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

Nabais Sá MJ, Venselaar H, Wiel L, Trimouille A, Lasseaux E, Naudion S, Lacombe D, Piton A, Vincent-Delorme C, Zweier C, Reis A, Trollmann R, Ruiz A, Gabau E, Vetro A, Guerrini R, Bakhtiari S, Kruer MC, Amor DJ, Cooper MS, Bijlsma EK, Barakat TS, van Dooren MF, van Slegtenhorst M, Pfundt R, Gilissen C, Willemsen MA, de Vries BB, de Brouwer AP, Koolen DA (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Genetics in Medicine Nature Publishing Group: Open Access Hybrid Model Option B

DOI: 10.1038/s41436-019-0703-y

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.

Authors with CRIS profile

Christiane Zweier Medizinische Fakultät André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Regina Trollmann Professur für Kinder- u. Jugendmedizin Schwerpunkt Neuropädiatrie

Involved external institutions

Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Centre Hospitalier Universitaire de Bordeaux / CHU Bordeaux FR France (FR) Institute of Genetics and Molecular and Cellular Biology / Institut de génétique et de biologie moléculaire et cellulaire (IGBMC) FR France (FR) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) FR France (FR) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona ES Spain (ES) Azienda Ospedaliera Universitaria Meyer IT Italy (IT) University of Arizona US United States (USA) (US) The Royal Children's Hospital Melbourne AU Australia (AU) Leiden University Medical Center NL Netherlands (NL) Erasmus University Medical Center (MC) NL Netherlands (NL)

How to cite

APA:

Nabais Sá, M.J., Venselaar, H., Wiel, L., Trimouille, A., Lasseaux, E., Naudion, S.,... Koolen, D.A. (2019). De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy. Genetics in Medicine. https://doi.org/10.1038/s41436-019-0703-y

MLA:

Nabais Sá, Maria J., 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." Genetics in Medicine (2019).

BibTeX: Download