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

Margot R. F. Reijnders, Kerry A. Miller, Mohsan Alvi, Jacqueline A. C. Goos, Melissa M. Lees, Anna de Burca, Alex Henderson, Alison Kraus, Barbara Mikat, Bert B. A. de Vries, Bertrand Isidor, Bronwyn Kerr, Carlo Marcelis, Caroline Schluth-Bolard, Charu Deshpande, Claudia A. L. Ruivenkamp, Dagmar Wieczorek, Diana Baralle, Edward M. Blair, Hartmut EngelsHermann-Josef Ludecke, Jacqueline Eason, Gijs W. E. Santen, Jill Clayton-Smith, Kate Chandler, Katrina Tatton-Brown, Katelyn Payne, Katherine Helbig, Kelly Radtke, Kimberly M. Nugent, Kirsten Cremer, Tim M. Strom, Lynne M. Bird, Margje Sinnema, Maria Bitner-Glindzicz, Marieke F. van Dooren, Marielle Alders, Marije Koopmans, Lauren Brick, Mariya Kozenko, Megan L. Harline, Merel Klaassens, Michelle Steinraths, Nicola S. Cooper, Patrick Edery, Patrick Yap, Paulien A. Terhal, Peter J. van der Spek, Alexander P. A. Stegmann, Han G. Brunner*, Deciphering Dev Disorders Study, Andrew O.M. Wilkie*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)1195-1203
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - 7 Jun 2018


  • Cell Line
  • Translocation, Genetic
  • Genetic Association Studies
  • Humans
  • Protein Kinases/genetics
  • Child, Preschool
  • Infant
  • Male
  • Loss of Function Mutation/genetics
  • RNA, Messenger/genetics
  • Young Adult
  • Inheritance Patterns/genetics
  • Base Sequence
  • Adolescent
  • Facies
  • Adult
  • Female
  • Child
  • Neurodevelopmental Disorders/genetics


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