Human Gene Module / Chromosome 7 / TRRAP

TRRAPtransformation/transcription domain associated protein

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
8 / 18
Rare Variants / Common Variants
63 / 0
Aliases
TRRAP, PAF350/400,  PAF400,  STAF40,  TR-AP,  Tra1
Associated Syndromes
-
Chromosome Band
7q22.1
Associated Disorders
ASD
Relevance to Autism

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

Molecular Function

This gene encodes a large multidomain protein of the phosphoinositide 3-kinase-related kinases (PIKK) family. The encoded protein is a common component of many histone acetyltransferase (HAT) complexes and plays a role in transcription and DNA repair by recruiting HAT complexes to chromatin.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TRRAP (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo mutations in epileptic encephalopathies Epi4K Consortium , et al. (2013) No -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
4 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
5 Support De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive disorder: a case report Mavros CF , et al. (2018) No -
6 Recent Recommendation Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity Coe BP , et al. (2018) No -
7 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
8 Recent Recommendation Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability Cogn B , et al. (2019) No ASD
9 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism Cappi C , et al. (2019) No -
10 Support - Li D et al. (2022) Yes -
11 Support - Zhou X et al. (2022) Yes -
12 Recent Recommendation - Pollina EA et al. (2023) No -
13 Support - Cirnigliaro M et al. (2023) Yes -
14 Support - Sheth F et al. (2023) Yes DD, ID
15 Support - Kirsten Furley et al. () No ASD
16 Support - Ruohao Wu et al. (2024) Yes -
17 Support - Miriam E Reyna-Fabián et al. (2024) No DD, epilepsy/seizures
18 Support - Axel Schmidt et al. (2024) No ASD
Rare Variants   (63)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3311A>G p.Glu1104Gly missense_variant De novo - - 28135719 et al. (2017)
c.3337G>A p.Val1113Met missense_variant De novo - - 28135719 et al. (2017)
c.4634C>T p.Ala1545Val missense_variant De novo - - 28135719 et al. (2017)
c.5596T>A p.Trp1866Arg missense_variant De novo - - 28135719 et al. (2017)
c.5598G>T p.Trp1866Cys missense_variant De novo - - 28135719 et al. (2017)
c.7697C>G p.Ala2566Gly missense_variant De novo - - 28135719 et al. (2017)
c.9300+4C>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.10096C>G p.His3366Asp missense_variant De novo - - 28135719 et al. (2017)
c.52A>T p.Met18Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.68A>G p.Gln23Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6G>A p.Ala2%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2386G>C p.Gly796Arg missense_variant Unknown - - 34968013 Li D et al. (2022)
c.8477+1G>A - splice_site_variant Unknown - - 38536866 Kirsten Furley et al. ()
c.1116G>T p.Arg372Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2320C>A p.Leu774Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2769C>G p.Ser923Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5786C>T p.Pro1929Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.11261C>T p.Thr3754Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3127G>A p.Ala1043Thr missense_variant De novo - - 30827496 Cogn B , et al. (2019)
c.6415T>C p.Trp2139Arg missense_variant De novo - - 30827496 Cogn B , et al. (2019)
c.5280C>T p.Phe1760%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.6904C>A p.Arg2302Ser synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.6011G>A p.Arg2004Gln missense_variant De novo - - 30424743 Mavros CF , et al. (2018)
c.2087G>A p.Arg696His missense_variant Unknown - Simplex 30564305 Guo H , et al. (2018)
c.5692A>G p.Lys1898Glu missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.8432A>C p.Lys2811Thr missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2413C>T p.Leu805Phe missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.2580C>G p.Phe860Leu missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.2678G>T p.Arg893Leu missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.3093T>G p.Ile1031Met missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.3104G>A p.Arg1035Gln missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.3127G>A p.Ala1043Thr missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.3311A>G p.Glu1104Gly missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.3331G>T p.Gly1111Trp missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.3475G>A p.Gly1159Arg missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.4465G>A p.Asp1489Asn missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.5596T>A p.Trp1866Arg missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.5598G>T p.Trp1866Cys missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.5647G>A p.Gly1883Arg missense_variant De novo - Simplex 30827496 Cogn B , et al. (2019)
c.9529G>A p.Val3177Met missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.310G>A p.Glu104Lys missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.5576G>A p.Arg1859His missense_variant De novo - Simplex 31771860 Cappi C , et al. (2019)
c.2446C>T p.Arg816Trp missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.3316G>A p.Glu1106Lys missense_variant De novo - Multiplex 30827496 Cogn B , et al. (2019)
c.3652G>A p.Ala1218Thr missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1195G>A p.Val399Ile missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.5575C>T p.Arg1859Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.11461C>T p.Arg3821Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3761C>A p.Ser1254Tyr missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.7090C>T p.Leu2364Phe missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.5592C>G p.Phe1864Leu missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.10775C>G p.Ser3592Cys missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2575G>A p.Asp859Asn missense_variant Unknown - Multi-generational 30827496 Cogn B , et al. (2019)
c.5795C>T p.Pro1932Leu missense_variant Familial Maternal Multiplex 30827496 Cogn B , et al. (2019)
c.3111C>A p.Ser1037Arg missense_variant De novo - Multi-generational 30827496 Cogn B , et al. (2019)
c.5647G>A p.Gly1883Arg missense_variant De novo - Multi-generational 30827496 Cogn B , et al. (2019)
c.11270G>A p.Arg3757Gln missense_variant De novo - Simplex 23934111 Epi4K Consortium , et al. (2013)
c.3316G>A p.Glu1106Lys missense_variant Unknown Not maternal Simplex 30827496 Cogn B , et al. (2019)
c.11270G>A p.Arg3757Gln missense_variant De novo - Extended multiplex 30827496 Cogn B , et al. (2019)
c.3127G>A p.Ala1043Thr missense_variant Unknown - Simplex 38909058 Miriam E Reyna-Fabián et al. (2024)
c.6110_6112del p.Met2037_Asp2038delinsAsn inframe_deletion De novo - Simplex 35982159 Zhou X et al. (2022)
c.7950_7951insAGATAAG p.Glu2651ArgfsTer2 frameshift_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.4250_4254del p.Thr1417ArgfsTer43 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

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."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

1/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

Reports Added
[De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.2019]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

Reports Added
[New Scoring Scheme]
1/1/2019
icon
4S

Increased from to 4S

Description

A de novo loss-of-function variant and multiple de novo missense variants in the TRRAP gene have been observed in ASD probands (Iossifov et al., 2014; Yuen et al., 2017), while multiple de novo missense variants in this gene have also been identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017) or epilepsy (Epi4K Consortium 2013). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified TRRAP as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Cogne et al., 2019 reported 24 individuals with 17 distinct de novo or apparently de novo missense variants that presented with two distinct clinical spectra: the first was a complex multi-systemic syndrome associated with various malformations of the brain, heart, kidneys and genitourinary system and a wide range of intellectual functioning in individuals with variants clustered between animo acids 1031 and 1159; the second spectrum manifested with autism spectrum disorder and/or intellectual disability and epilepsy in individuals with variants outside of this region.

Krishnan Probability Score

Score 0.49167643518953

Ranking 5259/25841 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 1

Ranking 6/18225 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
Iossifov Probability Score

Score 0.999

Ranking 5/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.75043382725747

Ranking 1559/18665 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 0.4270510239026

Ranking 1152/20870 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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