Human Gene Module / Chromosome 2 / XPO1

XPO1exportin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 12
Rare Variants / Common Variants
32 / 1
Aliases
XPO1, CRM-1,  CRM1,  emb,  exp1
Associated Syndromes
-
Chromosome Band
2p15
Associated Disorders
-
Relevance to Autism

In XPO1, rs6735330 was associated with autism in all four cohorts (P<0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P(FDR))=1.29 x 10(-5)), the AGRE cohort (P(FDR)=0.0011) and the combined families (P(FDR)=2.34 x 10(-9)). These results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region. van Oirsouw et al., 2025 collected the clinical data of 22 individuals with de novo XPO1 variants [11 individuals with putative loss-of-function variants and 11 with coding variants (10 missense variants and one in-frame deletion variant)] through online matchmaking and identified an overlapping phenotype consistent with a monogenic neurodevelopmental disorder characterized by developmental delay and/or intellectual disability, microcephaly, structural brain abnormalities, behavioral problems, dysmorphic features, and different organ anomalies; 5/11 individuals with a missense or in-frame deletion variant in XPO1 were reported to have autism spectrum disorder, compared to only 1/11 individuals with a putative loss-of-function variant (45% vs. 9%). Additional functional studies of XPO1 in Drosophila in van Oirsouw et al., 2025 demonstrated that GABAergic neuron-specific knockdown flies demonstrated impaired habituation. A total of six de novo missense variants in XPO1 (five of which had a MPC >2) were previously identified in five ASD probands from the Autism Sequencing Consortium, the SPARK cohort, and the Simons Simplex Collection (Satterstrom et al., 2020; Zhou et al., 2022; Fu et al., 2022).

Molecular Function

The protein encoded by this gene mediates leucine-rich nuclear export signal (NES)-dependent protein transport. Exportin 1 specifically inhibits the nuclear export of Rev and U snRNAs. It is involved in the control of several cellular processes by controlling the localization of cyclin B, MPAK, and MAPKAP kinase 2. This protein also regulates NFAT and AP-1.

External Links
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Reports related to XPO1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary 2p15-p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders Liu X , et al. (2011) Yes -
2 Support Haploinsufficiency of XPO1 and USP34 by a de novo 230 kb deletion in 2p15, in a patient with mild intellectual disability and cranio-facial dysmorphisms Fannemel M , et al. (2014) No -
3 Support Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis Bagheri H , et al. (2016) No -
4 Support Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome Lvy J , et al. (2017) No Motor delay, behavioral problems
5 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
6 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
8 Support Inhibition of Autism-Related Crm1 Disrupts Mitosis and Induces Apoptosis of the Cortical Neural Progenitors Li X , et al. (2020) No -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Fu JM et al. (2022) Yes -
11 Support - Soo-Whee Kim et al. (2024) Yes -
12 Recent Recommendation - Amber S E van Oirsouw et al. () No ASD, epilepsy/seizures
Rare Variants   (32)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 28573701 Lvy J , et al. (2017)
- - copy_number_loss Unknown - - 28573701 Lvy J , et al. (2017)
- - copy_number_loss De novo - - 24911659 Fannemel M , et al. (2014)
- - copy_number_gain De novo - - 31452935 Feliciano P et al. (2019)
c.2150T>G p.Met717Arg missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.656C>T p.Ala219Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1467G>C p.Trp489Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1927G>A p.Ala643Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.315C>G p.Tyr105Ter stop_gained De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.553C>T p.Gln185Ter stop_gained De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.913C>T p.Arg305Ter stop_gained De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.775A>G p.Met259Val missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.2293C>T p.Arg765Ter stop_gained De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.1675T>A p.Trp559Arg missense_variant De novo - Simplex 35982160 Fu JM et al. (2022)
c.888+1G>A p.? splice_site_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.1887+1G>T p.? splice_site_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.579T>G p.His193Gln missense_variant De novo - Multiplex 28714951 Lim ET , et al. (2017)
c.1343C>A p.Thr448Lys missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.1361A>G p.Tyr454Cys missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.1537G>A p.Glu513Lys missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.1575A>C p.Leu525Phe missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.1704G>T p.Lys568Asn missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.1949A>C p.Gln650Pro missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.2146G>T p.Asp716Tyr missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.2150T>G p.Met717Arg missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.2525C>G p.Pro842Arg missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.2738G>T p.Ser913Ile missense_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.2022+886_2314-728del - copy_number_loss De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.639+3_639+6del p.? splice_site_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.1643_1645del p.Val548del inframe_deletion De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.1282del p.Glu428ArgfsTer6 frameshift_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
c.3014_3018del p.Asn1005ArgfsTer22 frameshift_variant De novo - - 40819229 Amber S E van Oirsouw et al. ()
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.302-2033C>T;c.104-2033C>T;c.-92-2033C>T;c.-93-4449C>T;c.-2022-2033C>T - intron_variant - - - 21750575 Liu X , et al. (2011)
SFARI Gene score
2

Strong Candidate

A SNP in the XPO1 gene (rs6735330) was found to associate with autism in four cohorts, being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing of 1.29E-05), the AGRE cohort [P(FDR)=0.0011] and the combined families [P(FDR)=2.34E-09] (Liu et al., 2011). XPO1 has been proposed to be a candidate gene for 2p16.1-p15 microdeletion syndrome, a neurodevelopmental disorder in which many patients present with autism or autistic features. Functional analysis of candidate genes for 2p16.1-p15 microdeletion syndrome in zebrafish found that knockdown of xpo1a, one of the two copies of XPO1 in zebrafish, resulted in significant microcephaly and abnormal body shape (Bagheri et al., 2016).

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A SNP in the XPO1 gene (rs6735330) was found to associate with autism in four cohorts, being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing of 1.29E-05), the AGRE cohort [P(FDR)=0.0011] and the combined families [P(FDR)=2.34E-09] (Liu et al., 2011). XPO1 has been proposed to be a candidate gene for 2p16.1-p15 microdeletion syndrome, a neurodevelopmental disorder in which many patients present with autism or autistic features. Functional analysis of candidate genes for 2p16.1-p15 microdeletion syndrome in zebrafish found that knockdown of xpo1a, one of the two copies of XPO1 in zebrafish, resulted in significant microcephaly and abnormal body shape (Bagheri et al., 2016).

1/1/2020
3
icon
3

Decreased from 3 to 3

Description

A SNP in the XPO1 gene (rs6735330) was found to associate with autism in four cohorts, being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing of 1.29E-05), the AGRE cohort [P(FDR)=0.0011] and the combined families [P(FDR)=2.34E-09] (Liu et al., 2011). XPO1 has been proposed to be a candidate gene for 2p16.1-p15 microdeletion syndrome, a neurodevelopmental disorder in which many patients present with autism or autistic features. Functional analysis of candidate genes for 2p16.1-p15 microdeletion syndrome in zebrafish found that knockdown of xpo1a, one of the two copies of XPO1 in zebrafish, resulted in significant microcephaly and abnormal body shape (Bagheri et al., 2016).

Reports Added
[Inhibition of Autism-Related Crm1 Disrupts Mitosis and Induces Apoptosis of the Cortical Neural Progenitors.2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A SNP in the XPO1 gene (rs6735330) was found to associate with autism in four cohorts, being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing of 1.29E-05), the AGRE cohort [P(FDR)=0.0011] and the combined families [P(FDR)=2.34E-09] (Liu et al., 2011). XPO1 has been proposed to be a candidate gene for 2p16.1-p15 microdeletion syndrome, a neurodevelopmental disorder in which many patients present with autism or autistic features. Functional analysis of candidate genes for 2p16.1-p15 microdeletion syndrome in zebrafish found that knockdown of xpo1a, one of the two copies of XPO1 in zebrafish, resulted in significant microcephaly and abnormal body shape (Bagheri et al., 2016).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

A SNP in the XPO1 gene (rs6735330) was found to associate with autism in four cohorts, being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing of 1.29E-05), the AGRE cohort [P(FDR)=0.0011] and the combined families [P(FDR)=2.34E-09] (Liu et al., 2011). XPO1 has been proposed to be a candidate gene for 2p16.1-p15 microdeletion syndrome, a neurodevelopmental disorder in which many patients present with autism or autistic features. Functional analysis of candidate genes for 2p16.1-p15 microdeletion syndrome in zebrafish found that knockdown of xpo1a, one of the two copies of XPO1 in zebrafish, resulted in significant microcephaly and abnormal body shape (Bagheri et al., 2016).

Reports Added
[Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome.2017] [Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
10/1/2016
icon
4

Increased from to 4

Description

A SNP in the XPO1 gene (rs6735330) was found to associate with autism in four cohorts, being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing of 1.29E-05), the AGRE cohort [P(FDR)=0.0011] and the combined families [P(FDR)=2.34E-09] (Liu et al., 2011). XPO1 has been proposed to be a candidate gene for 2p16.1-p15 microdeletion syndrome, a neurodevelopmental disorder in which many patients present with autism or autistic features. Functional analysis of candidate genes for 2p16.1-p15 microdeletion syndrome in zebrafish found that knockdown of xpo1a, one of the two copies of XPO1 in zebrafish, resulted in significant microcephaly and abnormal body shape (Bagheri et al., 2016).

Reports Added
[Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.2016]
Krishnan Probability Score

Score 0.56920789488959

Ranking 1054/25841 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 0.99999956749666

Ranking 256/18225 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 0.9394771877121

Ranking 14224/18665 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
Larsen Cumulative Evidence Score

Score 3

Ranking 367/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.20174229520868

Ranking 4236/20870 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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