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

Reijnders, MRF; Miller, KA; Alvi, M; Goos, JAC; Lees, MM; de Burca, A; Henderson, A; Kraus, A; Mikat, B; de Vries, BBA; et al. Reijnders, MRF; Miller, KA; Alvi, M; Goos, JAC; Lees, MM; de Burca, A; Henderson, A; Kraus, A; Mikat, B; de Vries, BBA; Isidor, B; Kerr, B; Marcelis, C; Schluth-Bolard, C; Deshpande, C; Ruivenkamp, CAL; Wieczorek, D; Deciphering Developmental Disorders Study; Baralle, D; Blair, EM; Engels, H; Lüdecke, H-J; Eason, J; Santen, GWE; Clayton-Smith, J; Chandler, K; Tatton-Brown, K; Payne, K; Helbig, K; Radtke, K; Nugent, KM; Cremer, K; Strom, TM; Bird, LM; Sinnema, M; Bitner-Glindzicz, M; van Dooren, MF; Alders, M; Koopmans, M; Brick, L; Kozenko, M; Harline, ML; Klaassens, M; Steinraths, M; Cooper, NS; Edery, P; Yap, P; Terhal, PA; van der Spek, PJ; Lakeman, P; Taylor, RL; Littlejohn, RO; Pfundt, R; Mercimek-Andrews, S; Stegmann, APA; Kant, SG; McLean, S; Joss, S; Swagemakers, SMA; Douzgou, S; Wall, SA; Küry, S; Calpena, E; Koelling, N; McGowan, SJ; Twigg, SRF; Mathijssen, IMJ; Nellaker, C; Brunner, HG; Wilkie, AOM (2018) De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder. Am J Hum Genet, 102 (6). pp. 1195-1203. ISSN 1537-6605 https://doi.org/10.1016/j.ajhg.2018.04.014
SGUL Authors: Tatton-Brown, Katrina Louise

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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.

Item Type: Article
Additional Information: © 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Tousled-like, facial averaging, haploinsufficiency, intellectual disability, kinase, Genetics & Heredity, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Journal or Publication Title: Am J Hum Genet
ISSN: 1537-6605
Language: eng
Dates:
DateEvent
7 June 2018Published
31 May 2018Published Online
26 April 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
HICF-1009-003Wellcome Trusthttp://dx.doi.org/10.13039/100004440
MR/R024952/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/M014568/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0902418Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UU_12025Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
102731Wellcome Trusthttp://dx.doi.org/10.13039/100004440
WT098051Wellcome Trusthttp://dx.doi.org/10.13039/100004440
2922Innovation FundUNSPECIFIED
RC14_0107Health Regional AgencyUNSPECIFIED
PubMed ID: 29861108
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109920
Publisher's version: https://doi.org/10.1016/j.ajhg.2018.04.014

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