Human Gene Module / Chromosome 8 / TTI2

TTI2TELO2 interacting protein 2

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
2 / 3
Rare Variants / Common Variants
3 / 0
Aliases
TTI2, C8orf41
Associated Syndromes
-
Chromosome Band
8p12
Associated Disorders
-
Relevance to Autism

A homozygous missense variant in the TTI2 gene (c.1307T>A; p.I436N) was identified that segregated with severe intellectual disability, microcephaly, behavioral problems and autistic features, short stature, skeletal anomalies, and facial dysmorphism in a large consanguineous multiplex family (Langouet et al., 2013).

Molecular Function

This gene encodes a regulator of the DNA damage response. The protein is a component of the Triple T complex (TTT) which also includes telomere length regulation protein and TELO2 interacting protein 1. The TTT complex is involved in cellular resistance to DNA damage stresses and may act as a regulator of phosphoinositide-3-kinase-related protein kinase (PIKK) abundance.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TTI2 (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutation in TTI2 reveals a role for triple T complex in human brain development Langout M , et al. (2013) No -
2 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
3 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.719G>A p.Trp240Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.595G>T p.Glu199Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1307T>A p.Ile436Asn missense_variant Familial Both parents Multiplex 23956177 Langout M , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A homozygous missense variant in the TTI2 gene (c.1307T>A; p.Ile436Asn) was identified that segregated with severe intellectual disability, microcephaly, behavioral problems and autistic features, short stature, skeletal anomalies, and facial dysmorphism in a large consanguineous multiplex family (Langouet et al., 2013).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

A homozygous missense variant in the TTI2 gene (c.1307T>A; p.Ile436Asn) was identified that segregated with severe intellectual disability, microcephaly, behavioral problems and autistic features, short stature, skeletal anomalies, and facial dysmorphism in a large consanguineous multiplex family (Langouet et al., 2013).

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Score remained at S

Description

A homozygous missense variant in the TTI2 gene (c.1307T>A; p.Ile436Asn) was identified that segregated with severe intellectual disability, microcephaly, behavioral problems and autistic features, short stature, skeletal anomalies, and facial dysmorphism in a large consanguineous multiplex family (Langouet et al., 2013).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
Krishnan Probability Score

Score 0.36762320758887

Ranking 23762/25841 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 0.0018863367644348

Ranking 11305/18225 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 0.92938197497676

Ranking 11153/18665 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 0.30407213299576

Ranking 2675/20870 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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