TY - JOUR
T1 - De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy
AU - EuroEPINOMICS-RES MAE working group
AU - de Lange, Iris M.
AU - Helbig, Katherine L.
AU - Weckhuysen, Sarah
AU - Møller, Rikke S.
AU - Velinov, Milen
AU - Dolzhanskaya, Natalia
AU - Marsh, Eric
AU - Helbig, Ingo
AU - Devinsky, Orrin
AU - Tang, Sha
AU - Mefford, Heather C.
AU - Myers, Candace T.
AU - van Paesschen, Wim
AU - Striano, Pasquale
AU - van Gassen, Koen
AU - van Kempen, Marjan
AU - de Kovel, Carolien G.F.
AU - Piard, Juliette
AU - Minassian, Berge A.
AU - Nezarati, Marjan M.
AU - Pessoa, André
AU - Jacquette, Aurelia
AU - Maher, Bridget
AU - Balestrini, Simona
AU - Sisodiya, Sanjay
AU - Warde, Marie Therese Abi
AU - De St Martin, Anne
AU - Chelly, Jamel
AU - van 't Slot, Ruben
AU - Van Maldergem, Lionel
AU - Brilstra, Eva H.
AU - Koeleman, Bobby P.C.
AU - Craiu,
AU - Davila, Carol
AU - Obregia, Alexandru
AU - De Jonghe, Peter
AU - Guerrini, Renzo
AU - Lehesjoki, Anna Elina
AU - Marini, Carla
AU - Muhle, Hiltrud
AU - Neubauer, Bernd
AU - Pal, Deb
AU - Selmer, Kaja
AU - Stephani, Ulrich
AU - Sterbova, Katalin
AU - Talvik, Tiina
AU - von Spiczak, Sarah
AU - Caglayan, Hande
AU - Weber, Yvonne
AU - Hoffman-Zacharska, Dorota
N1 - Funding Information:
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.
PY - 2016/12/1
Y1 - 2016/12/1
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.
AB - 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.
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U2 - 10.1136/jmedgenet-2016-103909
DO - 10.1136/jmedgenet-2016-103909
M3 - Article
C2 - 27358180
AN - SCOPUS:84978982755
SN - 0022-2593
VL - 53
SP - 850
EP - 858
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 12
ER -