| Title: |
De Novo and Inherited Loss-of-Function Variants in TLK2:Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder |
| 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; 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; Genetica; Genetica Klinische Genetica; Child Health |
| Publication Year: |
2018 |
| Subject Terms: |
facial averaging; haploinsufficiency; intellectual disability; kinase; Tousled-like; Genetics; Genetics(clinical) |
| 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 |
| File Description: |
text/plain |
| Language: |
English |
| ISSN: |
0002-9297 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/377026 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/377026 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.D0EE7FC4 |
| Database: |
BASE |