Human Gene Module / Chromosome 17 / TLK2

TLK2tousled-like kinase 2

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
6 / 15
Rare Variants / Common Variants
51 / 0
Aliases
TLK2, PKU-ALPHA
Associated Syndromes
DD, West syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
17q23.2
Associated Disorders
DD/NDD, ASD
Relevance to Autism

O'Roak et al. (2011) identified a de novo missense mutation in the TLK2 gene in an autistic proband. No mutations were observed in controls.

Molecular Function

Regulates processes involved in chromatin assembly. Rapidly and transiently inhibited by phosphorylation following generation of DNA ds breaks during S-phase

Reports related to TLK2 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Identification of human Asf1 chromatin assembly factors as substrates of Tousled-like kinases. Sillj HH and Nigg EA (2001) No -
2 Primary Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. O'Roak BJ , et al. (2011) Yes -
3 Recent Recommendation The expression of Tousled kinases in CaP cell lines and its relation to radiation response and DSB repair. Ronald S , et al. (2011) No -
4 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
5 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
6 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
7 Recent Recommendation Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
8 Support Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Jin SC , et al. (2017) No Neurodevelopmental disorders (NDD)
9 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
10 Recent Recommendation De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder. Reijnders MRF , et al. (2018) No ASD
11 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly. Boonsawat P , et al. (2019) No DD, behavioral abnormality
12 Support Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop... Schluth-Bolard C , et al. (2019) No -
13 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder. Munnich A , et al. (2019) Yes -
14 Support Severe neurodevelopmental disease caused by a homozygous TLK2 variant. Tpf A , et al. (2019) No Behavioral abnormalities, microcephaly
15 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
Rare Variants   (51)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 29861108 Reijnders MRF , et al. (2018)
- - translocation De novo NA - 30923172 Schluth-Bolard C , et al. (2019)
c.16C>T p.His6Tyr stop_gained De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1624+1G>T - splice_site_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.886C>T p.Leu296= stop_gained De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1860-1G>T - splice_site_variant Unknown - - 29861108 Reijnders MRF , et al. (2018)
c.2092C>T p.Arg698Ter stop_gained De novo NA - 27479843 Lelieveld SH et al. (2016)
c.181C>T p.Arg61Ter stop_gained De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.202G>T p.Glu68Ter stop_gained De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.832-1G>A - splice_site_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.777C>A p.Tyr259Ter stop_gained De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.784C>T p.Arg262Ter stop_gained De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.989C>A p.Ser330Ter stop_gained De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1121+1G>A - splice_site_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1122-1G>T - splice_site_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1616+1G>A - splice_site_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1972-2A>G - splice_site_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.2145+1G>A - splice_site_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1651C>T p.Gln551Ter stop_gained De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.2170C>T p.Arg724Ter stop_gained De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1784C>T p.Pro595Leu missense_variant De novo NA - 21572417 O'Roak BJ , et al. (2011)
c.872+2T>G - splice_site_variant De novo NA Simplex 30842647 Boonsawat P , et al. (2019)
c.1273G>A p.Glu425Lys missense_variant Unknown - - 29861108 Reijnders MRF , et al. (2018)
c.890G>A p.Gly297Asp missense_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.995G>A p.Arg332Lys missense_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1015C>T p.Arg339Trp missense_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1487A>G p.Asn496Ser missense_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1636C>T p.Arg546Trp missense_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1973C>G p.Pro658Arg missense_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1113del p.Glu372SerfsTer5 frameshift_variant De novo NA - 28991257 Jin SC , et al. (2017)
c.1266G>A p.Glu422= splice_site_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1025+2dup - splice_site_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1302A>C p.Arg434Ser missense_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.948del p.Tyr316Ter splice_site_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1015C>T p.Arg339Trp missense_variant De novo NA Simplex 31406558 Munnich A , et al. (2019)
c.1875+46_1875+47del - intron_variant De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.1266G>T p.Glu422Asp splice_site_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1191-6C>G - splice_region_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1364+16_1364+23dup - intron_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1490A>G p.Asp497Gly missense_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.163A>G p.Lys55Glu missense_variant Familial Both parents Simplex 31558842 Tpf A , et al. (2019)
c.1725del p.Asn576MetfsTer3 frameshift_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1526+2T>G - splice_site_variant Familial Maternal Simplex 29861108 Reijnders MRF , et al. (2018)
c.1651dup p.Asp551GlyfsTer33 frameshift_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.664_667del p.Asn222ValfsTer6 frameshift_variant De novo NA - 29861108 Reijnders MRF , et al. (2018)
c.1453del p.Gln485LysfsTer4 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1147_1148del p.His383TyrfsTer9 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.1325A>G p.Asn442Ser missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1412A>G p.His471Arg missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1819G>A p.Gly607Arg missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1755_1762del p.Lys585AsnfsTer5 frameshift_variant Familial Maternal Simplex 29861108 Reijnders MRF , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

A de novo loss-of-function (LoF) variant and a damaging missense variant in the TLK2 gene were identified in ASD probands from the Simons Simplex Collection (ORoak et al., 2011; Iossifov et al., 2014;), while a second damaging missense variant in this gene was identified in a Japanese ASD proband in Takata et al., 2018. Two de novo LoF variants in TLK2 were identified in patients with intellectual disability from the Radboud University Medical Center (RUMC) in Lelieveld et al., 2016. Clinical and genotype-phenotype evaluation of 38 unrelated individuals and two affected mothers with de novo or inherited variants in the TLK2 gene in Reijnders et al., 2018 identified a neurodevelopmental disorder characterized by developmental delay (86%), behavioral disorders (68%), severe gastrointestinal problems (63%) and facial dysmorphic features; autism spectrum disorder was observed in 11 individuals (32%).

Score Delta: Score remained at 4S

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

1/1/2020
4S
icon
4S

Score remained at 4S

Description

A de novo loss-of-function (LoF) variant and a damaging missense variant in the TLK2 gene were identified in ASD probands from the Simons Simplex Collection (ORoak et al., 2011; Iossifov et al., 2014;), while a second damaging missense variant in this gene was identified in a Japanese ASD proband in Takata et al., 2018. Two de novo LoF variants in TLK2 were identified in patients with intellectual disability from the Radboud University Medical Center (RUMC) in Lelieveld et al., 2016. Clinical and genotype-phenotype evaluation of 38 unrelated individuals and two affected mothers with de novo or inherited variants in the TLK2 gene in Reijnders et al., 2018 identified a neurodevelopmental disorder characterized by developmental delay (86%), behavioral disorders (68%), severe gastrointestinal problems (63%) and facial dysmorphic features; autism spectrum disorder was observed in 11 individuals (32%).

10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

A de novo loss-of-function (LoF) variant and a damaging missense variant in the TLK2 gene were identified in ASD probands from the Simons Simplex Collection (ORoak et al., 2011; Iossifov et al., 2014;), while a second damaging missense variant in this gene was identified in a Japanese ASD proband in Takata et al., 2018. Two de novo LoF variants in TLK2 were identified in patients with intellectual disability from the Radboud University Medical Center (RUMC) in Lelieveld et al., 2016. Clinical and genotype-phenotype evaluation of 38 unrelated individuals and two affected mothers with de novo or inherited variants in the TLK2 gene in Reijnders et al., 2018 identified a neurodevelopmental disorder characterized by developmental delay (86%), behavioral disorders (68%), severe gastrointestinal problems (63%) and facial dysmorphic features; autism spectrum disorder was observed in 11 individuals (32%).

7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

A de novo loss-of-function (LoF) variant and a damaging missense variant in the TLK2 gene were identified in ASD probands from the Simons Simplex Collection (ORoak et al., 2011; Iossifov et al., 2014;), while a second damaging missense variant in this gene was identified in a Japanese ASD proband in Takata et al., 2018. Two de novo LoF variants in TLK2 were identified in patients with intellectual disability from the Radboud University Medical Center (RUMC) in Lelieveld et al., 2016. Clinical and genotype-phenotype evaluation of 38 unrelated individuals and two affected mothers with de novo or inherited variants in the TLK2 gene in Reijnders et al., 2018 identified a neurodevelopmental disorder characterized by developmental delay (86%), behavioral disorders (68%), severe gastrointestinal problems (63%) and facial dysmorphic features; autism spectrum disorder was observed in 11 individuals (32%).

4/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

A de novo loss-of-function (LoF) variant and a damaging missense variant in the TLK2 gene were identified in ASD probands from the Simons Simplex Collection (ORoak et al., 2011; Iossifov et al., 2014;), while a second damaging missense variant in this gene was identified in a Japanese ASD proband in Takata et al., 2018. Two de novo LoF variants in TLK2 were identified in patients with intellectual disability from the Radboud University Medical Center (RUMC) in Lelieveld et al., 2016. Clinical and genotype-phenotype evaluation of 38 unrelated individuals and two affected mothers with de novo or inherited variants in the TLK2 gene in Reijnders et al., 2018 identified a neurodevelopmental disorder characterized by developmental delay (86%), behavioral disorders (68%), severe gastrointestinal problems (63%) and facial dysmorphic features; autism spectrum disorder was observed in 11 individuals (32%).

10/1/2017
5
icon
5

Decreased from 5 to 5

Description

O'Roak et al. (2011) identified a de novo missense mutation in the TLK2 gene in an autistic proband. No mutations were observed in controls.

7/1/2016
5
icon
5

Decreased from 5 to 5

Description

O'Roak et al. (2011) identified a de novo missense mutation in the TLK2 gene in an autistic proband. No mutations were observed in controls.

1/1/2015
5
icon
5

Decreased from 5 to 5

Description

O'Roak et al. (2011) identified a de novo missense mutation in the TLK2 gene in an autistic proband. No mutations were observed in controls.

7/1/2014
No data
icon
5

Increased from No data to 5

Description

O'Roak et al. (2011) identified a de novo missense mutation in the TLK2 gene in an autistic proband. No mutations were observed in controls.

4/1/2014
No data
icon
5

Increased from No data to 5

Description

O'Roak et al. (2011) identified a de novo missense mutation in the TLK2 gene in an autistic proband. No mutations were observed in controls.

Krishnan Probability Score

Score 0.60203862092037

Ranking 381/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99999980589704

Ranking 218/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.15253351590689

Ranking 87/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 2

Ranking 410/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.19716396324882

Ranking 4309/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
RFPL3 Ret finger protein-like 3 Human Protein Binding 10738 O75679
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