De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy
AuthorNabais Sá, Maria J
Kruer, Michael C
Amor, David J
Cooper, Monica S
Bijlsma, Emilia K
Barakat, Tahsin Stefan
van Dooren, Marieke F
van Slegtenhorst, Marjon
Willemsen, Michèl A
de Vries, Bert B A
de Brouwer, Arjan P M
Koolen, David A
AffiliationUniv Arizona, Coll Med
MetadataShow full item record
PublisherNATURE PUBLISHING GROUP
CitationNabais 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
JournalGENETICS IN MEDICINE
Rights© American College of Medical Genetics and Genomics
Collection InformationThis 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 email@example.com.
AbstractPurpose 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.
Note6 month embargo; published online: 28 November 2019
VersionFinal accepted manuscript
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