IQSEC2-related encephalopathy in males and females

a comparative study including 37 novel patients

Cyril Mignot, Aoife C. McMahon, Claire Bar, Philippe M. Campeau, Claire Davidson, Julien Buratti, Caroline Nava, Marie Line Jacquemont, Marilyn Tallot, Mathieu Milh, Patrick Edery, Pauline Marzin, Giulia Barcia, Christine Barnerias, Claude Besmond, Thierry Bienvenu, Ange Line Bruel, Ledia Brunga, Berten Ceulemans, Christine Coubes & 66 others Ana G. Cristancho, Fiona Cunningham, Marie Bertille Dehouck, Elizabeth J. Donner, Bénédicte Duban-Bedu, Christèle Dubourg, Elena Gardella, Julie Gauthier, David Geneviève, Stéphanie Gobin-Limballe, Ethan M. Goldberg, Eveline Hagebeuk, Fadi F. Hamdan, Miroslava Hančárová, Laurence Hubert, Christine Ioos, Shoji Ichikawa, Sandra Janssens, Hubert Journel, Anna Kaminska, Boris Keren, Marije Koopmans, Caroline Lacoste, Petra Laššuthová, Damien Lederer, Daphné Lehalle, Dragan Marjanovic, Julia Métreau, Jacques L. Michaud, Kathryn Miller, Berge A. Minassian, Joannella Morales, Marie Laure Moutard, Arnold Munnich, Xilma R. Ortiz-Gonzalez, Jean Marc Pinard, Darina Prchalová, Audrey Putoux, Chloé Quelin, Alyssa R. Rosen, Joelle Roume, Elsa Rossignol, Marleen E.H. Simon, Thomas Smol, Natasha Shur, Ivan Shelihan, Katalin Štěrbová, Emílie Vyhnálková, Catheline Vilain, Julie Soblet, Guillaume Smits, Samuel P. Yang, Jasper J. van der Smagt, Peter M. van Hasselt, Marjan van Kempen, Sarah Weckhuysen, Ingo Helbig, Laurent Villard, Delphine Héron, Bobby Koeleman, Rikke S. Møller, Gaetan Lesca, Katherine L. Helbig, Rima Nabbout, Nienke E. Verbeek, Christel Depienne

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. Results: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. Conclusion: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

Original languageEnglish (US)
JournalGenetics in Medicine
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Brain Diseases
Intellectual Disability
Protein Isoforms
Seizures
X Chromosome Inactivation
Developmental Disabilities
Brain
Age of Onset
Sex Characteristics
Anticonvulsants
Synapses
Epilepsy
Phenotype
Proteins

Keywords

  • epilepsy
  • intellectual disability
  • IQSEC2
  • isoforms
  • X-linked inheritance

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Mignot, C., McMahon, A. C., Bar, C., Campeau, P. M., Davidson, C., Buratti, J., ... Depienne, C. (Accepted/In press). IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients. Genetics in Medicine. https://doi.org/10.1038/s41436-018-0268-1

IQSEC2-related encephalopathy in males and females : a comparative study including 37 novel patients. / Mignot, Cyril; McMahon, Aoife C.; Bar, Claire; Campeau, Philippe M.; Davidson, Claire; Buratti, Julien; Nava, Caroline; Jacquemont, Marie Line; Tallot, Marilyn; Milh, Mathieu; Edery, Patrick; Marzin, Pauline; Barcia, Giulia; Barnerias, Christine; Besmond, Claude; Bienvenu, Thierry; Bruel, Ange Line; Brunga, Ledia; Ceulemans, Berten; Coubes, Christine; Cristancho, Ana G.; Cunningham, Fiona; Dehouck, Marie Bertille; Donner, Elizabeth J.; Duban-Bedu, Bénédicte; Dubourg, Christèle; Gardella, Elena; Gauthier, Julie; Geneviève, David; Gobin-Limballe, Stéphanie; Goldberg, Ethan M.; Hagebeuk, Eveline; Hamdan, Fadi F.; Hančárová, Miroslava; Hubert, Laurence; Ioos, Christine; Ichikawa, Shoji; Janssens, Sandra; Journel, Hubert; Kaminska, Anna; Keren, Boris; Koopmans, Marije; Lacoste, Caroline; Laššuthová, Petra; Lederer, Damien; Lehalle, Daphné; Marjanovic, Dragan; Métreau, Julia; Michaud, Jacques L.; Miller, Kathryn; Minassian, Berge A.; Morales, Joannella; Moutard, Marie Laure; Munnich, Arnold; Ortiz-Gonzalez, Xilma R.; Pinard, Jean Marc; Prchalová, Darina; Putoux, Audrey; Quelin, Chloé; Rosen, Alyssa R.; Roume, Joelle; Rossignol, Elsa; Simon, Marleen E.H.; Smol, Thomas; Shur, Natasha; Shelihan, Ivan; Štěrbová, Katalin; Vyhnálková, Emílie; Vilain, Catheline; Soblet, Julie; Smits, Guillaume; Yang, Samuel P.; van der Smagt, Jasper J.; van Hasselt, Peter M.; van Kempen, Marjan; Weckhuysen, Sarah; Helbig, Ingo; Villard, Laurent; Héron, Delphine; Koeleman, Bobby; Møller, Rikke S.; Lesca, Gaetan; Helbig, Katherine L.; Nabbout, Rima; Verbeek, Nienke E.; Depienne, Christel.

In: Genetics in Medicine, 01.01.2018.

Research output: Contribution to journalArticle

Mignot, C, McMahon, AC, Bar, C, Campeau, PM, Davidson, C, Buratti, J, Nava, C, Jacquemont, ML, Tallot, M, Milh, M, Edery, P, Marzin, P, Barcia, G, Barnerias, C, Besmond, C, Bienvenu, T, Bruel, AL, Brunga, L, Ceulemans, B, Coubes, C, Cristancho, AG, Cunningham, F, Dehouck, MB, Donner, EJ, Duban-Bedu, B, Dubourg, C, Gardella, E, Gauthier, J, Geneviève, D, Gobin-Limballe, S, Goldberg, EM, Hagebeuk, E, Hamdan, FF, Hančárová, M, Hubert, L, Ioos, C, Ichikawa, S, Janssens, S, Journel, H, Kaminska, A, Keren, B, Koopmans, M, Lacoste, C, Laššuthová, P, Lederer, D, Lehalle, D, Marjanovic, D, Métreau, J, Michaud, JL, Miller, K, Minassian, BA, Morales, J, Moutard, ML, Munnich, A, Ortiz-Gonzalez, XR, Pinard, JM, Prchalová, D, Putoux, A, Quelin, C, Rosen, AR, Roume, J, Rossignol, E, Simon, MEH, Smol, T, Shur, N, Shelihan, I, Štěrbová, K, Vyhnálková, E, Vilain, C, Soblet, J, Smits, G, Yang, SP, van der Smagt, JJ, van Hasselt, PM, van Kempen, M, Weckhuysen, S, Helbig, I, Villard, L, Héron, D, Koeleman, B, Møller, RS, Lesca, G, Helbig, KL, Nabbout, R, Verbeek, NE & Depienne, C 2018, 'IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients', Genetics in Medicine. https://doi.org/10.1038/s41436-018-0268-1
Mignot, Cyril ; McMahon, Aoife C. ; Bar, Claire ; Campeau, Philippe M. ; Davidson, Claire ; Buratti, Julien ; Nava, Caroline ; Jacquemont, Marie Line ; Tallot, Marilyn ; Milh, Mathieu ; Edery, Patrick ; Marzin, Pauline ; Barcia, Giulia ; Barnerias, Christine ; Besmond, Claude ; Bienvenu, Thierry ; Bruel, Ange Line ; Brunga, Ledia ; Ceulemans, Berten ; Coubes, Christine ; Cristancho, Ana G. ; Cunningham, Fiona ; Dehouck, Marie Bertille ; Donner, Elizabeth J. ; Duban-Bedu, Bénédicte ; Dubourg, Christèle ; Gardella, Elena ; Gauthier, Julie ; Geneviève, David ; Gobin-Limballe, Stéphanie ; Goldberg, Ethan M. ; Hagebeuk, Eveline ; Hamdan, Fadi F. ; Hančárová, Miroslava ; Hubert, Laurence ; Ioos, Christine ; Ichikawa, Shoji ; Janssens, Sandra ; Journel, Hubert ; Kaminska, Anna ; Keren, Boris ; Koopmans, Marije ; Lacoste, Caroline ; Laššuthová, Petra ; Lederer, Damien ; Lehalle, Daphné ; Marjanovic, Dragan ; Métreau, Julia ; Michaud, Jacques L. ; Miller, Kathryn ; Minassian, Berge A. ; Morales, Joannella ; Moutard, Marie Laure ; Munnich, Arnold ; Ortiz-Gonzalez, Xilma R. ; Pinard, Jean Marc ; Prchalová, Darina ; Putoux, Audrey ; Quelin, Chloé ; Rosen, Alyssa R. ; Roume, Joelle ; Rossignol, Elsa ; Simon, Marleen E.H. ; Smol, Thomas ; Shur, Natasha ; Shelihan, Ivan ; Štěrbová, Katalin ; Vyhnálková, Emílie ; Vilain, Catheline ; Soblet, Julie ; Smits, Guillaume ; Yang, Samuel P. ; van der Smagt, Jasper J. ; van Hasselt, Peter M. ; van Kempen, Marjan ; Weckhuysen, Sarah ; Helbig, Ingo ; Villard, Laurent ; Héron, Delphine ; Koeleman, Bobby ; Møller, Rikke S. ; Lesca, Gaetan ; Helbig, Katherine L. ; Nabbout, Rima ; Verbeek, Nienke E. ; Depienne, Christel. / IQSEC2-related encephalopathy in males and females : a comparative study including 37 novel patients. In: Genetics in Medicine. 2018.
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title = "IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients",
abstract = "Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. Results: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. Conclusion: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.",
keywords = "epilepsy, intellectual disability, IQSEC2, isoforms, X-linked inheritance",
author = "Cyril Mignot and McMahon, {Aoife C.} and Claire Bar and Campeau, {Philippe M.} and Claire Davidson and Julien Buratti and Caroline Nava and Jacquemont, {Marie Line} and Marilyn Tallot and Mathieu Milh and Patrick Edery and Pauline Marzin and Giulia Barcia and Christine Barnerias and Claude Besmond and Thierry Bienvenu and Bruel, {Ange Line} and Ledia Brunga and Berten Ceulemans and Christine Coubes and Cristancho, {Ana G.} and Fiona Cunningham and Dehouck, {Marie Bertille} and Donner, {Elizabeth J.} and B{\'e}n{\'e}dicte Duban-Bedu and Christ{\`e}le Dubourg and Elena Gardella and Julie Gauthier and David Genevi{\`e}ve and St{\'e}phanie Gobin-Limballe and Goldberg, {Ethan M.} and Eveline Hagebeuk and Hamdan, {Fadi F.} and Miroslava Hanč{\'a}rov{\'a} and Laurence Hubert and Christine Ioos and Shoji Ichikawa and Sandra Janssens and Hubert Journel and Anna Kaminska and Boris Keren and Marije Koopmans and Caroline Lacoste and Petra Laššuthov{\'a} and Damien Lederer and Daphn{\'e} Lehalle and Dragan Marjanovic and Julia M{\'e}treau and Michaud, {Jacques L.} and Kathryn Miller and Minassian, {Berge A.} and Joannella Morales and Moutard, {Marie Laure} and Arnold Munnich and Ortiz-Gonzalez, {Xilma R.} and Pinard, {Jean Marc} and Darina Prchalov{\'a} and Audrey Putoux and Chlo{\'e} Quelin and Rosen, {Alyssa R.} and Joelle Roume and Elsa Rossignol and Simon, {Marleen E.H.} and Thomas Smol and Natasha Shur and Ivan Shelihan and Katalin Štěrbov{\'a} and Em{\'i}lie Vyhn{\'a}lkov{\'a} and Catheline Vilain and Julie Soblet and Guillaume Smits and Yang, {Samuel P.} and {van der Smagt}, {Jasper J.} and {van Hasselt}, {Peter M.} and {van Kempen}, Marjan and Sarah Weckhuysen and Ingo Helbig and Laurent Villard and Delphine H{\'e}ron and Bobby Koeleman and M{\o}ller, {Rikke S.} and Gaetan Lesca and Helbig, {Katherine L.} and Rima Nabbout and Verbeek, {Nienke E.} and Christel Depienne",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41436-018-0268-1",
language = "English (US)",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",

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TY - JOUR

T1 - IQSEC2-related encephalopathy in males and females

T2 - a comparative study including 37 novel patients

AU - Mignot, Cyril

AU - McMahon, Aoife C.

AU - Bar, Claire

AU - Campeau, Philippe M.

AU - Davidson, Claire

AU - Buratti, Julien

AU - Nava, Caroline

AU - Jacquemont, Marie Line

AU - Tallot, Marilyn

AU - Milh, Mathieu

AU - Edery, Patrick

AU - Marzin, Pauline

AU - Barcia, Giulia

AU - Barnerias, Christine

AU - Besmond, Claude

AU - Bienvenu, Thierry

AU - Bruel, Ange Line

AU - Brunga, Ledia

AU - Ceulemans, Berten

AU - Coubes, Christine

AU - Cristancho, Ana G.

AU - Cunningham, Fiona

AU - Dehouck, Marie Bertille

AU - Donner, Elizabeth J.

AU - Duban-Bedu, Bénédicte

AU - Dubourg, Christèle

AU - Gardella, Elena

AU - Gauthier, Julie

AU - Geneviève, David

AU - Gobin-Limballe, Stéphanie

AU - Goldberg, Ethan M.

AU - Hagebeuk, Eveline

AU - Hamdan, Fadi F.

AU - Hančárová, Miroslava

AU - Hubert, Laurence

AU - Ioos, Christine

AU - Ichikawa, Shoji

AU - Janssens, Sandra

AU - Journel, Hubert

AU - Kaminska, Anna

AU - Keren, Boris

AU - Koopmans, Marije

AU - Lacoste, Caroline

AU - Laššuthová, Petra

AU - Lederer, Damien

AU - Lehalle, Daphné

AU - Marjanovic, Dragan

AU - Métreau, Julia

AU - Michaud, Jacques L.

AU - Miller, Kathryn

AU - Minassian, Berge A.

AU - Morales, Joannella

AU - Moutard, Marie Laure

AU - Munnich, Arnold

AU - Ortiz-Gonzalez, Xilma R.

AU - Pinard, Jean Marc

AU - Prchalová, Darina

AU - Putoux, Audrey

AU - Quelin, Chloé

AU - Rosen, Alyssa R.

AU - Roume, Joelle

AU - Rossignol, Elsa

AU - Simon, Marleen E.H.

AU - Smol, Thomas

AU - Shur, Natasha

AU - Shelihan, Ivan

AU - Štěrbová, Katalin

AU - Vyhnálková, Emílie

AU - Vilain, Catheline

AU - Soblet, Julie

AU - Smits, Guillaume

AU - Yang, Samuel P.

AU - van der Smagt, Jasper J.

AU - van Hasselt, Peter M.

AU - van Kempen, Marjan

AU - Weckhuysen, Sarah

AU - Helbig, Ingo

AU - Villard, Laurent

AU - Héron, Delphine

AU - Koeleman, Bobby

AU - Møller, Rikke S.

AU - Lesca, Gaetan

AU - Helbig, Katherine L.

AU - Nabbout, Rima

AU - Verbeek, Nienke E.

AU - Depienne, Christel

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. Results: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. Conclusion: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

AB - Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. Results: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. Conclusion: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

KW - epilepsy

KW - intellectual disability

KW - IQSEC2

KW - isoforms

KW - X-linked inheritance

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DO - 10.1038/s41436-018-0268-1

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JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

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