Expanding the Phenotype of <scp> <i>TLK2</i> </scp> ‐Related Neurodevelopmental Disorder: Longitudinal Presentation in Two Young Adult Females

The TLK2 gene encodes a serine/threonine kinase essential for chromatin assembly. Loss-of-function heterozygous variants were recently identified as a cause of a rare neurodevelopmental disorder (TLK2-NDD) characterized by a variable spectrum of developmental delay, autism, behavioral issues, and severe constipation. We describe two unrelated young adult females presenting with neurodevelopmental delay, neurobehavioral abnormalities, and constipation since infancy secondary to truncating TLK2 variants. Case 1 is a 26-year-old female who was referred to our clinic for extended assessment of new-onset psychosis and concern for seizures. She has been diagnosed with autism spectrum disorder and has a history of developmental delay, constipation, and aggressive outbursts since early childhood. At the age of 24 years, she developed an acute onset of persistent daily auditory hallucinations with threatening content that was refractory to medical and electroconvulsive therapy. Video-EEG assessment found no correlates for hallucinations. Trio whole genome sequencing revealed a heterozygous de novo pathogenic TLK2 variant, NM_006852.6:c.367C>T (p.Arg123Ter). Case 2 is a 19-year-old female who was evaluated for developmental delay and intellectual disability. Her phenotype was also notable for constipation since infancy and suggestive hypothalamic features with obesity, metrorrhagia, and hypersomnia. Trio whole genome sequencing revealed a likely pathogenic heterozygous TLK2 variant NM_006852.6:c.587del(p.Ser196ThrfsTer19) inherited from an asymptomatic, mosaic father. We present the adult phenotype of two young females with truncating variants in TLK2 and unusual phenotypic features of refractory hallucinations and possible hypothalamic syndrome. While both features may be independent of TLK2-NDD, evidence from schizophrenia genome-wide association studies and tissue expression data indicates that these features might be a part of longitudinal phenotype development. Long-term follow-up studies are required to unfold the phenotypic spectrum of TLK2-NDD and to better understand the implications of these findings for management and prognosis.