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

Maria J Nabais Sá¹, Hanka Venselaar², Laurens Wiel^{2

3}, Aurélien Trimouille^{4

5}, Eulalie Lasseaux⁴, Sophie Naudion⁴, Didier Lacombe^{4

5}, Amélie Piton^{6

7}, Catherine Vincent-Delorme⁸, Christiane Zweier⁹, André Reis⁹, Regina Trollmann¹⁰, Anna Ruiz¹¹, Elisabeth Gabau¹², Annalisa Vetro¹³, Renzo Guerrini¹³, Somayeh Bakhtiari¹⁴, Michael C Kruer¹⁴, David J Amor^{15

16}, Monica S Cooper^{15

17}, Emilia K Bijlsma¹⁸, Tahsin Stefan Barakat¹⁹, Marieke F van Dooren¹⁹, Marjon van Slegtenhorst¹⁹, Rolph Pfundt¹, Christian Gilissen³, Michèl A Willemsen²⁰, Bert B A de Vries¹, Arjan P M de Brouwer¹, David A Koolen²¹

Affiliations

¹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center (Radboudumc), Nijmegen, The Netherlands.
² Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences (RIMLS), Radboudumc, Nijmegen, The Netherlands.
³ Department of Human Genetics, RIMLS, Radboudumc, Nijmegen, The Netherlands.
⁴ Department of Medical Genetics, CHU Bordeaux, Bordeaux, France.
⁵ Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), Inserm U1211, Bordeaux, France.
⁶ Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch-Graffenstaden, France.
⁷ INSERM U964, Illkirch-Graffenstaden, France.
⁸ Service de Génétique Clinique Guy Fontaine Hôpital Jeanne de Flandre, CHRU, Lille, France.
⁹ Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
¹⁰ Department of Pediatrics, Division of Neuropediatrics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
¹¹ Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.
¹² Paediatric Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.
¹³ Meyer Children's Hospital, University of Florence, Florence, Italy.
¹⁴ Barrow Neurological Institute, Phoenix Children's Hospital & University of Arizona College of Medicine, Phoenix, AZ, USA.
¹⁵ Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.
¹⁶ Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia.
¹⁷ Department of Neurodevelopment & Disability, Royal Children's Hospital, Melbourne, Australia.
¹⁸ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁹ Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
²⁰ Department of Pediatric Neurology, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, Amalia Children's Hospital, Nijmegen, The Netherlands.
²¹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center (Radboudumc), Nijmegen, The Netherlands. david.koolen@radboudumc.nl.

PMID: 31776469
DOI: 10.1038/s41436-019-0703-y

Free article

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

Maria J Nabais Sá et al. Genet Med. 2020 Apr.

Free article

. 2020 Apr;22(4):797-802.

doi: 10.1038/s41436-019-0703-y. Epub 2019 Nov 28.

Authors

Affiliations

¹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center (Radboudumc), Nijmegen, The Netherlands.
² Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences (RIMLS), Radboudumc, Nijmegen, The Netherlands.
³ Department of Human Genetics, RIMLS, Radboudumc, Nijmegen, The Netherlands.
⁴ Department of Medical Genetics, CHU Bordeaux, Bordeaux, France.
⁵ Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), Inserm U1211, Bordeaux, France.
⁶ Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch-Graffenstaden, France.
⁷ INSERM U964, Illkirch-Graffenstaden, France.
⁸ Service de Génétique Clinique Guy Fontaine Hôpital Jeanne de Flandre, CHRU, Lille, France.
⁹ Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
¹⁰ Department of Pediatrics, Division of Neuropediatrics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
¹¹ Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.
¹² Paediatric Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.
¹³ Meyer Children's Hospital, University of Florence, Florence, Italy.
¹⁴ Barrow Neurological Institute, Phoenix Children's Hospital & University of Arizona College of Medicine, Phoenix, AZ, USA.
¹⁵ Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.
¹⁶ Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia.
¹⁷ Department of Neurodevelopment & Disability, Royal Children's Hospital, Melbourne, Australia.
¹⁸ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁹ Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
²⁰ Department of Pediatric Neurology, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, Amalia Children's Hospital, Nijmegen, The Netherlands.
²¹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center (Radboudumc), Nijmegen, The Netherlands. david.koolen@radboudumc.nl.

PMID: 31776469
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.

Keywords: CLTC; intellectual disability; neurodevelopmental disorder.

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References

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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

Affiliations

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

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Medical