Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

Rikke S Møller; Line H G Larsen; Katrine M Johannesen; Inga Talvik; Tiina Talvik; Ulvi Vaher; Maria J Miranda; Muhammad Farooq; Jens E K Nielsen; L Lavard Svendsen; Ditte B Kjelgaard; Karen M Linnet; Qin Hao; Peter Uldall; Mimoza Frangu; Niels Tommerup; Shahid M Baig; U Abdullah; A P Born; Pia Gellert; Marina Nikanorova; Kern Olofsson; Birgit Jepsen; Dragan Marjanovic; Lana I K Al-Zehhawi; Sofia J Peñalva; Bente Krag-Olsen; Klaus Brusgaard; Helle Hjalgrim; G Rubboli; Deb K Pal; Hans A Dahl

doi:10.1159/000448369

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

Rikke S Møller, Line H G Larsen, Katrine M Johannesen, Inga Talvik, Tiina Talvik, Ulvi Vaher, Maria J Miranda, Muhammad Farooq, Jens E K Nielsen, L Lavard Svendsen, Ditte B Kjelgaard, Karen M Linnet, Qin Hao, Peter Uldall, Mimoza Frangu, Niels Tommerup, Shahid M Baig, U Abdullah, A P Born, Pia GellertMarina Nikanorova, Kern Olofsson, Birgit Jepsen, Dragan Marjanovic, Lana I K Al-Zehhawi, Sofia J Peñalva, Bente Krag-Olsen, Klaus Brusgaard, Helle Hjalgrim, G Rubboli, Deb K Pal, Hans A Dahl

55 Citations (Scopus)

Abstract

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

Original language	English
Journal	Molecular Syndromology
Volume	7
Issue number	4
Pages (from-to)	210-219
Number of pages	10
ISSN	1661-8769
DOIs	https://doi.org/10.1159/000448369
Publication status	Published - 1 Sept 2016

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Møller, R. S., Larsen, L. H. G., Johannesen, K. M., Talvik, I., Talvik, T., Vaher, U., Miranda, M. J., Farooq, M., Nielsen, J. E. K., Svendsen, L. L., Kjelgaard, D. B., Linnet, K. M., Hao, Q., Uldall, P., Frangu, M., Tommerup, N., Baig, S. M., Abdullah, U., Born, A. P., ... Dahl, H. A. (2016). Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies. Molecular Syndromology, 7(4), 210-219. https://doi.org/10.1159/000448369

Møller, RS, Larsen, LHG, Johannesen, KM, Talvik, I, Talvik, T, Vaher, U, Miranda, MJ , Farooq, M , Nielsen, JEK, Svendsen, LL, Kjelgaard, DB, Linnet, KM, Hao, Q, Uldall, P, Frangu, M, Tommerup, N, Baig, SM, Abdullah, U, Born, AP, Gellert, P, Nikanorova, M, Olofsson, K, Jepsen, B, Marjanovic, D, Al-Zehhawi, LIK, Peñalva, SJ, Krag-Olsen, B, Brusgaard, K, Hjalgrim, H, Rubboli, G, Pal, DK & Dahl, HA 2016, 'Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies', Molecular Syndromology, vol. 7, no. 4, pp. 210-219. https://doi.org/10.1159/000448369

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title = "Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies",

abstract = "In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.",

author = "M{\o}ller, {Rikke S} and Larsen, {Line H G} and Johannesen, {Katrine M} and Inga Talvik and Tiina Talvik and Ulvi Vaher and Miranda, {Maria J} and Muhammad Farooq and Nielsen, {Jens E K} and Svendsen, {L Lavard} and Kjelgaard, {Ditte B} and Linnet, {Karen M} and Qin Hao and Peter Uldall and Mimoza Frangu and Niels Tommerup and Baig, {Shahid M} and U Abdullah and Born, {A P} and Pia Gellert and Marina Nikanorova and Kern Olofsson and Birgit Jepsen and Dragan Marjanovic and Al-Zehhawi, {Lana I K} and Pe{\~n}alva, {Sofia J} and Bente Krag-Olsen and Klaus Brusgaard and Helle Hjalgrim and G Rubboli and Pal, {Deb K} and Dahl, {Hans A}",

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T1 - Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

AU - Møller, Rikke S

AU - Larsen, Line H G

AU - Johannesen, Katrine M

AU - Talvik, Inga

AU - Talvik, Tiina

AU - Vaher, Ulvi

AU - Miranda, Maria J

AU - Farooq, Muhammad

AU - Nielsen, Jens E K

AU - Svendsen, L Lavard

AU - Kjelgaard, Ditte B

AU - Linnet, Karen M

AU - Hao, Qin

AU - Uldall, Peter

AU - Frangu, Mimoza

AU - Tommerup, Niels

AU - Baig, Shahid M

AU - Abdullah, U

AU - Born, A P

AU - Gellert, Pia

AU - Nikanorova, Marina

AU - Olofsson, Kern

AU - Jepsen, Birgit

AU - Marjanovic, Dragan

AU - Al-Zehhawi, Lana I K

AU - Peñalva, Sofia J

AU - Krag-Olsen, Bente

AU - Brusgaard, Klaus

AU - Hjalgrim, Helle

AU - Rubboli, G

AU - Pal, Deb K

AU - Dahl, Hans A

PY - 2016/9/1

Y1 - 2016/9/1

N2 - In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

AB - In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

U2 - 10.1159/000448369

DO - 10.1159/000448369

M3 - Journal article

C2 - 27781031

SN - 1661-8769

VL - 7

SP - 210

EP - 219

JO - Molecular Syndromology

JF - Molecular Syndromology

IS - 4

ER -

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

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