De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy

Iris M. de Lange, Katherine L. Helbig, Sarah Weckhuysen, Rikke S. Møller, Milen Velinov, Natalia Dolzhanskaya, Eric Marsh, Ingo Helbig, Orrin Devinsky, Sha Tang, Heather C. Mefford, Candace T. Myers, Wim van Paesschen, Pasquale Striano, Koen van Gassen, Marjan van Kempen, Carolien G F de Kovel, Juliette Piard, Berge A. Minassian, Marjan M. NezaratiAndré Pessoa, Aurelia Jacquette, Bridget Maher, Simona Balestrini, Sanjay Sisodiya, Marie Therese Abi Warde, Anne De St Martin, Jamel Chelly, Ruben van 't Slot, Lionel Van Maldergem, Eva H. Brilstra, Bobby P C Koeleman, Dana Craiu, Carol Davila, Alexandru Obregia, Peter De Jonghe, Renzo Guerrini, Anna Elina Lehesjoki, Carla Marini, Hiltrud Muhle, Bernd Neubauer, Deb Pal, Kaja Selmer, Ulrich Stephani, Katalin Sterbova, Tiina Talvik, Sarah von Spiczak, Hande Caglayan, Yvonne Weber, Dorota Hoffman-Zacharska

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
JournalJournal of Medical Genetics
Publication statusAccepted/In press - Jun 29 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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