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Genet Med. 2019 Apr;21(4):837-849. doi: 10.1038/s41436-018-0268-1. Epub 2018 Sep 12.

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

Author information

1
INSERM, U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France. cyril.mignot@aphp.fr.
2
APHP, Hôpital Pitie-Salpetriere, Departement de Genetique et de Cytogenetique; Centre de Reference Deficience Intellectuelle de Causes Rares; GRC UPMC «Deficience Intellectuelle et Autisme», Paris, France. cyril.mignot@aphp.fr.
3
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
4
APHP, Reference Centre for Rare Epilepsies, Necker-Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France.
5
INSERM U1163, Imagine Institute, Paris, France.
6
Paris Descartes University, Paris, France.
7
Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, QC, Canada.
8
APHP, Hôpital Pitie-Salpetriere, Departement de Genetique et de Cytogenetique; Centre de Reference Deficience Intellectuelle de Causes Rares; GRC UPMC «Deficience Intellectuelle et Autisme», Paris, France.
9
INSERM, U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France.
10
CHU La Reunion-Groupe Hospitalier Sud Reunion, La Reunion, France.
11
APHM, Hôpital d'Enfants de La Timone, Service de Neurologie Pediatrique, centre de reference deficiences intellectuelles de cause rare, Marseille, France.
12
Aix Marseille University, INSERM, MMG, UMR-S 1251, Faculte de medecine, Marseille, France.
13
Service de Genetique, Centre de Reference Anomalies du Developpement, Hospices Civils de Lyon, Bron, France.
14
INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Universite Claude Bernard Lyon 1, Bron, France.
15
Claude Bernard Lyon I University, Lyon, France.
16
APHP, Service de genetique medicale, Necker-Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France.
17
APHP, Unite fonctionnelle de Neurologie, Necker-Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France.
18
APHP, Laboratoire de Genetique et Biologie Moleculaires, Hôpital Cochin, HUPC, Paris, France.
19
Universite Paris Descartes Paris, Institut de Psychiatrie et de Neurosciences de Paris, Inserm U894, Paris, France.
20
FHU-TRANSLAD, Universite de Bourgogne/CHU Dijon, Dijon, France.
21
INSERM UMR 1231 GAD team, Genetics of Developmental disorders, Universite de Bourgogne-Franche Comte, Dijon, France.
22
Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
23
Department of Pediatric Neurology, University Hospital and University of Antwerp, Antwerp, Belgium.
24
Departement de Genetique Medicale, Maladies rares et Medecine Personnalisee, CHU de Montpellier, Montpellier, France.
25
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
26
Centre de Genetique Chromosomique, Hôpital St-Vincent-de-Paul, GHICL, Lille, France.
27
CHU Rennes, Service de Genetique Moleculaire et Genomique, Rennes, France.
28
Danish Epilepsy Centre Filadelfia, Dianalund, Denmark.
29
Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
30
INSERM U1183, Montpellier, France.
31
Stichting Epilepsie Instellingen Nederland, SEIN, Zwolle, The Netherlands.
32
Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
33
APHP, University Hospital of Paris ïle-de-France ouest, Raymond Poincare Hospital, Garches, France.
34
Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA, USA.
35
Centre for Medical Genetics Ghent, Ghent University Hospital, C. Heymanslaan 10, Ghent, Belgium.
36
Service de Genetique Medicale, Hôpital Chubert, Vannes, France.
37
APHP, Department of Clinical Neurophysiology, Necker-Enfants Malades Hospital, Paris, France.
38
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
39
Departement de Genetique Medicale, APHM, Hopital d'Enfants de La Timone, Marseille, France.
40
Child Neurology Department, 2nd Faculty of Medicine, Charles University and Motol Hospital, Prague, Czech Republic.
41
Centre de Genetique Humaine, Institut de Pathologie et de Genetique, Gosselies, Belgium.
42
Unite fonctionnelle de genetique clinique, Centre Hospitalier Intercommunal de Creteil, Creteil, France.
43
APHP, Service de neurologie pediatrique, Hôpital Universitaire Bicetre, Le Kremlin-Bicetre, France.
44
Department of Pediatrics, Albany Medical Center, Albany, NY, USA.
45
APHP, Hôpital Trousseau, service de neuropediatrie, Paris, France.
46
Sorbonne Universite, GRC n°19, pathologies Congenitales du Cervelet-LeucoDystrophies, APHP, Hôpital Armand Trousseau, Paris, France.
47
Division of Neuropediatrics, CHU Raymond Poincare (APHP), Garches, France.
48
Service de Genetique Medicale, CLAD Ouest CHU Hôpital Sud, Rennes, France.
49
Unite de Genetique Medicale, Centre de Reference des Maladies rares du Developpement (AnD DI Rares), CHI Poissy-St Germain en Laye, Poissy, France.
50
Departments of Pediatrics and Neurosciences, CHU Sainte-Justine and University of Montreal, Montreal, Canada.
51
Institut de Genetique Medicale, CHRU Lille, Universite de Lille, Lille, France.
52
Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics, Universite Libre de Bruxelles, Brussels, Belgium.
53
Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Universite Libre de Bruxelles, Brussels, Belgium.
54
Interuniversity Institute of Bioinformatics in Brussels, Universite Libre de Bruxelles, Brussels, Belgium.
55
Clinical Genomics & Predictive Medicine, Providence Medical Group, Dayton, WA, USA.
56
Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
57
Neurogenetics Group, Center of Molecular Neurology, VIB, Antwerp, Belgium.
58
Neurology Department, University Hospital Antwerp, Antwerp, Belgium.
59
INSERM, U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France. christel.depienne@uni-due.de.
60
IGBMC, CNRS UMR 7104/INSERM U964/Universite de Strasbourg, Illkirch, France. christel.depienne@uni-due.de.
61
Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. christel.depienne@uni-due.de.

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

PMID:
30206421
DOI:
10.1038/s41436-018-0268-1
[Indexed for MEDLINE]

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