Human Gene Module / Chromosome 15 / TLN2

TLN2talin 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 9
Rare Variants / Common Variants
13 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
15q22.2
Associated Disorders
-
Relevance to Autism

A de novo missense variant with a CADD score > 25 was identified in the TLN2 gene in a Korean ASD proband in Kim et al., 2024; this gene was subsequently classified as an ASD candidate gene in males following a combined TADA analysis consisting of the Korean ASD cohort described in Kim et al., 2024 in addition to the Simons Simplex Collection and the SPARK cohort. A number of de novo variants in the TLN2 gene, including a de novo loss-of-function variant and eight de novo missense variants (four of which were predicted to be deleterious by CADD or REVEL), were previously reported in ASD probands from the Autism Sequencing Consortium, the Simons Simplex Collection, the MSSNG cohort, the SPARK cohort, and a Chinese ASD cohort (De Rubeis et al., 2014; Iossifov et al., 2014; Yuen et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022; Yuan et al., 2023).

Molecular Function

This gene encodes a protein related to talin 1, a cytoskeletal protein that plays a significant role in the assembly of actin filaments and in spreading and migration of various cell types, including fibroblasts and osteoclasts. This protein has a different pattern of expression compared to talin 1 but, like talin 1, is thought to associate with unique transmembrane receptors to form novel linkages between extracellular matrices and the actin cytoskeleton. Di Paolo et al., 2002 reported that Tln2 was the predominant talin that interacted with PIP5K1C in rat brain, and this interaction induced clustering of PIP5K1C and talin at focal adhesions and increased the local production of phosphatidylinositol-4,5-bisphosphate; Morgan et al., 2004 subsequently reported that microinjection of reagents into large lamprey axons that competed with the talin-PIP kinase interaction resulted in a dramatic decrease of synaptic actin and an impairment of clathrin-mediated synaptic vesicle endocytosis.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TLN2 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Gilbert Di Paolo et al. (2002) No -
2 Support - Jennifer R Morgan et al. (2004) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
6 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Yuan B et al. (2023) Yes -
9 Primary - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2954A>T p.Gln985Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2299C>G p.Leu767Val missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.3310A>G p.Met1104Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1279G>T p.Val427Phe missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.2805C>T p.Ile935= synonymous_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.6144G>A p.Ala2048= synonymous_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2243G>A p.Arg748His missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.2746del p.Ile916LeufsTer57 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.5014C>T p.Arg1672Trp missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.6838G>A p.Ala2280Thr missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.7418G>T p.Arg2473Leu missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.7232C>T p.Ala2411Val missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.601_606del p.Tyr201_Ser202del inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.56514513366239

Ranking 1254/25841 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.
Original Source
ExAC Score

Score 0.9998532307737

Ranking 737/18225 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
Original Source
Sanders TADA Score

Score 0.95035174805138

Ranking 18458/18665 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).
Original Source
Zhang D Score

Score 0.28842164639639

Ranking 2909/20870 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.
Original Source
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