Structural genomic variation in childhood epilepsies with complex phenotypes

Ingo Helbig; Marielle E M Swinkels; Emmelien Aten; Almuth Caliebe; Ruben van 't Slot; Rainer Boor; Sarah von Spiczak; Hiltrud Muhle; Johanna A Jähn; Ellen van Binsbergen; Onno van Nieuwenhuizen; Floor E Jansen; Kees P J Braun; Gerrit-Jan de Haan; Niels Tommerup; Ulrich Stephani; Helle Hjalgrim; Martin Poot; Dick Lindhout; Eva H Brilstra; Rikke S Møller; Bobby P C Koeleman

doi:10.1038/ejhg.2013.262

Structural genomic variation in childhood epilepsies with complex phenotypes

Ingo Helbig, Marielle E M Swinkels, Emmelien Aten, Almuth Caliebe, Ruben van 't Slot, Rainer Boor, Sarah von Spiczak, Hiltrud Muhle, Johanna A Jähn, Ellen van Binsbergen, Onno van Nieuwenhuizen, Floor E Jansen, Kees P J Braun, Gerrit-Jan de Haan, Niels Tommerup, Ulrich Stephani, Helle Hjalgrim, Martin Poot, Dick Lindhout, Eva H BrilstraRikke S Møller, Bobby P C Koeleman

Medical Genetics Program

20 Citations (Scopus)

Abstract

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.

Original language	English
Journal	European Journal of Human Genetics
Volume	22
Issue number	7
Pages (from-to)	896-901
Number of pages	6
ISSN	1018-4813
DOIs	https://doi.org/10.1038/ejhg.2013.262
Publication status	Published - Jul 2014

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Helbig, I., Swinkels, M. E. M., Aten, E., Caliebe, A., van 't Slot, R., Boor, R., von Spiczak, S., Muhle, H., Jähn, J. A., van Binsbergen, E., van Nieuwenhuizen, O., Jansen, F. E., Braun, K. P. J., de Haan, G-J., Tommerup, N., Stephani, U., Hjalgrim, H., Poot, M., Lindhout, D., ... Koeleman, B. P. C. (2014). Structural genomic variation in childhood epilepsies with complex phenotypes. European Journal of Human Genetics, 22(7), 896-901. https://doi.org/10.1038/ejhg.2013.262

Helbig, I, Swinkels, MEM, Aten, E, Caliebe, A, van 't Slot, R, Boor, R, von Spiczak, S, Muhle, H, Jähn, JA, van Binsbergen, E, van Nieuwenhuizen, O, Jansen, FE, Braun, KPJ, de Haan, G-J, Tommerup, N, Stephani, U, Hjalgrim, H, Poot, M, Lindhout, D, Brilstra, EH, Møller, RS & Koeleman, BPC 2014, 'Structural genomic variation in childhood epilepsies with complex phenotypes', European Journal of Human Genetics, vol. 22, no. 7, pp. 896-901. https://doi.org/10.1038/ejhg.2013.262

@article{299823c1c7b44384a84d8db171df1588,

title = "Structural genomic variation in childhood epilepsies with complex phenotypes",

abstract = "A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.",

author = "Ingo Helbig and Swinkels, {Marielle E M} and Emmelien Aten and Almuth Caliebe and {van 't Slot}, Ruben and Rainer Boor and {von Spiczak}, Sarah and Hiltrud Muhle and J{\"a}hn, {Johanna A} and {van Binsbergen}, Ellen and {van Nieuwenhuizen}, Onno and Jansen, {Floor E} and Braun, {Kees P J} and {de Haan}, Gerrit-Jan and Niels Tommerup and Ulrich Stephani and Helle Hjalgrim and Martin Poot and Dick Lindhout and Brilstra, {Eva H} and M{\o}ller, {Rikke S} and Koeleman, {Bobby P C}",

year = "2014",

month = jul,

doi = "10.1038/ejhg.2013.262",

language = "English",

volume = "22",

pages = "896--901",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

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T1 - Structural genomic variation in childhood epilepsies with complex phenotypes

AU - Helbig, Ingo

AU - Swinkels, Marielle E M

AU - Aten, Emmelien

AU - Caliebe, Almuth

AU - van 't Slot, Ruben

AU - Boor, Rainer

AU - von Spiczak, Sarah

AU - Muhle, Hiltrud

AU - Jähn, Johanna A

AU - van Binsbergen, Ellen

AU - van Nieuwenhuizen, Onno

AU - Jansen, Floor E

AU - Braun, Kees P J

AU - de Haan, Gerrit-Jan

AU - Tommerup, Niels

AU - Stephani, Ulrich

AU - Hjalgrim, Helle

AU - Poot, Martin

AU - Lindhout, Dick

AU - Brilstra, Eva H

AU - Møller, Rikke S

AU - Koeleman, Bobby P C

PY - 2014/7

Y1 - 2014/7

N2 - A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.

AB - A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.

U2 - 10.1038/ejhg.2013.262

DO - 10.1038/ejhg.2013.262

M3 - Journal article

C2 - 24281369

SN - 1018-4813

VL - 22

SP - 896

EP - 901

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 7

ER -

Structural genomic variation in childhood epilepsies with complex phenotypes

Abstract

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