ArticleAmerican journal of human genetics2018
De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.
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Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 48 citations in OpenAlex.
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- Circulating blood circular RNA in Parkinson's Disease; from involvement in pathology to diagnostic tools in at-risk individuals.NPJ Parkinson's disease · 2024Article
- Report of one case with de novo mutation in TLK2 and literature review.BMC pediatrics · 2024Review
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- Discovery and optimization of narrow spectrum inhibitors of Tousled like kinase 2 (TLK2) using quantitative structure activity relationships.European journal of medicinal chemistry · 2024Article
- Case report: A novelFrontiers in genetics · 2024Article
- Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships.bioRxiv : the preprint server for biology · 2023Article
- Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome.Scientific reports · 2023Article
- A microdeletion del(12)(p11.21p11.23) with a cryptic unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome.Research square · 2023Article
- Overexpression of tousled-like kinase 2 predicts poor prognosis in HBV-related hepatocellular carcinoma patients after radical resection.Frontiers in genetics · 2023Article
- The benefit of diagnostic whole genome sequencing in schizophrenia and other psychotic disorders.Molecular psychiatry · 2022Article
- Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry.Nature communications · 2022Article
- Functional analysis ofJournal of medical genetics · 2022Article
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Authors and funding
70 authors at 20 institutions in 8 countries.
Margot R F ReijndersDepartment of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands.
Kerry A MillerClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Mohsan AlviVisual Geometry Group, Department of Engineering Science, University of Oxford, Oxford OX1 2JD, UK.
Jacqueline A C GoosDepartment of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Melissa M LeesDepartment of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
Anna de BurcaOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK.
Alex HendersonNorthern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK.
Alison KrausYorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
Barbara MikatInstitut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
Bert B A de VriesDepartment of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands.
Bertrand IsidorCHU de Nantes, Service de Génétique Médicale, Nantes 44093 Cedex 1, France; INSERM, UMR-S 957, 1 Rue Gaston Veil, Nantes 44035, France.
Bronwyn KerrDivision 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.
Carlo MarcelisDepartment of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
Caroline Schluth-BolardHospices 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.
Charu DeshpandeSouth East Thames Regional Genetics Service, Guy's Hospital, London SE1 9RT, UK.
Claudia A L RuivenkampDepartment of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
Dagmar WieczorekInstitut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany; Institute of Human Genetics, Heinrich-Heine-University, Medical Faculty, 40225 Düsseldorf, Germany.
Deciphering Developmental Disorders StudyWellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Diana BaralleHuman Development and Health, Duthie Building, University of Southampton, Southampton SO16 6YD, UK; Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK.
Edward M BlairOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK.
Hartmut EngelsInstitute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, 53127 Bonn, Germany.
Hermann-Josef LüdeckeInstitut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany; Institute of Human Genetics, Heinrich-Heine-University, Medical Faculty, 40225 Düsseldorf, Germany.
Jacqueline EasonNottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
Gijs W E SantenDepartment of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
Jill Clayton-SmithDivision 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.
Kate ChandlerDivision 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.
Katrina Tatton-BrownSouthwest Thames Regional Genetics Centre, St George's University Hospitals NHS Foundation Trust, St George's University of London, London SW17 0RE, UK.
Katelyn PayneRiley Hospital for Children, Indianapolis, Indiana, IN 46202, USA.
Katherine HelbigDivision of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
Kelly RadtkeDivision of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
Kimberly M NugentDepartment 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.
Kirsten CremerInstitute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, 53127 Bonn, Germany.
Tim M StromInstitute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
Lynne M BirdUniversity of California, San Diego, Department of Pediatrics; Genetics and Dysmorphology, Rady Children's Hospital San Diego, San Diego, CA 92123, USA.
Margje SinnemaDepartment of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht 6229 ER, the Netherlands.
Maria Bitner-GlindziczGenetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Marieke F van DoorenDepartment of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 21455, 3001 AL Rotterdam, the Netherlands.
Marielle AldersDepartment of Clinical Genetics, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
Marije KoopmansDepartment of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
Lauren BrickDivision of Genetics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Mariya KozenkoDivision of Genetics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Megan L HarlineDepartment of Pediatrics, Baylor College of Medicine, The Children's Hospital of San Antonio, San Antonio, TX 78207, USA.
Merel KlaassensDepartment of Paediatrics, Maastricht University Medical Center, Maastricht 6229 ER, the Netherlands.
Michelle SteinrathsDepartment of Medical Genetics, University of British Columbia, Vancouver, BC V8Z 6R5, Canada.
Nicola S CooperWest Midlands Regional Clinical Genetics Unit, Birmingham Women's & Children's NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK.
Patrick EderyHospices 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.
Patrick YapGenetic 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.
Paulien A TerhalDepartment of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
Peter J van der SpekDepartment of Pathology & Department of Bioinformatics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Phillis LakemanDepartment of Clinical Genetics, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
Rachel L TaylorDivision 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.
Rebecca O LittlejohnDepartment 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.
Rolph PfundtDepartment of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands.
Saadet Mercimek-AndrewsDivision 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.
Alexander P A StegmannDepartment of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht 6229 ER, the Netherlands.
Sarina G KantDepartment of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
Scott McLeanDepartment 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.
Shelagh JossWest of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
Sigrid M A SwagemakersDepartment of Pathology & Department of Bioinformatics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Sofia DouzgouDivision 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.
Steven A WallCraniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Sébastien KüryCHU de Nantes, Service de Génétique Médicale, 44093 Nantes Cedex 1, France.
Eduardo CalpenaClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Nils KoellingClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Simon J McGowanComputational Biology Research Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Stephen R F TwiggClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Irene M J MathijssenDepartment of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Christoffer NellakerNuffield 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.
Han G BrunnerDepartment 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.
Andrew O M WilkieClinical 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.
Erasmus MC · NLChildren's Hospital of San Antonio · USMaastricht University · NLRadboud University Nijmegen · NLUniversity of Manchester · GBUniversity of Oxford · GBLeiden University Medical Center · NLMRC Weatherall Institute of Molecular Medicine · GBAmbry Genetics (United States) · USAmsterdam UMC Location University of Amsterdam · NLEssen University Hospital · DEJohn Radcliffe Hospital · GBMcMaster University · CAOxford University Hospitals NHS Trust · GBUniversity Medical Center Utrecht · NLUniversity of Bonn · DEBirmingham Women’s and Children’s NHS Foundation Trust · GBCentre Hospitalier Universitaire de Nantes · FRCentre National de la Recherche Scientifique · FRChapel Allerton Hospital · GB
Funding
Department of Health RP-2016-07-011Medical Research Council G0902418Medical Research Council MR/M014568/1Medical Research Council MR/R024952/1Wellcome Trust 102731/Z/13/Z
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.
Indexed as
Genetic Association StudiesAdolescentAdultBase SequenceCell LineChildChild, PreschoolFaciesFemaleHumansInfantInheritance PatternsLoss of Function MutationMaleNeurodevelopmental DisordersProtein KinasesProtein Kinasesprotein kinase URNA, Messengerfacial averaginghaploinsufficiencyintellectual disabilitykinaseTousled-like
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