TLK2-associated intellectual disability: report of six novel cases and molecular characterization of p.(Asp551Gly) and p.(Ser617Leu) variants

ABSTRACT: Introduction The Tousled-Like Kinases 1 and 2 (TLK1 and TLK2) are involved in many fun-damental processes, including DNA replication, cell cycle checkpoint recovery and chromatin remodelling. Mutations in TLK2 were recently associated with “Mental Retardation Autoso-mal Dominant 57” (MRD57), a neurodevelopmental disorder characterized by a highly varia-ble phenotype, including mild-to-moderate intellectual disability, behavioural abnormalities, facial dysmorphisms, microcephaly, epilepsy and skeletal anomalies. Methods By whole exome sequencing and array-CGH analysis, we identified three independ-ent MRD57 cases. Two were de novo, including a likely pathogenic variant (c.1652A>G; p.(Asp551Gly)) and a 39-kb deletion encompassing TLK2, and one was familial with three sib-lings who inherited a nonsense change from an affected mother (c.1423G>T; p.(Glu475Ter)). Using spatial proteomics (BioID) and single gel electrophoresis, we investigated the proximity interaction landscape of TLK2 and analysed the effects of our missense variant and of another de novo variant reported in the Autism Sequencing Consortium Database (c.1850C>T; p.(Ser617Leu)) on TLK2 interactions, localization and activity. Results Identified clinical phenotypes were in accordance with previously reported cases. Our molecular results demonstrated that TLK2 activity is strongly impaired by both missense mu-tations and we identified proximal interactions between TLK2 and other factors implicated in neurological disorders, including CHD7, CHD8, BRD4, NACC1 and others. Moreover, we demonstrated a more relaxed state of chromatin in lymphoblastoid cells harbouring the p.(Asp551Gly) variant compared to control cells, which confers susceptibility to DNA damage. Conclusion Our study identified novel TLK2-patients carrying pathogenic variants and pro-vides new insights into their potential role in intellectual disability.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Marina Gay  

LAB HEAD: Travis H. Stracker

PROVIDER: PXD019450 | Pride | 2021-05-13

REPOSITORIES: Pride