De novo variants in neurodevelopmental disorders with epilepsy

Henrike O. Heyne; Tarjinder Singh; Hannah Stamberger; Rami Abou Jamra; Hande Caglayan; Dana Craiu; Peter De Jonghe; Renzo Guerrini; Katherine L. Helbig; Bobby P.C. Koeleman; Jack A. Kosmicki; Tarja Linnankivi; Patrick May; Hiltrud Muhle; Rikke S. Møller; Bernd A. Neubauer; Aarno Palotie; Manuela Pendziwiat; Pasquale Striano; Sha Tang; Sitao Wu; EuroEPINOMICS RES Consortium; Zaid Afawi; Carolien De Kovel; Petia Dimova; Tania Djémié; Milda Endziniene; Dorota Hoffman-Zacharska; Johanna Jähn; Christian Korff; Anna Elina Lehesjoki; Carla Marini; Stefanie H. Müller; Deb Pal; Niklas Schwarz; Kaja Selmer; Jose Serratosa; Ulrich Stephani; Katalin Štěrbová; Arvid Suls; Steffen Syrbe; Inga Talvik; Shan Tang; Sarah Von Spiczak; Federico Zara; Annapurna Poduri; Yvonne G. Weber; Sarah Weckhuysen; Sanjay M. Sisodiya; Mark J. Daly; Ingo Helbig

doi:10.1038/s41588-018-0143-7

De novo variants in neurodevelopmental disorders with epilepsy

Henrike O. Heyne^*, Tarjinder Singh, Hannah Stamberger, Rami Abou Jamra, Hande Caglayan, Dana Craiu, Peter De Jonghe, Renzo Guerrini, Katherine L. Helbig, Bobby P.C. Koeleman, Jack A. Kosmicki, Tarja Linnankivi, Patrick May, Hiltrud Muhle, Rikke S. Møller, Bernd A. Neubauer, Aarno Palotie, Manuela Pendziwiat, Pasquale Striano, Sha TangSitao Wu, EuroEPINOMICS RES Consortium, Zaid Afawi, Carolien De Kovel, Petia Dimova, Tania Djémié, Milda Endziniene, Dorota Hoffman-Zacharska, Johanna Jähn, Christian Korff, Anna Elina Lehesjoki, Carla Marini, Stefanie H. Müller, Deb Pal, Niklas Schwarz, Kaja Selmer, Jose Serratosa, Ulrich Stephani, Katalin Štěrbová, Arvid Suls, Steffen Syrbe, Inga Talvik, Shan Tang, Sarah Von Spiczak, Federico Zara, Annapurna Poduri, Yvonne G. Weber, Sarah Weckhuysen, Sanjay M. Sisodiya, Mark J. Daly, Ingo Helbig

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

205 Citations (Scopus)

Abstract

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.

Original language	English
Pages (from-to)	1048-1053
Number of pages	6
Journal	Nature Genetics
Volume	50
Issue number	7
Early online date	25 Jun 2018
DOIs	https://doi.org/10.1038/s41588-018-0143-7
Publication status	Published - 1 Jul 2018

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Heyne, H. O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Møller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., ... Helbig, I. (2018). De novo variants in neurodevelopmental disorders with epilepsy. Nature Genetics, 50(7), 1048-1053. https://doi.org/10.1038/s41588-018-0143-7

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title = "De novo variants in neurodevelopmental disorders with epilepsy",

abstract = "Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.",

author = "Heyne, {Henrike O.} and Tarjinder Singh and Hannah Stamberger and {Abou Jamra}, Rami and Hande Caglayan and Dana Craiu and {De Jonghe}, Peter and Renzo Guerrini and Helbig, {Katherine L.} and Koeleman, {Bobby P.C.} and Kosmicki, {Jack A.} and Tarja Linnankivi and Patrick May and Hiltrud Muhle and M{\o}ller, {Rikke S.} and Neubauer, {Bernd A.} and Aarno Palotie and Manuela Pendziwiat and Pasquale Striano and Sha Tang and Sitao Wu and {EuroEPINOMICS RES Consortium} and Zaid Afawi and {De Kovel}, Carolien and Petia Dimova and Tania Dj{\'e}mi{\'e} and Milda Endziniene and Dorota Hoffman-Zacharska and Johanna J{\"a}hn and Christian Korff and Lehesjoki, {Anna Elina} and Carla Marini and M{\"u}ller, {Stefanie H.} and Deb Pal and Niklas Schwarz and Kaja Selmer and Jose Serratosa and Ulrich Stephani and Katalin {\v S}t{\v e}rbov{\'a} and Arvid Suls and Steffen Syrbe and Inga Talvik and Shan Tang and {Von Spiczak}, Sarah and Federico Zara and Annapurna Poduri and Weber, {Yvonne G.} and Sarah Weckhuysen and Sisodiya, {Sanjay M.} and Daly, {Mark J.} and Ingo Helbig",

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doi = "10.1038/s41588-018-0143-7",

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Heyne, HO, Singh, T, Stamberger, H, Abou Jamra, R, Caglayan, H, Craiu, D, De Jonghe, P, Guerrini, R, Helbig, KL, Koeleman, BPC, Kosmicki, JA, Linnankivi, T, May, P, Muhle, H, Møller, RS, Neubauer, BA, Palotie, A, Pendziwiat, M, Striano, P, Tang, S, Wu, S, EuroEPINOMICS RES Consortium, Afawi, Z, De Kovel, C, Dimova, P, Djémié, T, Endziniene, M, Hoffman-Zacharska, D, Jähn, J, Korff, C, Lehesjoki, AE, Marini, C, Müller, SH, Pal, D, Schwarz, N, Selmer, K, Serratosa, J, Stephani, U, Štěrbová, K, Suls, A, Syrbe, S, Talvik, I, Tang, S, Von Spiczak, S, Zara, F, Poduri, A, Weber, YG, Weckhuysen, S, Sisodiya, SM, Daly, MJ & Helbig, I 2018, 'De novo variants in neurodevelopmental disorders with epilepsy', Nature Genetics, vol. 50, no. 7, pp. 1048-1053. https://doi.org/10.1038/s41588-018-0143-7

TY - JOUR

T1 - De novo variants in neurodevelopmental disorders with epilepsy

AU - Heyne, Henrike O.

AU - Singh, Tarjinder

AU - Stamberger, Hannah

AU - Abou Jamra, Rami

AU - Caglayan, Hande

AU - Craiu, Dana

AU - De Jonghe, Peter

AU - Guerrini, Renzo

AU - Helbig, Katherine L.

AU - Koeleman, Bobby P.C.

AU - Kosmicki, Jack A.

AU - Linnankivi, Tarja

AU - May, Patrick

AU - Muhle, Hiltrud

AU - Møller, Rikke S.

AU - Neubauer, Bernd A.

AU - Palotie, Aarno

AU - Pendziwiat, Manuela

AU - Striano, Pasquale

AU - Tang, Sha

AU - Wu, Sitao

AU - EuroEPINOMICS RES Consortium

AU - Afawi, Zaid

AU - De Kovel, Carolien

AU - Dimova, Petia

AU - Djémié, Tania

AU - Endziniene, Milda

AU - Hoffman-Zacharska, Dorota

AU - Jähn, Johanna

AU - Korff, Christian

AU - Lehesjoki, Anna Elina

AU - Marini, Carla

AU - Müller, Stefanie H.

AU - Pal, Deb

AU - Schwarz, Niklas

AU - Selmer, Kaja

AU - Serratosa, Jose

AU - Stephani, Ulrich

AU - Štěrbová, Katalin

AU - Suls, Arvid

AU - Syrbe, Steffen

AU - Talvik, Inga

AU - Tang, Shan

AU - Von Spiczak, Sarah

AU - Zara, Federico

AU - Poduri, Annapurna

AU - Weber, Yvonne G.

AU - Weckhuysen, Sarah

AU - Sisodiya, Sanjay M.

AU - Daly, Mark J.

AU - Helbig, Ingo

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.

AB - Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.

UR - http://www.scopus.com/inward/record.url?scp=85049011462&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0143-7

DO - 10.1038/s41588-018-0143-7

M3 - Article

AN - SCOPUS:85049011462

SN - 1061-4036

VL - 50

SP - 1048

EP - 1053

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

De novo variants in neurodevelopmental disorders with epilepsy

Abstract

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