Relevance to Autism

A de novo loss-of-function (LoF) variant and a damaging missense variant in the TLK2 gene were identified in ASD probands from the Simons Simplex Collection (ORoak et al., 2011; Iossifov et al., 2014;), while a second damaging missense variant in this gene was identified in a Japanese ASD proband in Takata et al., 2018. Two de novo LoF variants in TLK2 were identified in patients with intellectual disability from the Radboud University Medical Center (RUMC) in Lelieveld et al., 2016. Clinical and genotype-phenotype evaluation of 38 unrelated individuals and two affected mothers with de novo or inherited variants in the TLK2 gene in Reijnders et al., 2018 identified a neurodevelopmental disorder characterized by developmental delay (86%), behavioral disorders (68%), severe gastrointestinal problems (63%) and facial dysmorphic features; autism spectrum disorder was observed in 11 individuals (32%). Two de novo protein-truncating variants and a de novo missense variant that was predicted to be deleterious (defined as having an MPC score 2) were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified TLK2 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified TLK2 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

Regulates processes involved in chromatin assembly. Rapidly and transiently inhibited by phosphorylation following generation of DNA ds breaks during S-phase

External Links

References