TY - JOUR AU - Sa, MJN AU - Venselaar, H AU - Wiel, L AU - Trimouille, A AU - Lasseaux, E AU - Naudion, S AU - Lacombe, D AU - Piton, A AU - Vincent-Delorme, C AU - Zweier, C AU - Reis, A AU - Trollmann, R AU - Ruiz, A AU - Gabau, E AU - Vetro, A AU - Guerrini, R AU - Bakhtiari, S AU - Kruer, MC AU - Amor, DJ AU - Cooper, MS AU - Bijlsma, EK AU - Barakat, TS AU - van Dooren, MF AU - van Slegtenhorst, M AU - Pfundt, R AU - Gilissen, C AU - Willemsen, MA AU - de Vries, BBA AU - de Brouwer, APM AU - Koolen, DA Y2 - 2020/12/14 Y1 - 2020/04/01 SN - 1098-3600 UR - http://hdl.handle.net/11343/253974 AB - 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. LA - English PB - NATURE PUBLISHING GROUP T1 - De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy DO - 10.1038/s41436-019-0703-y IS - Genetics in Medicine VL - 22 IS - 4 SP - 797-802 ER -