Article Text
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
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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.