De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy
Author
Nabais Sá, Maria JVenselaar, Hanka
Wiel, Laurens
Trimouille, Aurélien
Lasseaux, Eulalie
Naudion, Sophie
Lacombe, Didier
Piton, Amélie
Vincent-Delorme, Catherine
Zweier, Christiane
Reis, André
Trollmann, Regina
Ruiz, Anna
Gabau, Elisabeth
Vetro, Annalisa
Guerrini, Renzo
Bakhtiari, Somayeh
Kruer, Michael C
Amor, David J
Cooper, Monica S
Bijlsma, Emilia K
Barakat, Tahsin Stefan
van Dooren, Marieke F
van Slegtenhorst, Marjon
Pfundt, Rolph
Gilissen, Christian
Willemsen, Michèl A
de Vries, Bert B A
de Brouwer, Arjan P M
Koolen, David A
Affiliation
Univ Arizona, Coll MedIssue Date
2020-04
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NATURE PUBLISHING GROUPCitation
Nabais Sá, M.J., Venselaar, H., Wiel, L. et al. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy. Genet Med 22, 797–802 (2020). https://doi.org/10.1038/s41436-019-0703-yJournal
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© American College of Medical Genetics and GenomicsCollection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Purpose To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. Methods We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. Results All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. Conclusions The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.Note
6 month embargo; published online: 28 November 2019ISSN
1098-3600EISSN
1530-0366PubMed ID
31776469Version
Final accepted manuscriptae974a485f413a2113503eed53cd6c53
10.1038/s41436-019-0703-y
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