Reijnders, Margot R.F.Miller, Kerry A.Alvi, MohsanGoos, Jacqueline A.C.Lees, Melissa M.de Burca, AnnaHenderson, AlexKraus, AlisonMikat, Barbarade Vries, Bert B.A.Isidor, BertrandKerr, BronwynMarcelis, CarloSchluth-Bolard, CarolineDeshpande, CharuRuivenkamp, Claudia A.L.Wieczorek, DagmarBaralle, DianaBlair, Edward M.Engels, HartmutLüdecke, Hermann-JosefEason, JacquelineSanten, Gijs W.E.Clayton-Smith, JillChandler, KateTatton-Brown, KatrinaPayne, KatelynHelbig, KatherineRadtke, KellyNugent, Kimberly M.Cremer, KirstenStrom, Tim M.Bird, Lynne M.Sinnema, MargjeBitner-Glindzicz, Mariavan Dooren, Marieke F.Alders, MarielleKoopmans, MarijeBrick, LaurenKozenko, MariyaHarline, Megan L.Klaassens, MerelSteinraths, MichelleCooper, Nicola S.Edery, PatrickYap, PatrickTerhal, Paulien A.van der Spek, Peter J.Lakeman, PhillisTaylor, Rachel L.Littlejohn, Rebecca O.Pfundt, RolphMercimek-Andrews, SaadetStegmann, Alexander P.A.Kant, Sarina G.McLean, ScottJoss, ShelaghSwagemakers, Sigrid M.A.Douzgou, SofiaWall, Steven A.Küry, SebastianCalpena, EduardoKoelling, NilsMcGowan, Simon J.Twigg, Stephen R.F.Mathijssen, Irene M.J.Nellaker, ChristofferBrunner, Han G.Wilkie, Andrew O.M.2019-05-212019-05-212018-06-07Reijnders, M., Miller, K. A., Alvi, M., Goos, J., Lees, M. M., de Burca, A., … Wilkie, A. (2018). De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder. American journal of human genetics, 102(6), 1195–1203. doi:10.1016/j.ajhg.2018.04.014https://hdl.handle.net/1805/19420Next-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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesTousled-likeFacial averagingHaploinsufficiencyIntellectual disabilityKinaseArticle