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

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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
Genetics in Medicine ( IF 6.6 ) Pub Date : 2019-11-28 , DOI: 10.1038/s41436-019-0703-y
Maria J Nabais Sá ₁ , Hanka Venselaar ₂ , Laurens Wiel _{2,

3} , Aurélien Trimouille _{4,

5} , Eulalie Lasseaux ₄ , Sophie Naudion ₄ , Didier Lacombe _{4,

5} , Amélie Piton _{6,

7} , Catherine Vincent-Delorme ₈ , Christiane Zweier ₉ , André Reis ₉ , Regina Trollmann ₁₀ , Anna Ruiz ₁₁ , Elisabeth Gabau ₁₂ , Annalisa Vetro ₁₃ , Renzo Guerrini ₁₃ , Somayeh Bakhtiari ₁₄ , Michael C Kruer ₁₄ , David J Amor _{15,

16} , Monica S Cooper _{15,

17} , Emilia K Bijlsma ₁₈ , Tahsin Stefan Barakat ₁₉ , Marieke F van Dooren ₁₉ , Marjon van Slegtenhorst ₁₉ , Rolph Pfundt ₁ , Christian Gilissen ₃ , Michèl A Willemsen ₂₀ , Bert B A de Vries ₁ , Arjan P M de Brouwer ₁ , David A Koolen ₁

Affiliation

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

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.

中文翻译：

从头 CLTC 变异与从轻度到重度智力障碍、小头畸形、胼胝体发育不全和癫痫的可变表型相关

目的

描述CLTC基因中可能存在致病性变异的个体的基因型-表型相关性。

方法

我们描述了 13 个具有新发 CLTC变体的个体。变异的因果关系通过使用CLTC的耐受性景观和适用的计算机辅助分子建模来确定。将在识别为错义和框内变异的个体中观察到的表型异常与在CLTC中具有无义或移码变异的个体进行比较。

结果

所有从头变体都被判断为因果关系。将我们的数据与之前报道的 14 名受影响个体 ( n = 27) 的数据相结合，所有这些人都有智力障碍 (ID)，范围从轻度到中度/重度，有或没有额外的神经、行为、颅面、眼科和胃肠道特征。小头畸形、胼胝体发育不全和癫痫在具有错义和框内变异的个体中比在具有无义和移码变异的个体中更常见。然而，这种差异并不显着。