De novo and inherited loss-of-function variants in TLK2: clinical and genotype-phenotype evaluation of a distinct neurodevelopmental disorder

Journal article

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.

Authors: Reijnders, M; Miller, K; Alvi, M; Calpena, E; Koelling, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: American Journal of Human Genetics
• Volume: 102
• Issue: 6
• Pages: 1195-1203
• Publication date: 2018-05-31
• Acceptance date: 2018-04-26
• DOI: 10.1016/j.ajhg.2018.04.014
• ISSN: 0002-9297
• Keywords: tousled-like; kinase; intellectual disability; haploinsufficiency; facial averaging