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IQSEC2-related encephalopathy in males and females : a comparative study including 37 novel patients

(2018) GENETICS IN MEDICINE. 21(4). p.837-849
Author
Organization
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 Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants.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
IQSEC2, X-linked inheritance, epilepsy, intellectual disability, isoforms, X-CHROMOSOME INACTIVATION, DE-NOVO MUTATIONS, NUCLEOTIDE EXCHANGE FACTOR, INTELLECTUAL DISABILITY, EPILEPTIC ENCEPHALOPATHY, POSTSYNAPTIC DENSITY, IQSEC2, GENE, ESCAPE, EXPRESSION

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MLA
Mignot, Cyril et al. “IQSEC2-related Encephalopathy in Males and Females : a Comparative Study Including 37 Novel Patients.” GENETICS IN MEDICINE 21.4 (2018): 837–849. Print.
APA
Mignot, C., McMahon, A. C., Bar, C., Campeau, P. M., Davidson, C., Buratti, J., Nava, C., et al. (2018). IQSEC2-related encephalopathy in males and females : a comparative study including 37 novel patients. GENETICS IN MEDICINE, 21(4), 837–849.
Chicago author-date
Mignot, Cyril, Aoife C McMahon, Claire Bar, Philippe M Campeau, Claire Davidson, Julien Buratti, Caroline Nava, et al. 2018. “IQSEC2-related Encephalopathy in Males and Females : a Comparative Study Including 37 Novel Patients.” Genetics in Medicine 21 (4): 837–849.
Chicago author-date (all authors)
Mignot, Cyril, 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, 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 EH 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, and Christel Depienne. 2018. “IQSEC2-related Encephalopathy in Males and Females : a Comparative Study Including 37 Novel Patients.” Genetics in Medicine 21 (4): 837–849.
Vancouver
1.
Mignot C, McMahon AC, Bar C, Campeau PM, Davidson C, Buratti J, et al. IQSEC2-related encephalopathy in males and females : a comparative study including 37 novel patients. GENETICS IN MEDICINE. 2018;21(4):837–49.
IEEE
[1]
C. Mignot et al., “IQSEC2-related encephalopathy in males and females : a comparative study including 37 novel patients,” GENETICS IN MEDICINE, vol. 21, no. 4, pp. 837–849, 2018.
@article{8611669,
  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.},
  author       = {Mignot, Cyril and McMahon, Aoife C and Bar, Claire and Campeau, Philippe M and Davidson, Claire and Buratti, Julien and Nava, Caroline and Jacquemont, Marie-Line and Tallot, Marilyn and Milh, Mathieu and Edery, Patrick and Marzin, Pauline and Barcia, Giulia and Barnerias, Christine and Besmond, Claude and Bienvenu, Thierry and Bruel, Ange-Line and Brunga, Ledia and Ceulemans, Berten and Coubes, Christine and Cristancho, Ana G and Cunningham, Fiona and Dehouck, Marie-Bertille and Donner, Elizabeth J and Duban-Bedu, Bénédicte and Dubourg, Christèle and Gardella, Elena and Gauthier, Julie and Geneviève, David and Gobin-Limballe, Stéphanie and Goldberg, Ethan M and Hagebeuk, Eveline and Hamdan, Fadi F and Hančárová, Miroslava and Hubert, Laurence and Ioos, Christine and Ichikawa, Shoji and Janssens, Sandra and Journel, Hubert and Kaminska, Anna and Keren, Boris and Koopmans, Marije and Lacoste, Caroline and Laššuthová, Petra and Lederer, Damien and Lehalle, Daphné and Marjanovic, Dragan and Métreau, Julia and Michaud, Jacques L and Miller, Kathryn and Minassian, Berge A and Morales, Joannella and Moutard, Marie-Laure and Munnich, Arnold and Ortiz-Gonzalez, Xilma R and Pinard, Jean-Marc and Prchalová, Darina and Putoux, Audrey and Quelin, Chloé and Rosen, Alyssa R and Roume, Joelle and Rossignol, Elsa and Simon, Marleen EH and Smol, Thomas and Shur, Natasha and Shelihan, Ivan and Štěrbová, Katalin and Vyhnálková, Emílie and Vilain, Catheline and Soblet, Julie and Smits, Guillaume and Yang, Samuel P and van der Smagt, Jasper J and van Hasselt, Peter M and van Kempen, Marjan and Weckhuysen, Sarah and Helbig, Ingo and Villard, Laurent and Héron, Delphine and Koeleman, Bobby and Møller, Rikke S and Lesca, Gaetan and Helbig, Katherine L and Nabbout, Rima and Verbeek, Nienke E and Depienne, Christel},
  issn         = {1098-3600},
  journal      = {GENETICS IN MEDICINE},
  keywords     = {IQSEC2,X-linked inheritance,epilepsy,intellectual disability,isoforms,X-CHROMOSOME INACTIVATION,DE-NOVO MUTATIONS,NUCLEOTIDE EXCHANGE FACTOR,INTELLECTUAL DISABILITY,EPILEPTIC ENCEPHALOPATHY,POSTSYNAPTIC DENSITY,IQSEC2,GENE,ESCAPE,EXPRESSION},
  language     = {eng},
  number       = {4},
  pages        = {837--849},
  title        = {IQSEC2-related encephalopathy in males and females : a comparative study including 37 novel patients},
  url          = {http://dx.doi.org/10.1038/s41436-018-0268-1},
  volume       = {21},
  year         = {2018},
}

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