TLK2 – Intellectual disability, autosomal dominant 57

Tousled-like kinase 2 (TLK2) haploinsufficiency due to heterozygous variants is causally associated with Intellectual disability, autosomal dominant 57 ([MONDO:0054837]). A consistent neurodevelopmental phenotype includes global developmental delay, behavioral abnormalities, gastrointestinal involvement, distinctive facial features, and variable additional findings such as short stature and sleep disturbances.

Genetic evidence derives from at least 9 unrelated probands: two de novo cases with a splice-site (c.1121+1G>A) and a frameshift (c.6del p.(Glu3LysfsTer?)) variant ([PMID:34821460]), five patients from three MRD57 families with missense (c.1652A>G; p.Gln551Arg) or truncating (c.1423G>T; p.Glu475Ter) variants and a gene-spanning deletion ([PMID:33323470]), plus additional de novo and familial cases in a Chinese pedigree (c.49dup p.(Glu17GlyfsTer10)) ([PMID:39296544]) and a 5-year-old proband (c.1015C>T p.(Arg339Trp)) ([PMID:39538191]). Segregation analysis shows variant transmission in 5 affected relatives across pedigrees.

The variant spectrum encompasses loss-of-function alleles (nonsense, frameshift, splice), missense changes clustering at the C-terminus, and structural deletions. A canonical splice-donor variant, c.1121+1G>A, exemplifies the recurrent disruption of TLK2 expression ([PMID:34821460]).

Functional assays demonstrate that pathogenic missense variants (p.Asp551Gly, p.Ser617Leu) severely impair TLK2 kinase activity, alter chromatin maintenance, and increase DNA damage susceptibility in patient cells ([PMID:33323470]). Truncating variants trigger haploinsufficiency consistent with reduced TLK2 dosage.

A homozygous missense change (c.163A>G; p.Lys55Glu) in a single patient causes a distinct, more severe neurodevelopmental syndrome, indicating that different allelic configurations may underlie divergent phenotypes but do not refute the dominant ID57 association ([PMID:31558842]).

Collectively, robust de novo and familial segregation data, coupled with concordant functional evidence, support a Strong ClinGen-level clinical validity for the TLK2–ID57 association. Key take-home: TLK2 sequence analysis should be included in diagnostic panels for unexplained intellectual disability and developmental delay.

References

• American journal of medical genetics. Part A • 2022 • Report of two children with global developmental delay in association with de novo TLK2 variant and literature review. PMID:34821460
• Journal of medical genetics • 2022 • Functional analysis of TLK2 variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis. PMID:33323470
• Frontiers in genetics • 2024 • Case report: A novel TLK2 variant with a neuropsychiatric phenotype from a Chinese family. PMID:39296544
• BMC pediatrics • 2024 • Report of one case with de novo mutation in TLK2 and literature review. PMID:39538191
• European journal of human genetics : EJHG • 2020 • Severe neurodevelopmental disease caused by a homozygous TLK2 variant. PMID:31558842

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