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., Isidor B., Kerr B., Marcelis C., Schluth-Bolard C., Deshpande C., Ruivenkamp CAL., Wieczorek D., 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.
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.