Intellectual disability
Gene: TLK2

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

2 reviews

Ellen McDonagh (Genomics England Curator)

Comment on list classification: New evidence to promote this gene from Red to Green has arisen. 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: 1 Jun 2018, 7:33 a.m.

Comment on mode of inheritance: Heterozygous de novo or maternally inherited variants reported in Reijnders & Miller et al, AJHG (2018).
Created: 1 Jun 2018, 7:08 a.m.

Comment on publications: New publication "De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder" Reijnders & Miller et al, AJHG, published Online: May 31, 2018. (https://doi.org/10.1016/j.ajhg.2018.04.014 - PMID not yet available).
Created: 1 Jun 2018, 7:07 a.m.

Created: 1 Jun 2018, 7:07 a.m.

Panel version: 2.83

Rebecca Foulger (Genomics England curator)

Red List (low evidence)

Added gene to panel but insufficient evidence to rate as diagnostic-grade. Current evidence comes from PMID:27479843 (2016) who perform meta-analysis on 2,637 de novo mutations identified from the exomes of 2,104 patient-parent trios, and identify TLK2 as a candidate ID gene.
Created: 31 Oct 2017, 10:18 a.m.

Phenotypes
intellectual disability

Publications

27479843

Created: 31 Oct 2017, 9:25 a.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.4

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Victorian Clinical Genetics Services
Expert Review Green

Phenotypes

Mental retardation, autosomal dominant 57, OMIM:618050
Mental retardation, autosomal dominant 57, MONDO:0054837

OMIM

608439

Clinvar variants

Variants in TLK2

Penetrance

None

Publications

Panels with this gene

History Filter Activity

31 Mar 2022, Gel status: 3

Set publications

Arina Puzriakova (Genomics England Curator)

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

8 Jan 2021, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: TLK2 were changed from intellectual disability to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837

29 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to TLK2.

1 Jun 2018, Gel status: 3