Kahn, Eva

ABSTRACT 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.

Abstract Chromosome 4p16.3 microdeletions are known to cause Wolf–Hirschhorn syndrome (WHS), which is characterized by a distinct craniofacial gestalt and multiple congenital malformations. The 4p16.3 region encompasses WHS critical region 1 (WHSCR1) and 2 (WHSCR2). The WHSCR contains several genes that have been implicated in the WHS phenotype including: WHS candidate 1 [WHSC1(aka NSD2, OMIM 602952)], WHS candidate 2 [WHSC2 (aka NELFA, OMIM 606026)], and LETM1 (OMIM 604407). Although several patients harboring 4p16.3 microdeletions that are associated with WHS phenotypes have been reported, the precise molecular underpinnings of WHS are subjects of active investigations. The potential role(s) of genes within the 4p16.3 are increasingly being investigated. Here we report the first documented case of 4p16.3 terminal microdeletion that is not associated with the characteristic WHS phenotype. We studied Individual A (7-months-old female) and her father, Individual B (27-year-old), who both carry a terminal 4p16.3 microdeletion (about 555kb) that is distal to the WHSCR [(WHSCR1) and (WHSCR2)], and does not include WHSC1, WHSC2, or LETM1. Overall, our findings expand the phenotypic spectrum associated with 4p16.3 microdeletions and suggest that, in some individuals, microdeletions within 4p16.3 region may not be sufficient to cause WHS.