TLK2tousled-like kinase 2
Autism Reports / Total Reports
8 / 22Rare Variants / Common Variants
65 / 0Chromosome Band
17q23.2Associated Disorders
DD/NDD, ADHD, ASDGenetic Category
Rare Single Gene Mutation, SyndromicRelevance to Autism
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%). Two de novo protein-truncating variants and a de novo missense variant that was predicted to be deleterious (defined as having an MPC score 2) were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified TLK2 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified TLK2 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
Regulates processes involved in chromatin assembly. Rapidly and transiently inhibited by phosphorylation following generation of DNA ds breaks during S-phase
External Links
SFARI Genomic Platforms
Reports related to TLK2 (22 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 developmental disorders | 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 | - |
16 | Support | - | Pavinato L et al. (2020) | No | ASD, ADHD |
17 | Support | - | Brunet T et al. (2021) | No | - |
18 | Support | - | Brea-Fernández AJ et al. (2022) | No | - |
19 | Support | - | Zhou X et al. (2022) | Yes | - |
20 | Support | - | Spataro N et al. (2023) | No | - |
21 | Support | - | Kipkemoi P et al. (2023) | No | - |
22 | Support | - | Kuokuo Li et al. (2024) | Yes | - |
Rare Variants (65)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
- | - | translocation | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
- | - | translocation | De novo | - | - | 30923172 | Schluth-Bolard C , et al. (2019) | |
- | - | copy_number_loss | De novo | - | Simplex | 33323470 | Pavinato L et al. (2020) | |
c.973C>T | p.Gln325Ter | stop_gained | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.267+3A>C | - | splice_region_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.187C>T | p.Arg63Trp | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.267G>T | p.Glu89Asp | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.16C>T | p.His6Tyr | stop_gained | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1016G>A | p.Arg339Gln | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.1624+1G>T | - | splice_site_variant | De novo | - | - | 27479843 | Lelieveld SH et al. (2016) | |
c.886C>T | p.Leu296= | stop_gained | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.2092C>T | p.Arg698Ter | stop_gained | De novo | - | - | 27479843 | Lelieveld SH et al. (2016) | |
c.181C>T | p.Arg61Ter | stop_gained | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.202G>T | p.Glu68Ter | stop_gained | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.832-1G>A | - | splice_site_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1488dup | p.Lys497Ter | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.968+1G>C | - | splice_site_variant | De novo | - | Unknown | 33619735 | Brunet T et al. (2021) | |
c.777C>A | p.Tyr259Ter | stop_gained | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.784C>T | p.Arg262Ter | stop_gained | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.989C>A | p.Ser330Ter | stop_gained | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1121+1G>A | - | splice_site_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1122-1G>T | - | splice_site_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1616+1G>A | - | splice_site_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1860-1G>T | - | splice_site_variant | Unknown | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1972-2A>G | - | splice_site_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.2145+1G>A | - | splice_site_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1637G>A | p.Arg546Gln | missense_variant | De novo | - | - | 36980980 | Spataro N et al. (2023) | |
c.1651C>T | p.Gln551Ter | stop_gained | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.2170C>T | p.Arg724Ter | stop_gained | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1784C>T | p.Pro595Leu | missense_variant | De novo | - | - | 21572417 | O'Roak BJ , et al. (2011) | |
c.754C>T | p.Gln252Ter | stop_gained | Familial | Maternal | - | 36980980 | Spataro N et al. (2023) | |
c.872+2T>G | - | splice_site_variant | De novo | - | Simplex | 30842647 | Boonsawat P , et al. (2019) | |
c.890G>A | p.Gly297Asp | missense_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.995G>A | p.Arg332Lys | missense_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1015C>T | p.Arg339Trp | missense_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1273G>A | p.Glu425Lys | missense_variant | Unknown | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1487A>G | p.Asn496Ser | missense_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1636C>T | p.Arg546Trp | missense_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1973C>G | p.Pro658Arg | missense_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1113del | p.Glu372SerfsTer5 | frameshift_variant | De novo | - | - | 28991257 | Jin SC , et al. (2017) | |
c.1266G>A | p.Glu422= | splice_site_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1025+2dup | - | splice_site_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1302A>C | p.Arg434Ser | missense_variant | De novo | - | Simplex | 29346770 | Takata A , et al. (2018) | |
c.948del | p.Tyr316Ter | splice_site_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1015C>T | p.Arg339Trp | missense_variant | De novo | - | Simplex | 31406558 | Munnich A , et al. (2019) | |
c.1652A>G | p.Gln551Arg | missense_variant | De novo | - | Simplex | 33323470 | Pavinato L et al. (2020) | |
c.1655T>C | p.Ile552Thr | missense_variant | De novo | - | Simplex | 37463579 | Kipkemoi P et al. (2023) | |
c.1875+46_1875+47del | - | intron_variant | De novo | - | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
c.1266G>T | p.Glu422Asp | splice_site_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1191-6C>G | - | splice_region_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1364+16_1364+23dup | - | intron_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1784C>T | p.Ser595Leu | missense_variant | De novo | - | - | 35322241 | Brea-Fernández AJ et al. (2022) | |
c.1490A>G | p.Asp497Gly | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1725del | p.Asn576MetfsTer3 | frameshift_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1423G>T | p.Glu475Ter | stop_gained | Familial | Maternal | Multiplex | 33323470 | Pavinato L et al. (2020) | |
c.1651dup | p.Asp551GlyfsTer33 | frameshift_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.163A>G | p.Lys55Glu | missense_variant | Familial | Both parents | Simplex | 31558842 | Tpf A , et al. (2019) | |
c.1526+2T>G | - | splice_site_variant | Familial | Maternal | Simplex | 29861108 | Reijnders MRF , et al. (2018) | |
c.664_667del | p.Asn222ValfsTer6 | frameshift_variant | De novo | - | - | 29861108 | Reijnders MRF , et al. (2018) | |
c.1453del | p.Gln485LysfsTer4 | frameshift_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1147_1148del | p.His383TyrfsTer9 | frameshift_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
c.1325A>G | p.Asn442Ser | missense_variant | De novo | - | Unknown | 25533962 | Deciphering Developmental Disorders Study (2014) | |
c.1412A>G | p.His471Arg | missense_variant | De novo | - | Unknown | 25533962 | Deciphering Developmental Disorders Study (2014) | |
c.1819G>A | p.Gly607Arg | missense_variant | De novo | - | 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
High Confidence, Syndromic
Score Delta: Score remained at 1S
criteria met
See SFARI Gene'scoring criteriaWe 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.
The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."
1/1/2021
Score remained at 1
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%).
1/1/2020
Score remained at 1
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
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
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
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%).
7/1/2018
Decreased from 5 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
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
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.
1/1/2016
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.
Reports Added
[Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Identification of human Asf1 chromatin assembly factors as substrates of Tousled-like kinases.2001] [The expression of Tousled kinases in CaP cell lines and its relation to radiation response and DSB repair.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014]1/1/2015
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
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
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]
ExAC Score
Score 0.99999980589704
Ranking 218/18225 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.15253351590689
Ranking 87/18665 scored genes
[Show Scoring Methodology]
Larsen Cumulative Evidence Score
Score 2
Ranking 410/461 scored genes
[Show Scoring Methodology]
Zhang D Score
Score 0.19716396324882
Ranking 4309/20870 scored genes
[Show Scoring Methodology]
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
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 |