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Am J Hum Genet. 2018 Jun 7;102(6):1195-1203. doi: 10.1016/j.ajhg.2018.04.014. Epub 2018 May 31.

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

Author information

1
Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands.
2
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
3
Visual Geometry Group, Department of Engineering Science, University of Oxford, Oxford OX1 2JD, UK.
4
Department of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
5
Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
6
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK.
7
Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK.
8
Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
9
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
10
CHU de Nantes, Service de Génétique Médicale, Nantes 44093 Cedex 1, France; INSERM, UMR-S 957, 1 Rue Gaston Veil, Nantes 44035, France.
11
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK.
12
Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
13
Hospices Civils de Lyon, Service de Génétique, Centre de Référence Anomalies du Développement, 69500 Bron, France; INSERM U1028, CNRS UMR5292, UCB Lyon 1, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, 69500 Bron, France.
14
South East Thames Regional Genetics Service, Guy's Hospital, London SE1 9RT, UK.
15
Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
16
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany; Institute of Human Genetics, Heinrich-Heine-University, Medical Faculty, 40225 Düsseldorf, Germany.
17
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
18
Human Development and Health, Duthie Building, University of Southampton, Southampton SO16 6YD, UK; Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK.
19
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, 53127 Bonn, Germany.
20
Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
21
Southwest Thames Regional Genetics Centre, St George's University Hospitals NHS Foundation Trust, St George's University of London, London SW17 0RE, UK.
22
Riley Hospital for Children, Indianapolis, Indiana, IN 46202, USA.
23
Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
24
Department of Pediatrics, Baylor College of Medicine, The Children's Hospital of San Antonio, San Antonio, TX 78207, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
25
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
26
University of California, San Diego, Department of Pediatrics; Genetics and Dysmorphology, Rady Children's Hospital San Diego, San Diego, CA 92123, USA.
27
Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht 6229 ER, the Netherlands.
28
Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
29
Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 21455, 3001 AL Rotterdam, the Netherlands.
30
Department of Clinical Genetics, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
31
Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
32
Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, ON L8N 3Z5, Canada.
33
Department of Pediatrics, Baylor College of Medicine, The Children's Hospital of San Antonio, San Antonio, TX 78207, USA.
34
Department of Paediatrics, Maastricht University Medical Center, Maastricht 6229 ER, the Netherlands.
35
Department of Medical Genetics, University of British Columbia, Vancouver, BC V8Z 6R5, Canada.
36
West Midlands Regional Clinical Genetics Unit, Birmingham Women's & Children's NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK.
37
Genetic Health Service New Zealand, Auckland 1142, New Zealand; Victorian Clinical Genetic Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; University of Auckland, Auckland 1142, New Zealand.
38
Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
39
Department of Pathology & Department of Bioinformatics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
40
Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1X8, Canada.
41
West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
42
Craniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
43
CHU de Nantes, Service de Génétique Médicale, 44093 Nantes Cedex 1, France.
44
Computational Biology Research Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
45
Nuffield Department of Women's and Reproductive Health, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DS, UK; Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford OX3 7FZ, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.
46
Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht 6229 ER, the Netherlands. Electronic address: han.brunner@radboudumc.nl.
47
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Craniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK. Electronic address: andrew.wilkie@imm.ox.ac.uk.

Abstract

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

KEYWORDS:

Tousled-like; facial averaging; haploinsufficiency; intellectual disability; kinase

PMID:
29861108
PMCID:
PMC5992133
DOI:
10.1016/j.ajhg.2018.04.014
[Indexed for MEDLINE]
Free PMC Article

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