The molecular and phenotypic spectrum of IQSEC2-related epilepsy.
IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants.



Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians.



Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features.



The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.
Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Institute of Medical Genetics, Holon, Israel.
Ayelet
A
Zerem
Department of Neurology, Takuto Rehabilitation Center for Children, Miyagi Children's Hospital, Sendai, Japan.
Kazuhiro
K
Haginoya
Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Institute of Medical Genetics, Holon, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Dorit
D
Lev
Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Institute of Medical Genetics, Holon, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Lubov
L
Blumkin
Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Institute of Medical Genetics, Holon, Israel.
Sara
S
Kivity
Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Institute of Medical Genetics, Holon, Israel.
Ilan
I
Linder
Department of Paediatrics, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
Cheryl
C
Shoubridge
GOLD Genetics of Learning Disability Service, Waratah, New South Wales, Australia.|University of New South Wales, Sydney, New South Wales, Australia.|Department of Obstetrics and Gynecology, The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Elizabeth Emma
EE
Palmer
GOLD Genetics of Learning Disability Service, Waratah, New South Wales, Australia.|University of New South Wales, Sydney, New South Wales, Australia.
Michael
M
Field
GOLD Genetics of Learning Disability Service, Waratah, New South Wales, Australia.|University of New South Wales, Sydney, New South Wales, Australia.
Jackie
J
Boyle
Department of Obstetrics and Gynecology, The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.|Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital of Sickkids, University of Toronto, Toronto, Ontario, Canada.
David
D
Chitayat
Pediatrics and Neurology, Division Epilepsy and Neurophysiology, Comprehensive Pediatric Epilepsy Program, Center for Neuroscience Research, Children's National Medical Center, George Washington University, Washington, District of Columbia, U.S.A.
William D
WD
Gaillard
Departments of Pediatrics and Neurology, The Johns Hopkins Hospital, Baltimore, Maryland, U.S.A.
Eric H
EH
Kossoff
Department of Medical Genetics, Rare Diseases and Personalized Medicine, Faculty of Medicine, Unit INSERM 1183, CHU Montpellier, University of Montpellier, Montpellier, France.
Marjolaine
M
Willems
Department of Medical Genetics, Rare Diseases and Personalized Medicine, Faculty of Medicine, Unit INSERM 1183, CHU Montpellier, University of Montpellier, Montpellier, France.
David
D
Geneviève
Department of Medical Genetics, Rare Diseases and Personalized Medicine, Faculty of Medicine, Unit INSERM 1183, CHU Montpellier, University of Montpellier, Montpellier, France.
Frederic
F
Tran-Mau-Them
Pediatric Neurology Department, Pediatric Epilepsy Service, Asaf Harofeh Medical Center, Zerifin, Israel.
Orna
O
Epstein
Pediatric Neurology Department, Pediatric Epilepsy Service, Asaf Harofeh Medical Center, Zerifin, Israel.
Eli
E
Heyman
Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, U.S.A.
Sarah
S
Dugan
Reference Center for Developmental Anomalies and Syndromes, Children's Hospital, CHU Dijon, Dijon, France.
Alice
A
Masurel-Paulet
Department of Translational Medicine and Neurogenetics, IGBMC, CNRS UMR 7104/INSERM U964/Strasbourg University, Strasbourg, France.|Genetic Diagnostic Laboratory, University Hospitals of Strasbourg, Strasbourg, France.
Ame'lie
A
Piton
Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
Tjitske
T
Kleefstra
Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
Rolph
R
Pfundt
Department of Neurology, Takuto Rehabilitation Center for Children, Miyagi Children's Hospital, Sendai, Japan.
Ryo
R
Sato
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany.|Institute of Clinical Genetics, Technische Universität Dresden, Dresden, Germany.
Andreas
A
Tzschach
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Naomichi
N
Matsumoto
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Hirotomo
H
Saitsu
Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Institute of Medical Genetics, Holon, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Esther
E
Leshinsky-Silver
Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Institute of Medical Genetics, Holon, Israel.|Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Tally
T
Lerman-Sagie
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004569:Electroencephalography; D004827:Epilepsy / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D056726:Genetic Association Studies; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
D020662:Guanine Nucleotide Exchange Factors; C550083:IQSEC2 protein, human
Epileptic encephalopathy; Exome sequencing; Intellectual disability; X-linked