Human Gene Module / Chromosome 8 / TRAPPC9

TRAPPC9trafficking protein particle complex 9

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 25
Rare Variants / Common Variants
63 / 0
Aliases
TRAPPC9, IBP,  IKBKBBP,  MRT13,  NIBP,  T1,  TRS120
Associated Syndromes
-
Chromosome Band
8q24.3
Associated Disorders
DD/NDD, ID
Relevance to Autism

De novo damaging missense variants in the TRAPPC9 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were observed in ASD probands from the Simons Simplex Collection in Krumm et al. 201 and in a cohort of Chinese ASD probands in Guo et al., 2017. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified TRAPPC9 as an ASD candidate gene with a PTADA of 0.000561. A novel compound heterozygous mutation in the TRAPPC9 gene (consisting of a paternally-inherited frameshift variant and a maternally-inherited splice-site variant) was identified in a female proband diagnosed with ASD and her older brother, who presented with intellectual disability, born to healthy and non-consanguineous Thai parents (Hnoonual et al., 2019).

Molecular Function

Functions as an activator of NF-kappa-B through increased phosphorylation of the IKK complex. May function in neuronal cells differentiation. May play a role in vesicular transport from endoplasmic reticulum to Golgi. Homozygous mutations in the TRAPPC9 gene are associated with a form of autosomal recessive mental retardation (MRT13; OMIM 613192), a disorder characterized by postnatal microcephaly and white matter abnormalities (Mochida et al., 2009; Philippe et al., 2009; Mir et al., 2009; Kakar et al., 2012; Marangi et al., 2013).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TRAPPC9 (25 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly Mochida GH , et al. (2009) No ID, microcephaly
2 Support Combination of linkage mapping and microarray-expression analysis identifies NF-kappaB signaling defect as a cause of autosomal-recessive mental retardation Philippe O , et al. (2009) No ID, microcephaly
3 Support Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation Mir A , et al. (2009) No ID
4 Support TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype Marangi G , et al. (2012) No ID
5 Support A homozygous splice site mutation in TRAPPC9 causes intellectual disability and microcephaly Kakar N , et al. (2012) No ID
6 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
7 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
8 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
9 Recent Recommendation Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
10 Support Expanding the genetic heterogeneity of intellectual disability Anazi S , et al. (2017) No -
11 Support Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications Kalsner L , et al. (2017) Yes -
12 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No DD, stereotypies
13 Support Novel Compound Heterozygous Mutations in the TRAPPC9 Gene in Two Siblings With Autism and Intellectual Disability Hnoonual A , et al. (2019) Yes Microcephaly
14 Support Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity Liang ZS et al. (2020) No DD, stereotypy
15 Support - Alvarez-Mora MI et al. (2021) No -
16 Support - Aslanger AD et al. (2022) No -
17 Support - Álvarez-Mora MI et al. (2022) No -
18 Support - Leite AJDC et al. (2022) No -
19 Support - Zhou X et al. (2022) Yes -
20 Support - Asif M et al. (2022) No -
21 Support - Hu M et al. (2023) No -
22 Support - Cirnigliaro M et al. (2023) Yes -
23 Support - Mona Abdi et al. (2023) Yes DD, ID
24 Support - Purvi Majethia et al. (2024) No DD
25 Support - Marwa Kharrat et al. () No -
Rare Variants   (63)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.224G>A p.Gly75Glu missense_variant Familial - - 28831199 Li J , et al. (2017)
c.823A>C p.Thr275Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1522G>C p.Glu508Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1576G>A p.Gly526Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3225C>A p.Tyr1075Ter stop_gained Unknown - - 29271092 Kalsner L , et al. (2017)
c.3449C>T p.Ala1150Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Paternal - 35183220 Álvarez-Mora MI et al. (2022)
c.1453C>T p.Arg485Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3279+1G>A - splice_site_variant Familial Paternal - 35390071 Leite AJDC et al. (2022)
- - copy_number_loss Familial Paternal Multiplex 33921338 Alvarez-Mora MI et al. (2021)
c.1634del p.Leu545HisfsTer2 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.2785C>T p.Arg929Ter stop_gained - Both parents Simplex 28940097 Anazi S , et al. (2017)
c.268C>T p.Arg90Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3355C>T p.Arg1119Trp missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.289G>T p.Glu97Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.584+1G>A - splice_site_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
CT>C - frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.457G>T p.Glu153Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1854+1G>A - splice_site_variant Familial Maternal Unknown 32877400 Liang ZS et al. (2020)
c.2851-1G>C - splice_site_variant Familial Paternal Unknown 32877400 Liang ZS et al. (2020)
c.2674C>T p.Arg892Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2957G>A p.Trp986Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2565del p.Tyr855Ter frameshift_variant Familial Maternal - 35390071 Leite AJDC et al. (2022)
c.3214C>T p.Arg1072Ter stop_gained Familial Both parents - 30842647 Boonsawat P , et al. (2019)
c.2699+1G>A - splice_site_variant Familial Both parents - 38374498 Purvi Majethia et al. (2024)
c.688G>A p.Val230Met missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1013A>T p.Lys338Met missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1013A>T p.Lys338Met missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1019C>T p.Ala340Val missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1019C>T p.Ala340Val missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1196G>A p.Gly399Asp missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1234G>T p.Ala412Ser missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1373C>T p.Ala458Val missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1618G>A p.Val540Ile missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1684G>T p.Gly562Cys missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1773C>G p.Phe591Leu missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1898C>T p.Ala633Val missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2399G>A p.Cys800Tyr missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2473C>T p.Arg825Trp missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2590G>A p.Gly864Arg missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2597C>T p.Pro866Leu missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2622G>T p.Arg874Ser missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2653G>A p.Glu885Lys missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2704C>T p.Arg902Trp missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2794G>A p.Ala932Thr missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2800G>A p.Glu934Lys missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1708C>T p.Arg570Ter stop_gained Familial Both parents Simplex 37805537 Mona Abdi et al. (2023)
c.3163G>A p.Val1055Ile missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3163G>A p.Val1055Ile missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.3211G>A p.Gly1071Ser missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3332C>T p.Thr1111Met missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2700-2A>T - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2920C>T p.Arg974Ter stop_gained Familial Both parents Multiplex 38467738 Marwa Kharrat et al. ()
c.2674C>T p.Arg892Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1037G>A p.Gly346Glu missense_variant Familial Maternal - 35183220 Álvarez-Mora MI et al. (2022)
c.696C>G p.Phe232Leu missense_variant Familial Both parents Simplex 34983975 Aslanger AD et al. (2022)
c.531dup p.Leu178SerfsTer6 frameshift_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.743G>A p.Gly248Glu missense_variant Familial Maternal Multiplex 33921338 Alvarez-Mora MI et al. (2021)
c.670del p.Val224CysfsTer13 frameshift_variant Familial Both parents Multiplex 36672789 Asif M et al. (2022)
c.3055+1G>A - splice_site_variant Familial Maternal and paternal Multiplex 30853973 Hnoonual A , et al. (2019)
c.2122dup p.His708ProfsTer9 frameshift_variant Familial Maternal and paternal Multiplex 30853973 Hnoonual A , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo damaging missense variants in the TRAPPC9 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were observed in ASD probands from the Simons Simplex Collection in Krumm et al. 201 and in a cohort of Chinese ASD probands in Guo et al., 2017. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified TRAPPC9 as an ASD candidate gene with a PTADA of 0.000561. Homozygous mutations in the TRAPPC9 gene are associated with a form of autosomal recessive mental retardation (MRT13; OMIM 613192), a disorder characterized by postnatal microcephaly and white matter abnormalities (Mochida et al., 2009; Philippe et al., 2009; Mir et al., 2009; Kakar et al., 2012; Marangi et al., 2013). A novel compound heterozygous mutation in the TRAPPC9 gene (consisting of a paternally-inherited frameshift variant and a maternally-inherited splice-site variant) was identified in a female proband diagnosed with ASD and her older brother, who presented with intellectual disability, born to healthy and non-consanguineous Thai parents (Hnoonual et al., 2019).

Score Delta: Score remained at 2

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.

4/1/2021
2
icon
2

Score remained at 2

Description

De novo damaging missense variants in the TRAPPC9 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were observed in ASD probands from the Simons Simplex Collection in Krumm et al. 201 and in a cohort of Chinese ASD probands in Guo et al., 2017. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified TRAPPC9 as an ASD candidate gene with a PTADA of 0.000561. Homozygous mutations in the TRAPPC9 gene are associated with a form of autosomal recessive mental retardation (MRT13; OMIM 613192), a disorder characterized by postnatal microcephaly and white matter abnormalities (Mochida et al., 2009; Philippe et al., 2009; Mir et al., 2009; Kakar et al., 2012; Marangi et al., 2013). A novel compound heterozygous mutation in the TRAPPC9 gene (consisting of a paternally-inherited frameshift variant and a maternally-inherited splice-site variant) was identified in a female proband diagnosed with ASD and her older brother, who presented with intellectual disability, born to healthy and non-consanguineous Thai parents (Hnoonual et al., 2019).

Reports Added
[Novel Compound Heterozygous Mutation in TRAPPC9 Gene: The Relevance of Whole Genome Sequencing2021]
10/1/2020
2
icon
2

Score remained at 2

Description

De novo damaging missense variants in the TRAPPC9 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were observed in ASD probands from the Simons Simplex Collection in Krumm et al. 201 and in a cohort of Chinese ASD probands in Guo et al., 2017. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified TRAPPC9 as an ASD candidate gene with a PTADA of 0.000561. Homozygous mutations in the TRAPPC9 gene are associated with a form of autosomal recessive mental retardation (MRT13; OMIM 613192), a disorder characterized by postnatal microcephaly and white matter abnormalities (Mochida et al., 2009; Philippe et al., 2009; Mir et al., 2009; Kakar et al., 2012; Marangi et al., 2013). A novel compound heterozygous mutation in the TRAPPC9 gene (consisting of a paternally-inherited frameshift variant and a maternally-inherited splice-site variant) was identified in a female proband diagnosed with ASD and her older brother, who presented with intellectual disability, born to healthy and non-consanguineous Thai parents (Hnoonual et al., 2019).

Reports Added
[Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

De novo damaging missense variants in the TRAPPC9 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were observed in ASD probands from the Simons Simplex Collection in Krumm et al. 201 and in a cohort of Chinese ASD probands in Guo et al., 2017. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified TRAPPC9 as an ASD candidate gene with a PTADA of 0.000561. Homozygous mutations in the TRAPPC9 gene are associated with a form of autosomal recessive mental retardation (MRT13; OMIM 613192), a disorder characterized by postnatal microcephaly and white matter abnormalities (Mochida et al., 2009; Philippe et al., 2009; Mir et al., 2009; Kakar et al., 2012; Marangi et al., 2013). A novel compound heterozygous mutation in the TRAPPC9 gene (consisting of a paternally-inherited frameshift variant and a maternally-inherited splice-site variant) was identified in a female proband diagnosed with ASD and her older brother, who presented with intellectual disability, born to healthy and non-consanguineous Thai parents (Hnoonual et al., 2019).

Reports Added
[New Scoring Scheme]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

De novo damaging missense variants in the TRAPPC9 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were observed in ASD probands from the Simons Simplex Collection in Krumm et al. 201 and in a cohort of Chinese ASD probands in Guo et al., 2017. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified TRAPPC9 as an ASD candidate gene with a PTADA of 0.000561. Homozygous mutations in the TRAPPC9 gene are associated with a form of autosomal recessive mental retardation (MRT13; OMIM 613192), a disorder characterized by postnatal microcephaly and white matter abnormalities (Mochida et al., 2009; Philippe et al., 2009; Mir et al., 2009; Kakar et al., 2012; Marangi et al., 2013).

Reports Added
[Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.2019] [Novel Compound Heterozygous Mutations in the TRAPPC9 Gene in Two Siblings With Autism and Intellectual Disability.2019]
7/1/2017
icon
3

Increased from to 3

Description

De novo damaging missense variants in the TRAPPC9 gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function and damaging missense variants in this gene were observed in ASD probands from the Simons Simplex Collection in Krumm et al. 201 and in a cohort of Chinese ASD probands in Guo et al., 2017. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified TRAPPC9 as an ASD candidate gene with a PTADA of 0.000561. Homozygous mutations in the TRAPPC9 gene are associated with a form of autosomal recessive mental retardation (MRT13; OMIM 613192), a disorder characterized by postnatal microcephaly and white matter abnormalities (Mochida et al., 2009; Philippe et al., 2009; Mir et al., 2009; Kakar et al., 2012; Marangi et al., 2013).

Krishnan Probability Score

Score 0.45113272971021

Ranking 10725/25841 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 5.7603895345558E-6

Ranking 14438/18225 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 0.90854397167571

Ranking 7339/18665 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 0.32117304496662

Ranking 2418/20870 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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