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    De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

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    Author
    Nabais Sá, Maria J
    Venselaar, 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
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    Affiliation
    Univ Arizona, Coll Med
    Issue Date
    2020-04
    Keywords
    CLTC
    intellectual disability
    neurodevelopmental disorder
    
    Metadata
    Show full item record
    Publisher
    NATURE PUBLISHING GROUP
    Citation
    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-y
    Journal
    GENETICS IN MEDICINE
    Rights
    © American College of Medical Genetics and Genomics
    Collection 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 2019
    ISSN
    1098-3600
    EISSN
    1530-0366
    PubMed ID
    31776469
    DOI
    10.1038/s41436-019-0703-y
    Version
    Final accepted manuscript
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41436-019-0703-y
    Scopus Count
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