TY - JOUR T1 - De novo mutations of <em>KIAA2022</em> in females cause intellectual disability and intractable epilepsy JF - Journal of Medical Genetics JO - J Med Genet SP - 850 LP - 858 DO - 10.1136/jmedgenet-2016-103909 VL - 53 IS - 12 AU - Iris M de Lange AU - Katherine L Helbig AU - Sarah Weckhuysen AU - Rikke S Møller AU - Milen Velinov AU - Natalia Dolzhanskaya AU - Eric Marsh AU - Ingo Helbig AU - Orrin Devinsky AU - Sha Tang AU - Heather C Mefford AU - Candace T Myers AU - Wim van Paesschen AU - Pasquale Striano AU - Koen van Gassen AU - Marjan van Kempen AU - Carolien G F de Kovel AU - Juliette Piard AU - Berge A Minassian AU - Marjan M Nezarati AU - André Pessoa AU - Aurelia Jacquette AU - Bridget Maher AU - Simona Balestrini AU - Sanjay Sisodiya AU - Marie Therese Abi Warde AU - Anne De St Martin AU - Jamel Chelly AU - EuroEPINOMICS-RES MAE working group AU - Ruben van ‘t Slot AU - Lionel Van Maldergem AU - Eva H Brilstra AU - Bobby P C Koeleman Y1 - 2016/12/01 UR - http://jmg.bmj.com/content/53/12/850.abstract N2 - 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. ER -