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

EuroEPINOMICS-RES MAE working group

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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.

Original languageEnglish (US)
Pages (from-to)850-858
Number of pages9
JournalJournal of Medical Genetics
Volume53
Issue number12
DOIs
StatePublished - Dec 1 2016

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Intellectual Disability
Mutation
X Chromosome Inactivation
Phenotype
Epilepsy
RNA
Myoclonic Epilepsy
Absence Epilepsy
Microcephaly
Mosaicism
Genetic Testing
Drug Resistant Epilepsy
Alleles
Growth
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy. / EuroEPINOMICS-RES MAE working group.

In: Journal of Medical Genetics, Vol. 53, No. 12, 01.12.2016, p. 850-858.

Research output: Contribution to journalArticle

EuroEPINOMICS-RES MAE working group. / De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy. In: Journal of Medical Genetics. 2016 ; Vol. 53, No. 12. pp. 850-858.
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title = "De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy",
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.",
author = "{EuroEPINOMICS-RES MAE working group} and {de Lange}, {Iris M.} and Helbig, {Katherine L.} and Sarah Weckhuysen and M{\o}ller, {Rikke S.} and Milen Velinov and Natalia Dolzhanskaya and Eric Marsh and Ingo Helbig and Orrin Devinsky and Sha Tang and Mefford, {Heather C.} and Myers, {Candace T.} and {van Paesschen}, Wim and Pasquale Striano and {van Gassen}, Koen and {van Kempen}, Marjan and {de Kovel}, {Carolien G.F.} and Juliette Piard and Minassian, {Berge A.} and Nezarati, {Marjan M.} and Andr{\'e} Pessoa and Aurelia Jacquette and Bridget Maher and Simona Balestrini and Sanjay Sisodiya and Warde, {Marie Therese Abi} and {De St Martin}, Anne and Jamel Chelly and {van 't Slot}, Ruben and {Van Maldergem}, Lionel and Brilstra, {Eva H.} and Koeleman, {Bobby P.C.} and Craiu and Carol Davila and Alexandru Obregia and {De Jonghe}, Peter and Renzo Guerrini and Lehesjoki, {Anna Elina} and Carla Marini and Hiltrud Muhle and Bernd Neubauer and Deb Pal and Kaja Selmer and Ulrich Stephani and Katalin Sterbova and Tiina Talvik and {von Spiczak}, Sarah and Hande Caglayan and Yvonne Weber and Dorota Hoffman-Zacharska",
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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

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

VL - 53

SP - 850

EP - 858

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 12

ER -