title: De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy.
abstract: Mutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellectual disability and epilepsy.
  
  
  
  Reported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation and expression studies were performed when possible.
  
  
  
  All mutations were predicted to result in a frameshift or premature stop. 12 out of 14 patients had intractable epilepsy with myoclonic and/or absence seizures, and generalised in 11. Thirteen patients had mild to severe intellectual disability. This female phenotype partially overlaps with the reported male phenotype which consists of more severe intellectual disability, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation, complete absence of RNA expression in blood and a phenotype similar to male patients. In the six other tested patients, X-inactivation was random, confirmed by a non-significant twofold to threefold decrease of RNA expression in blood, consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles.
  
  
  
  Heterozygous loss of KIAA2022 expression is a cause of intellectual disability in females. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Iris M
authors.initials: IM
authors.lastname: de Lange
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Helbig
authors.affiliation: Epilepsy Unit, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpital de la Pitié Salpêtrière, Centre de reference épilepsies rares, Paris, France.|Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Danish Epilepsy Centre, Dianalund, Denmark.|Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA.|Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Milen
authors.initials: M
authors.lastname: Velinov
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA.|Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Dolzhanskaya
authors.affiliation: Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Marsh
authors.affiliation: Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: NYU Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, New York, USA.
authors.forename: Orrin
authors.initials: O
authors.lastname: Devinsky
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Candace T
authors.initials: CT
authors.lastname: Myers
authors.affiliation: Department of Neurology, UZ Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: van Paesschen
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, G. Gaslini Institute, University of Genoa, Genova, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Koen
authors.initials: K
authors.lastname: van Gassen
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marjan
authors.initials: M
authors.lastname: van Kempen
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: Centre de génétique humaine, Université de Franche-Comté, Besançon, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Piard
authors.affiliation: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
authors.affiliation: Genetics Program, North York General Hospital and Prenatal Diagnosis & Medical Genetics, Mt. Sinai Hospital, Toronto, Canada.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Nezarati
authors.affiliation: University of Fortaleza, Fortaleza, Brazil.
authors.forename: André
authors.initials: A
authors.lastname: Pessoa
authors.affiliation: Service de génétique, GHU Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Jacquette
authors.affiliation: UCL Institute of Neurology, London, UK.|Epilepsy Society, Bucks, UK.
authors.forename: Bridget
authors.initials: B
authors.lastname: Maher
authors.affiliation: UCL Institute of Neurology, London, UK.|Epilepsy Society, Bucks, UK.
authors.forename: Simona
authors.initials: S
authors.lastname: Balestrini
authors.affiliation: UCL Institute of Neurology, London, UK.|Epilepsy Society, Bucks, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sisodiya
authors.affiliation: Service de Pédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France.
authors.forename: Marie Therese Abi
authors.initials: MT
authors.lastname: Warde
authors.affiliation: Service de Pédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France.
authors.forename: Anne
authors.initials: A
authors.lastname: De St Martin
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France.|Service de Diagnostic Génétique, Hôpital Civil de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: van 't Slot
authors.affiliation: Centre de génétique humaine, Université de Franche-Comté, Besançon, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D018389:Codon, Nonsense; D000069279:Drug Resistant Epilepsy / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016368:Frameshift Mutation; D050172:Genes, X-Linked; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009030:Mosaicism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D013577:Syndrome; D049951:X Chromosome Inactivation
chemical_list: D018389:Codon, Nonsense; C000598871:NEXMIF protein, human; D009419:Nerve Tissue Proteins
keywords: <i>KIAA2022</i>; Clinical genetics; Epilepsy and seizures; X-linked