TLK2 encodes a serine-threonine kinase involved in chromatin assembly, and DNA replication, transcription, and repair. Although de novo variants in TLK2 had been observed in large-scale sequencing studies of individuals with neurodevelopmental disorders since 2014 (PMIDs: 25363768, 25533962), the first report highlighting TLK2 variants as a cause of autosomal dominant complex neurodevelopmental disorder was published in 2016 (Lelieveld et al., PMID: 27479843). The disorder is characterized by a highly variable phenotype, including global developmental delay; borderline, mild or moderate intellectual disability; behavioral disorders including autism; gastrointestinal problems; and facial dysmorphism (PMID: 29861108). Other variable features include short stature, microcephaly, abnormalities of skull shape, and seizures.
Eight variants (2 frameshift, 1 nonsense, 3 splice, and 2 missense) that have been reported in eight probands in four publications (PMIDs: 25363768, 29861108, 33323470, 34821460) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants occur primarily de novo but can be inherited from mildly affected parents. TLK2 is highly constrained for both truncating and missense variants (gnomAD v4.1.0). The mechanism of pathogenicity appears to be loss of function, as most cases are heterozygous for truncating variants (PMID: 29861108). Reported missense variants cluster mainly in the C-terminal kinase domain; variants localized in this region show a reduction of kinase activity (PMID: 29955062). TLK2 activation requires dimerization through a coiled-coil domain, suggesting that inactive mutants could have a dominant negative effect (PMID: 29955062).
This gene-disease relationship is also supported by experimental evidence, including in vitro functional assays of variants showing impaired kinase activity and decreased autophosphorylation (PMID: 29955062), and protein interactions with CHD7 and CHD8, which are also involved in neurodevelopmental disorders (PMID: 29955062).
In summary, there is definitive evidence supporting the relationship between TLK2 and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 5, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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