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

Date Published: June 07, 2018

Publisher: Elsevier

Author(s): 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 Engels, Hermann-Josef Lüdecke, 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, Phillis Lakeman, Rachel L. Taylor, Rebecca O. Littlejohn, Rolph Pfundt, Saadet Mercimek-Andrews, Alexander P.A. Stegmann, Sarina G. Kant, Scott McLean, Shelagh Joss, Sigrid M.A. Swagemakers, Sofia Douzgou, Steven A. Wall, Sébastien Küry, Eduardo Calpena, Nils Koelling, Simon J. McGowan, Stephen R.F. Twigg, Irene M.J. Mathijssen, Christoffer Nellaker, Han G. Brunner, Andrew O.M. Wilkie.


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.

Partial Text

The introduction of whole-exome sequencing (WES) as a diagnostic test for individuals with unexplained neurodevelopmental disorders (NDDs) has led to the identification of dozens of disease-associated genes. As a recent example, statistical analysis of aggregated exome data uncovered variants in ten different genes as likely causes of intellectual disability, a subtype of NDDs characterized by deficits in both intellectual and adaptive functioning.1, 2 One such gene was Tousled-like kinase 2 (TLK2 [MIM: 608439]), which was originally named because of homology to the Arabidopsis gene Tousled.3TLK2, ubiquitously expressed in all tissues including fetal brain, encodes a serine/threonine kinase comprising a catalytic domain and multiple highly conserved coiled-coil motifs.3, 4 TLK2 is known to have maximal activity during the S-phase of the cell cycle and is therefore tightly linked to DNA replication.3 DNA double-strand breaks lead to rapid and transient inhibition of TLK activity, suggesting a role in checkpoint regulation.5 With the discovery of both H3-H4 chaperone Asf1 and histone H3 as physiological substrates of TLKs, its protein function has been linked to chromatin assembly.6, 7, 8, 9, 10

The authors declare no competing interests.




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