Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients

Carolien G F de Kovel, Eva H Brilstra, Marjan J A van Kempen, Ruben Van't Slot, Isaac J Nijman, Zaid Afawi, Peter De Jonghe, Tania Djémié, Renzo Guerrini, Katia Hardies, Ingo Helbig, Rik Hendrickx, Moine Kanaan, Uri Kramer, Anna-Elina E Lehesjoki, Johannes R Lemke, Carla Marini, Davide Mei, Rikke Steensbjerre Møller, Manuela PendziwiatHannah Stamberger, Arvid Suls, Sarah Weckhuysen, Bobby P C Koeleman, EuroEPINOMICS RES Consortium

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Resumé

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.

OriginalsprogEngelsk
TidsskriftMolecular Genetics & Genomic Medicine
Vol/bind4
Udgave nummer5
Sider (fra-til)568-580
ISSN2324-9269
DOI
StatusUdgivet - sep. 2016

Fingeraftryk

Febrile Seizures
X-Linked Genes
Mutation

Citer dette

de Kovel, C. G. F., Brilstra, E. H., van Kempen, M. J. A., Van't Slot, R., Nijman, I. J., Afawi, Z., ... EuroEPINOMICS RES Consortium (2016). Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. Molecular Genetics & Genomic Medicine, 4(5), 568-580. https://doi.org/10.1002/mgg3.235
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 Steensbjerre ; Pendziwiat, Manuela ; Stamberger, Hannah ; Suls, Arvid ; Weckhuysen, Sarah ; Koeleman, Bobby P C ; EuroEPINOMICS RES Consortium. / Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. I: Molecular Genetics & Genomic Medicine. 2016 ; Bind 4, Nr. 5. s. 568-580.
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title = "Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients",
abstract = "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.",
author = "{de Kovel}, {Carolien G F} and Brilstra, {Eva H} and {van Kempen}, {Marjan J A} and {Van't Slot}, Ruben and Nijman, {Isaac J} and Zaid Afawi and {De Jonghe}, Peter and Tania Dj{\'e}mi{\'e} and Renzo Guerrini and Katia Hardies and Ingo Helbig and Rik Hendrickx and Moine Kanaan and Uri Kramer and Lehesjoki, {Anna-Elina E} and Lemke, {Johannes R} and Carla Marini and Davide Mei and M{\o}ller, {Rikke Steensbjerre} and Manuela Pendziwiat and Hannah Stamberger and Arvid Suls and Sarah Weckhuysen and Koeleman, {Bobby P C} and {EuroEPINOMICS RES Consortium}",
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journal = "Molecular Genetics & Genomic Medicine",
issn = "2324-9269",
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de Kovel, CGF, Brilstra, EH, van Kempen, MJA, Van't Slot, R, Nijman, IJ, Afawi, Z, De Jonghe, P, Djémié, T, Guerrini, R, Hardies, K, Helbig, I, Hendrickx, R, Kanaan, M, Kramer, U, Lehesjoki, A-EE, Lemke, JR, Marini, C, Mei, D, Møller, RS, Pendziwiat, M, Stamberger, H, Suls, A, Weckhuysen, S, Koeleman, BPC & EuroEPINOMICS RES Consortium 2016, 'Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients', Molecular Genetics & Genomic Medicine, bind 4, nr. 5, s. 568-580. https://doi.org/10.1002/mgg3.235

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 Steensbjerre; Pendziwiat, Manuela; Stamberger, Hannah; Suls, Arvid; Weckhuysen, Sarah; Koeleman, Bobby P C; EuroEPINOMICS RES Consortium.

I: Molecular Genetics & Genomic Medicine, Bind 4, Nr. 5, 09.2016, s. 568-580.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients

AU - de Kovel, Carolien G F

AU - Brilstra, Eva H

AU - van Kempen, Marjan J A

AU - Van't Slot, Ruben

AU - Nijman, Isaac J

AU - Afawi, Zaid

AU - De Jonghe, Peter

AU - Djémié, Tania

AU - Guerrini, Renzo

AU - Hardies, Katia

AU - Helbig, Ingo

AU - Hendrickx, Rik

AU - Kanaan, Moine

AU - Kramer, Uri

AU - Lehesjoki, Anna-Elina E

AU - Lemke, Johannes R

AU - Marini, Carla

AU - Mei, Davide

AU - Møller, Rikke Steensbjerre

AU - Pendziwiat, Manuela

AU - Stamberger, Hannah

AU - Suls, Arvid

AU - Weckhuysen, Sarah

AU - Koeleman, Bobby P C

AU - EuroEPINOMICS RES Consortium

PY - 2016/9

Y1 - 2016/9

N2 - 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.

AB - 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.

U2 - 10.1002/mgg3.235

DO - 10.1002/mgg3.235

M3 - Journal article

C2 - 27652284

VL - 4

SP - 568

EP - 580

JO - Molecular Genetics & Genomic Medicine

JF - Molecular Genetics & Genomic Medicine

SN - 2324-9269

IS - 5

ER -