De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder
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.; The Deciphering Developmental Disorders Study
(2018) American Journal of Human Genetics, volume 102, issue 6, pp. 1195 - 1203
(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
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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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Keywords: facial averaging, haploinsufficiency, intellectual disability, kinase, Tousled-like, Genetics, Genetics(clinical)
ISSN: 0002-9297
Publisher: Cell Press
Note: Funding Information: We thank H. Mlcochova, V.P. Sharma, and M. van Zeijl for technical support. We thank Sandra Yang for her help in contacting referring clinicians from GeneDx. This project was supported by the French Ministry of Health (DGOS) and the French National Agency for Research (ANR) ( PRTS 2013 grant to C.S.-B.), the MRC through a Skills Development Fellowship ( MR/R024952/1 to R.L.T.), Methodology Research Fellowship ( MR/M014568/1 to C.N.), the Weatherall Institute of Molecular Medicine Strategic Alliance ( G0902418 , MC_UU_12025 ), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (A.O.M.W.), and Wellcome Investigator Award 102731 (A.O.M.W.). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003 ), a parallel funding partnership between the Wellcome Trust and the Department of Health , and the Wellcome Trust Sanger Institute (grant number WT098051 ). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The research team acknowledges the support of the NIHR, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER, which is funded by the Wellcome Trust . ErasmusMC acknowledges Complete Genomics which donated 100 WGS trios for the centennial anniversary of the Erasmus University. J.A.C.G. was supported by the Innovation Fund (project number 2922 ). We acknowledge the HUGODIMS consortium, which was supported by a grant from the French Ministry of Health and from the Health Regional Agency from Poitou-Charentes ( HUGODIMS, 2013, RC14_0107 ); we are grateful to Frédérique Allaire from the Health Regional Agency of Poitou-Charentes for supporting this project. Funding Information: We thank H. Mlcochova, V.P. Sharma, and M. van Zeijl for technical support. We thank Sandra Yang for her help in contacting referring clinicians from GeneDx. This project was supported by the French Ministry of Health (DGOS) and the French National Agency for Research (ANR) (PRTS 2013 grant to C.S.-B.), the MRC through a Skills Development Fellowship (MR/R024952/1 to R.L.T.), Methodology Research Fellowship (MR/M014568/1 to C.N.), the Weatherall Institute of Molecular Medicine Strategic Alliance (G0902418, MC_UU_12025), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (A.O.M.W.), and Wellcome Investigator Award 102731 (A.O.M.W.). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The research team acknowledges the support of the NIHR, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER, which is funded by the Wellcome Trust. ErasmusMC acknowledges Complete Genomics which donated 100 WGS trios for the centennial anniversary of the Erasmus University. J.A.C.G. was supported by the Innovation Fund (project number 2922). We acknowledge the HUGODIMS consortium, which was supported by a grant from the French Ministry of Health and from the Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107); we are grateful to Fr?d?rique Allaire from the Health Regional Agency of Poitou-Charentes for supporting this project. Publisher Copyright: © 2018 The Authors
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