Craniosynostosis

Gene: TLK2

Green List (high evidence)

TLK2 (tousled like kinase 2)
EnsemblGeneIds (GRCh38): ENSG00000146872
EnsemblGeneIds (GRCh37): ENSG00000146872
OMIM: 608439, Gene2Phenotype
TLK2 is in 4 panels

3 reviews

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

Reijinders et al 2018 report a new disorder. Abnormalities of skull shape were observed in 31% with clinically proven CSS in 4 (11%). Note added by GOSH: 0% exome coverage [Pseudogenes of TLK2 are present on chromosomes 10 and 17 (TLK2P1 & TLK2P2)] ; Review on behalf of Tracy Lester and Andrew Wilkie
Created: 5 Mar 2019, 11:33 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
AD MR type 57 - 618050

Publications

  • 27479843
  • https://doi.org/10.1016/j.ajhg.2018.04.014

Eleanor Williams (Genomics England Curator)

I don't know

Comment on publications: https://doi.org/10.1016/j.ajhg.2018.04.014 is PMID: 29861108
Created: 11 May 2019, 10:33 a.m.
This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: TLK2; Suggested initial gene rating: green
Created: 5 Mar 2019, 11:21 a.m.

Ellen McDonagh (Genomics England Curator)

Comment from Helen Brittain, Genomics England Clinical Team, regarding adding this gene to this panel as well as the Intellectual Disability (ID) panel: "Although only 11% had craniosynostosis, a large proportion had hypertelorism, plagiocephaly or facial asymmetry and, given the ID is often mild, they may present via other routes than the ID category".
Created: 13 Aug 2018, 4:31 p.m.
After discussion with the internal Genomics England Clinical Team, added this gene to this panel. A publication (Reijnders & Miller et al, AJHG, published online May 31, 2018) reports heterozygous loss-of-function or missense variants in this gene in 38 unrelated individuals and two affected mothers. Affected individuals had mild-boderline neurodevelopmental delay, behavioral disorders, severe gastro-intestinal problems and facial dysmorphism. 6% of the individuals had normal IQ levels (85–100), 14% had borderline ID (IQ 70–85), and from the 72% diagnosed with ID (IQ < 70), most had mild ID (IQ 50–70). 3 individuals were too young for formal assessment of their neurodevelopmental phenotype, but all had language and motor delay. Five loss-of-function variants were identified in gnomAD at a frequency of around 0.00002. None of the missense were identified in Exac or an in-house database of healthy individuals. Only one missense variant was identified in gnomAD in one individual (an allele frequency of 0.000004). The pseudogenes similar to TLK2 were investigated, and the sequences at the site of each recurrent mutation corresponded to wild-type TLK2, excluding a gene conversion mechanism. Analysis of ExAC demonstrated TLK2 is extremely intolerant for LOF variants with a pLI score of 1. Tlk2-null mice have been previously reported as embryonically lethal, due to placental failure.
Created: 13 Aug 2018, 4:29 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

  • 27479843
  • https://doi.org/10.1016/j.ajhg.2018.04.014

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • NHS GMS
  • Expert Review Green
  • Literature
Phenotypes
  • AD MR type 57 - 618050
OMIM
608439
Clinvar variants
Variants in TLK2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

11 May 2019, Gel status: 4

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Added phenotypes AD MR type 57 - 618050 for gene: TLK2

11 May 2019, Gel status: 4

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: TLK2 were set to 27479843; https://doi.org/10.1016/j.ajhg.2018.04.014

5 Mar 2019, Gel status: 3

Added New Source, Status Update

Eleanor Williams (Genomics England Curator)

Source NHS GMS was added to TLK2. Rating Changed from Green List (high evidence) to Green List (high evidence)

13 Aug 2018, Gel status: 3

Entity classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

Gene: tlk2 has been classified as Green List (High Evidence).

13 Aug 2018, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

TLK2 was added to Craniosynostosis syndromes phenotypes panel. Sources: Literature

13 Aug 2018, Gel status: 1

Created

Ellen McDonagh (Genomics England Curator)

TLK2 was created by Ellen McDonagh