De Novo and Inherited Loss-of-Function Variants in TLK2 :Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder
| Title: | De Novo and Inherited Loss-of-Function Variants in TLK2 :Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder |
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| Authors: | 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; Ludecke, 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.; Stegmann, Alexander P. A.; Brunner, Han G.; Wilkie, Andrew O.M. |
| Source: | Reijnders, M R F, Miller, K A, Alvi, M, Goos, J A C, Lees, M M, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, B B A, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, C A L, Wieczorek, D, Baralle, D, Blair, E M, Engels, H, Ludecke, H-J, Eason, J, Santen, G W E, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, K M, Cremer, K, Strom, T M, Bird, L M, Sinnema, M, Bitner-Glindzicz, M, van Dooren, M F, Alders, M, Koopmans, M, Brick, L, Kozenko, .... |
| Publication Year: | 2018 |
| Collection: | Maastricht University Research Publications |
| Subject Terms: | TOUSLED-LIKE KINASES; GENES; MUTATIONS; 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; Neurodevelopmental Disorders/genetics |
| Description: | 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. |
| Document Type: | article in journal/newspaper |
| Language: | English |
| ISSN: | 0002-9297; 1537-6605 |
| Relation: | info:eu-repo/semantics/altIdentifier/wos/000434946200015; info:eu-repo/semantics/altIdentifier/pissn/0002-9297; info:eu-repo/semantics/altIdentifier/eissn/1537-6605 |
| DOI: | 10.1016/j.ajhg.2018.04.014 |
| Availability: | https://cris.maastrichtuniversity.nl/en/publications/694818f3-5c2c-4380-85f2-cc7867ebe360; https://doi.org/10.1016/j.ajhg.2018.04.014 |
| Rights: | info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: | edsbas.7CFA9129 |
| Database: | BASE |