendziwiat, Manuela Stamberger, Hannah Suls, Arvid Weckhuysen, Sarah Koeleman, Bobby P.C. R, Balling N, Barisic S, Baulac HS, Caglayan DC, Craiu C, Depienne P, Gormley H, Hjalgrim D, Hoffman‐Zacharska J, Jähn KM, Klein V, Komarek E, LeGuern H, Lerche P, May H, Muhle D, Pal A, Palotie F, Rosenow K, Selmer JM, Serratosa SM, Sisodiya U, Stephani K, Sterbova P, Striano T, Talvik M, van Haelst N, Verbeek S, von Spiczak YG, Weber Mol Genet Genomic Med Original Articles BACKGROUND: Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation. METHODS: To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes. RESULTS: Twenty‐nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X‐linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X‐linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed‐up candidate genes, and the patient's phenotype was similar to a few recent publications. CONCLUSION: Mutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss‐of‐function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life. John Wiley and Sons Inc. 2016-07-30 /pmc/articles/PMC5023942/ /pubmed/27652284 http://dx.doi.org/10.1002/mgg3.235 Text en © 2016 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles de Kovel, Carolien G.F. Brilstra, Eva H. van Kempen, Marjan J.A. van‘t Slot, Ruben Nijman, Isaac J. Afawi, Zaid De Jonghe, Peter Djémié, Tania Guerrini, Renzo Hardies, Katia Helbig, Ingo Hendrickx, Rik Kanaan, Moine Kramer, Uri Lehesjoki, Anna‐Elina E. Lemke, Johannes R. Marini, Carla Mei, Davide Møller, Rikke S. Pendziwiat, Manuela Stamberger, Hannah Suls, Arvid Weckhuysen, Sarah Koeleman, Bobby P.C. R, Balling N, Barisic S, Baulac HS, Caglayan DC, Craiu C, Depienne P, Gormley H, Hjalgrim D, Hoffman‐Zacharska J, Jähn KM, Klein V, Komarek E, LeGuern H, Lerche P, May H, Muhle D, Pal A, Palotie F, Rosenow K, Selmer JM, Serratosa SM, Sisodiya U, Stephani K, Sterbova P, Striano T, Talvik M, van Haelst N, Verbeek S, von Spiczak YG, Weber Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients |
title | Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients |
title_full | Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients |
title_fullStr | Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients |
title_full_unstemmed | Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients |
title_short | Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients |
title_sort | targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023942/ https://www.ncbi.nlm.nih.gov/pubmed/27652284 http://dx.doi.org/10.1002/mgg3.235 |
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