Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

Gabrielle Rudolf, Gaetan Lesca, Mana M. Mehrjouy, Audrey Labalme, Manal Salmi, Iben Bache, Nadine Bruneau, Manuela Pendziwiat, Joel Fluss, Julitta De Bellescize, Julia Scholly, Rikke S. Møller, Dana Craiu, Niels Tommerup, Maria Paola Valenti-Hirsch, Caroline Schluth-Bolard, Frédérique Sloan-Béna, Katherine L. Helbig, Sarah Weckhuysen, Patrick Edery & 21 others Safia Coulbaut, Mohamed Abbas, Ingrid E. Scheffer, Sha Tang, Candace T. Myers, Hannah Stamberger, Gemma L. Carvill, Deepali N. Shinde, Heather C. Mefford, Elena Neagu, Robert Huether, Hsiao Mei Lu, Alice Dica, Julie S. Cohen, Catrinel Iliescu, Cristina Pomeran, James Rubenstein, Ingo Helbig, Damien Sanlaville, Edouard Hirsch, Pierre Szepetowski

Research output: Contribution to journalArticle

Abstract

Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66∗)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249-1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.

Original languageEnglish (US)
Pages (from-to)1761-1770
Number of pages10
JournalEuropean Journal of Human Genetics
Volume24
Issue number12
DOIs
StatePublished - Dec 1 2016

Fingerprint

Generalized Epilepsy
Retinoids
Cytoplasmic and Nuclear Receptors
Epilepsy
Exome
Genes
Orphan Nuclear Receptors
Absence Epilepsy
Eyelids
Intellectual Disability
Exons
Seizures
Technology
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Rudolf, G., Lesca, G., Mehrjouy, M. M., Labalme, A., Salmi, M., Bache, I., ... Szepetowski, P. (2016). Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. European Journal of Human Genetics, 24(12), 1761-1770. https://doi.org/10.1038/ejhg.2016.80

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. / Rudolf, Gabrielle; Lesca, Gaetan; Mehrjouy, Mana M.; Labalme, Audrey; Salmi, Manal; Bache, Iben; Bruneau, Nadine; Pendziwiat, Manuela; Fluss, Joel; De Bellescize, Julitta; Scholly, Julia; Møller, Rikke S.; Craiu, Dana; Tommerup, Niels; Valenti-Hirsch, Maria Paola; Schluth-Bolard, Caroline; Sloan-Béna, Frédérique; Helbig, Katherine L.; Weckhuysen, Sarah; Edery, Patrick; Coulbaut, Safia; Abbas, Mohamed; Scheffer, Ingrid E.; Tang, Sha; Myers, Candace T.; Stamberger, Hannah; Carvill, Gemma L.; Shinde, Deepali N.; Mefford, Heather C.; Neagu, Elena; Huether, Robert; Lu, Hsiao Mei; Dica, Alice; Cohen, Julie S.; Iliescu, Catrinel; Pomeran, Cristina; Rubenstein, James; Helbig, Ingo; Sanlaville, Damien; Hirsch, Edouard; Szepetowski, Pierre.

In: European Journal of Human Genetics, Vol. 24, No. 12, 01.12.2016, p. 1761-1770.

Research output: Contribution to journalArticle

Rudolf, G, Lesca, G, Mehrjouy, MM, Labalme, A, Salmi, M, Bache, I, Bruneau, N, Pendziwiat, M, Fluss, J, De Bellescize, J, Scholly, J, Møller, RS, Craiu, D, Tommerup, N, Valenti-Hirsch, MP, Schluth-Bolard, C, Sloan-Béna, F, Helbig, KL, Weckhuysen, S, Edery, P, Coulbaut, S, Abbas, M, Scheffer, IE, Tang, S, Myers, CT, Stamberger, H, Carvill, GL, Shinde, DN, Mefford, HC, Neagu, E, Huether, R, Lu, HM, Dica, A, Cohen, JS, Iliescu, C, Pomeran, C, Rubenstein, J, Helbig, I, Sanlaville, D, Hirsch, E & Szepetowski, P 2016, 'Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy', European Journal of Human Genetics, vol. 24, no. 12, pp. 1761-1770. https://doi.org/10.1038/ejhg.2016.80
Rudolf, Gabrielle ; Lesca, Gaetan ; Mehrjouy, Mana M. ; Labalme, Audrey ; Salmi, Manal ; Bache, Iben ; Bruneau, Nadine ; Pendziwiat, Manuela ; Fluss, Joel ; De Bellescize, Julitta ; Scholly, Julia ; Møller, Rikke S. ; Craiu, Dana ; Tommerup, Niels ; Valenti-Hirsch, Maria Paola ; Schluth-Bolard, Caroline ; Sloan-Béna, Frédérique ; Helbig, Katherine L. ; Weckhuysen, Sarah ; Edery, Patrick ; Coulbaut, Safia ; Abbas, Mohamed ; Scheffer, Ingrid E. ; Tang, Sha ; Myers, Candace T. ; Stamberger, Hannah ; Carvill, Gemma L. ; Shinde, Deepali N. ; Mefford, Heather C. ; Neagu, Elena ; Huether, Robert ; Lu, Hsiao Mei ; Dica, Alice ; Cohen, Julie S. ; Iliescu, Catrinel ; Pomeran, Cristina ; Rubenstein, James ; Helbig, Ingo ; Sanlaville, Damien ; Hirsch, Edouard ; Szepetowski, Pierre. / Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. In: European Journal of Human Genetics. 2016 ; Vol. 24, No. 12. pp. 1761-1770.
@article{7edb11a31788428988f34eda6a271d29,
title = "Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy",
abstract = "Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66∗)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249-1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.",
author = "Gabrielle Rudolf and Gaetan Lesca and Mehrjouy, {Mana M.} and Audrey Labalme and Manal Salmi and Iben Bache and Nadine Bruneau and Manuela Pendziwiat and Joel Fluss and {De Bellescize}, Julitta and Julia Scholly and M{\o}ller, {Rikke S.} and Dana Craiu and Niels Tommerup and Valenti-Hirsch, {Maria Paola} and Caroline Schluth-Bolard and Fr{\'e}d{\'e}rique Sloan-B{\'e}na and Helbig, {Katherine L.} and Sarah Weckhuysen and Patrick Edery and Safia Coulbaut and Mohamed Abbas and Scheffer, {Ingrid E.} and Sha Tang and Myers, {Candace T.} and Hannah Stamberger and Carvill, {Gemma L.} and Shinde, {Deepali N.} and Mefford, {Heather C.} and Elena Neagu and Robert Huether and Lu, {Hsiao Mei} and Alice Dica and Cohen, {Julie S.} and Catrinel Iliescu and Cristina Pomeran and James Rubenstein and Ingo Helbig and Damien Sanlaville and Edouard Hirsch and Pierre Szepetowski",
year = "2016",
month = "12",
day = "1",
doi = "10.1038/ejhg.2016.80",
language = "English (US)",
volume = "24",
pages = "1761--1770",
journal = "European Journal of Human Genetics",
issn = "1018-4813",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

AU - Rudolf, Gabrielle

AU - Lesca, Gaetan

AU - Mehrjouy, Mana M.

AU - Labalme, Audrey

AU - Salmi, Manal

AU - Bache, Iben

AU - Bruneau, Nadine

AU - Pendziwiat, Manuela

AU - Fluss, Joel

AU - De Bellescize, Julitta

AU - Scholly, Julia

AU - Møller, Rikke S.

AU - Craiu, Dana

AU - Tommerup, Niels

AU - Valenti-Hirsch, Maria Paola

AU - Schluth-Bolard, Caroline

AU - Sloan-Béna, Frédérique

AU - Helbig, Katherine L.

AU - Weckhuysen, Sarah

AU - Edery, Patrick

AU - Coulbaut, Safia

AU - Abbas, Mohamed

AU - Scheffer, Ingrid E.

AU - Tang, Sha

AU - Myers, Candace T.

AU - Stamberger, Hannah

AU - Carvill, Gemma L.

AU - Shinde, Deepali N.

AU - Mefford, Heather C.

AU - Neagu, Elena

AU - Huether, Robert

AU - Lu, Hsiao Mei

AU - Dica, Alice

AU - Cohen, Julie S.

AU - Iliescu, Catrinel

AU - Pomeran, Cristina

AU - Rubenstein, James

AU - Helbig, Ingo

AU - Sanlaville, Damien

AU - Hirsch, Edouard

AU - Szepetowski, Pierre

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66∗)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249-1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.

AB - Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66∗)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249-1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.

UR - http://www.scopus.com/inward/record.url?scp=84976349143&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84976349143&partnerID=8YFLogxK

U2 - 10.1038/ejhg.2016.80

DO - 10.1038/ejhg.2016.80

M3 - Article

VL - 24

SP - 1761

EP - 1770

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 12

ER -