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De Novo and inherited loss-of-function variants in TLK2: Clinical and genotype-phenotype evaluation of a distinct neurodevelopmental disorder

De Novo and inherited loss-of-function variants in TLK2: Clinical and genotype-phenotype evaluation of a distinct neurodevelopmental disorder
De Novo and inherited loss-of-function variants in TLK2: Clinical and genotype-phenotype evaluation of a distinct neurodevelopmental disorder
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.
0002-9297
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Reijnders, Margot R.F., Miller, Kerry A., Alvi, Mohsan, Goos, Jacqueline A.C., Lees, Melissa M., De Burca, Anna, Henderson, Alex, Kraus, Alison, Mikat, Barbara, De Vries, Bert B.A., Isidor, Bertrand, Kerr, Bronwyn, Marcelis, Carlo, Schluth-Bolard, Caroline, Deshpande, Charu, Ruivenkamp, Claudia A.l., Wieczorek, Dagmar, Baralle, Diana, Blair, Edward M., Engels, Hartmut, Lüdecke, Hermann-Josef, Eason, Jacqueline, Santen, Gijs W.E., Clayton-Smith, Jill, Chandler, Kate, Tatton-Brown, Katrina, Payne, Katelyn, Helbig, Katherine, Radtke, Kelly, Nugent, Kimberly M., Cremer, Kirsten, Strom, Tim M., Bird, Lynne M., Sinnema, Margje, Bitner-Glindzicz, Maria, Van Dooren, Marieke F., Alders, Marielle, Koopmans, Marije, Brick, Lauren, Kozenko, Mariya, Harline, Megan L., Klaassens, Merel, Steinraths, Michelle, Cooper, Nicola S., Edery, Patrick, Yap, Patrick, Terhal, Paulien A., Van Der Spek, Peter J., Lakeman, Phillis, Taylor, Rachel L., Littlejohn, Rebecca O., Pfundt, Rolph, Mercimek-Andrews, Saadet, Stegmann, Alexander P.A., Kant, Sarina G., Mclean, Scott, Joss, Shelagh, Swagemakers, Sigrid M.A., Douzgou, Sofia, Wall, Steven A., Küry, Sébastien, Calpena, Eduardo, Koelling, Nils, Mcgowan, Simon J., Twigg, Stephen R.F., Mathijssen, Irene M.J., Nellaker, Christoffer, Brunner, Han G. and Wilkie, Andrew O.M. (2018) De Novo and inherited loss-of-function variants in TLK2: Clinical and genotype-phenotype evaluation of a distinct neurodevelopmental disorder. The American Journal of Human Genetics, 102 (6), 1195-1203. (doi:10.1016/j.ajhg.2018.04.014).

Record type: Article

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.

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Article incl suppl TLK2 AJHG - Accepted Manuscript
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Accepted/In Press date: 26 April 2018
e-pub ahead of print date: 22 May 2018
Published date: 7 June 2018

Identifiers

Local EPrints ID: 421446
URI: http://eprints.soton.ac.uk/id/eprint/421446
ISSN: 0002-9297
PURE UUID: 8008fbc4-9691-425c-bb8f-29a45776061d
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

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Date deposited: 12 Jun 2018 16:30
Last modified: 16 Mar 2024 03:57

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Contributors

Author: Margot R.F. Reijnders
Author: Kerry A. Miller
Author: Mohsan Alvi
Author: Jacqueline A.C. Goos
Author: Melissa M. Lees
Author: Anna De Burca
Author: Alex Henderson
Author: Alison Kraus
Author: Barbara Mikat
Author: Bert B.A. De Vries
Author: Bertrand Isidor
Author: Bronwyn Kerr
Author: Carlo Marcelis
Author: Caroline Schluth-Bolard
Author: Charu Deshpande
Author: Claudia A.l. Ruivenkamp
Author: Dagmar Wieczorek
Author: Diana Baralle ORCID iD
Author: Edward M. Blair
Author: Hartmut Engels
Author: Hermann-Josef Lüdecke
Author: Jacqueline Eason
Author: Gijs W.E. Santen
Author: Jill Clayton-Smith
Author: Kate Chandler
Author: Katrina Tatton-Brown
Author: Katelyn Payne
Author: Katherine Helbig
Author: Kelly Radtke
Author: Kimberly M. Nugent
Author: Kirsten Cremer
Author: Tim M. Strom
Author: Lynne M. Bird
Author: Margje Sinnema
Author: Maria Bitner-Glindzicz
Author: Marieke F. Van Dooren
Author: Marielle Alders
Author: Marije Koopmans
Author: Lauren Brick
Author: Mariya Kozenko
Author: Megan L. Harline
Author: Merel Klaassens
Author: Michelle Steinraths
Author: Nicola S. Cooper
Author: Patrick Edery
Author: Patrick Yap
Author: Paulien A. Terhal
Author: Peter J. Van Der Spek
Author: Phillis Lakeman
Author: Rachel L. Taylor
Author: Rebecca O. Littlejohn
Author: Rolph Pfundt
Author: Saadet Mercimek-Andrews
Author: Alexander P.A. Stegmann
Author: Sarina G. Kant
Author: Scott Mclean
Author: Shelagh Joss
Author: Sigrid M.A. Swagemakers
Author: Sofia Douzgou
Author: Steven A. Wall
Author: Sébastien Küry
Author: Eduardo Calpena
Author: Nils Koelling
Author: Simon J. Mcgowan
Author: Stephen R.F. Twigg
Author: Irene M.J. Mathijssen
Author: Christoffer Nellaker
Author: Han G. Brunner
Author: Andrew O.M. Wilkie

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