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New disease loci
Original article
De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy
  1. Iris M de Lange1,
  2. Katherine L Helbig2,
  3. Sarah Weckhuysen3,4,5,
  4. Rikke S Møller6,7,
  5. Milen Velinov8,9,
  6. Natalia Dolzhanskaya8,9,
  7. Eric Marsh10,
  8. Ingo Helbig10,
  9. Orrin Devinsky11,
  10. Sha Tang2,
  11. Heather C Mefford12,
  12. Candace T Myers12,
  13. Wim van Paesschen13,
  14. Pasquale Striano14,
  15. Koen van Gassen1,
  16. Marjan van Kempen1,
  17. Carolien G F de Kovel1,
  18. Juliette Piard15,
  19. Berge A Minassian16,
  20. Marjan M Nezarati17,
  21. André Pessoa18,
  22. Aurelia Jacquette19,
  23. Bridget Maher20,21,
  24. Simona Balestrini20,21,
  25. Sanjay Sisodiya20,21,
  26. Marie Therese Abi Warde22,23,
  27. Anne De St Martin22,23,
  28. Jamel Chelly23,24,
  29. EuroEPINOMICS-RES MAE working group,
  30. Ruben van ‘t Slot1,
  31. Lionel Van Maldergem15,
  32. Eva H Brilstra1,
  33. Bobby P C Koeleman1
  1. 1Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA
  3. 3Epilepsy 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
  4. 4Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium
  5. 5Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
  6. 6Danish Epilepsy Centre, Dianalund, Denmark
  7. 7Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
  8. 8New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA
  9. 9Albert Einstein College of Medicine, Bronx, New York, USA
  10. 10Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  11. 11NYU Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, New York, USA
  12. 12Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA
  13. 13Department of Neurology, UZ Leuven, Leuven, Belgium
  14. 14Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, G. Gaslini Institute, University of Genoa, Genova, Italy
  15. 15Centre de génétique humaine, Université de Franche-Comté, Besançon, France
  16. 16Division of Neurology, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Canada
  17. 17Genetics Program, North York General Hospital and Prenatal Diagnosis & Medical Genetics, Mt. Sinai Hospital, Toronto, Canada
  18. 18University of Fortaleza, Fortaleza, Brazil
  19. 19Service de génétique, GHU Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France
  20. 20UCL Institute of Neurology, London, UK
  21. 21Epilepsy Society, Bucks, UK
  22. 22Service de Pédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  23. 23Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France
  24. 24Service de Diagnostic Génétique, Hôpital Civil de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  1. Correspondence to Iris M de Lange, Lundlaan 6, 3584CG, Utrecht, The Netherlands; i.m.delange-2{at}umcutrecht.nl

Abstract

Background 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.

Methods Reported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation and expression studies were performed when possible.

Results 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.

Conclusions 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.

  • Clinical genetics
  • Epilepsy and seizures
  • <i>KIAA2022</i>
  • X-linked

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/jmedgenet-2016-103909

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    Footnotes

    • LVM, EHB and BPCK contributed equally

    • Collaborators EuroEpinomics consortium.

    • Contributors IMdL, KLH, SW, RSM, MV, ND, EM, IH, OD, ST, HCM, CTM, WvP, PS, KvG, CGFdK, JP, PS, BAM, MMN, AP, AJ, BM, SB, SS, MTAW, ADSM, JC, LVM, EB and BK contributed to drafting/revising the manuscript for content, including medical writing for content. EB and BK contributed to the study concept or design. IMdL, KLH, SW, ST, HCM, CTM, KvG, MvK, CGFdK, Rv‘tS, BM, EB and BK contributed to analysis or interpretation of data. KLH, SW, RSM, MV, EM, IH, WvP, JP, BAM, MMN, AP, AJ, SB, SS, MT AW, ADSM, JC, LVM, EB and BK contributed to acquisition of data. CGFdK performed the statistical analysis. BK and EB performed study supervision or coordination.

    • List of EuroEPINOMICS-RES MAE working group coinvestigators Dana Craiu (Pediatric Neurology Clinic II, Department of Neurology, Pediatric Neurology, Psychiatry, Neurosurgery, Carol Davila (University of Medicine, Bucharest, Romania; Pediatric Neurology Clinic), Professor Doctor Alexandru Obregia (Clinical Hospital, Bucharest, Romania), Peter De Jonghe (Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium), Ingo Helbig (Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany), Renzo Guerrini (Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer, University of Florence, Florence, Italy), Anna-Elina Lehesjoki (Folkhälsan Institute of Genetics, Helsinki, Finland; Research Programs Unit, Molecular Neurology and Neuroscience Center, University of Helsinki, Helsinki, Finland), Carla Marini (Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer, University of Florence, Florence, Italy), Hiltrud Muhle (Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany), Rikke S Møller (Danish Epilepsy Centre, Dianalund, Denmark), Bernd Neubauer (Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, Giessen, Germany), Deb Pal (Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, UK), Kaja Selmer (Department of Medical Genetics, Oslo University Hospital, Oslo, Norway), Ulrich Stephani (Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany), Katalin Sterbova (Child Neurology Department, University Hospital Motol, Prague, Czech Republic), Pasquale Striano (Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, ‘G Gaslini Institute’, Genova, Italy), Tiina Talvik (Department of Pediatrics, University of Tartu, Tartu, Estonia; Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia), Sarah von Spiczak (Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany), Sarah Weckhuysen (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), Hande Caglayan (Department of Molecular Biology and Genetics Istanbul, Boğaziçi University, Istanbul, Turkey), Yvonne Weber (Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany), Dorota Hoffman-Zacharska (Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland).

    • Funding This study was supported by the ‘Stichting Vrienden WKZ’ (project 1614054) on behalf of Stichting Panta Rhei and the Wellcome Trust (Grant number: 104033/Z/14/Z). Funders had no involvement in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.

    • Competing interests KLH and ST are employed by and receive a salary from Ambry Genetics. BAM was supported by Genome Canada and the Ontario Brain Institute. BM, SB and SS are funded by the Epilepsy Society and Wellcome Trust. Part of this work was undertaken at University College London Hospitals, which received a proportion of funding from the NIHR Biomedical Research Centres funding scheme.

    • Ethics approval The ethical committees of the respective local institutions.

    • Provenance and peer review Not commissioned; externally peer reviewed.