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  -