Human Gene Module / Chromosome 1 / SPEN

SPENspenfamily transcriptional repressor

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 16
Rare Variants / Common Variants
90 / 0
Aliases
SPEN, HIAA0929,  MINT,  RBM15C,  SHARP
Associated Syndromes
-
Chromosome Band
1p36.21-p36.13
Associated Disorders
ASD
Relevance to Autism

De novo likely gene-disruptive (LGD) variants in the SPEN gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2016) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SPEN as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo missense variants in SPEN have also been observed in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Molecular Function

his gene encodes a hormone inducible transcriptional repressor. Repression of transcription by this gene product can occur through interactions with other repressors, by the recruitment of proteins involved in histone deacetylation, or through sequestration of transcriptional activators. The product of this gene contains a carboxy-terminal domain that permits binding to other corepressor proteins. This domain also permits interaction with members of the NuRD complex, a nucleosome remodeling protein complex that contains deacetylase activity. In addition, this repressor contains several RNA recognition motifs that confer binding to a steroid receptor RNA coactivator; this binding can modulate the activity of both liganded and nonliganded steroid receptors.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SPEN (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
4 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
5 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) 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 Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No Autistic features
8 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
9 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
10 Recent Recommendation Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
11 Recent recommendation - Radio FC et al. (2021) No ASD
12 Support - Bertoli-Avella AM et al. (2021) No -
13 Support - Woodbury-Smith M et al. (2022) Yes -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Spataro N et al. (2023) No Autistic features
16 Support - Omri Bar et al. (2024) Yes Learning disability, epilepsy/seizures
Rare Variants   (90)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.7503G>A p.Trp2501Ter stop_gained De novo - - 28135719 et al. (2017)
c.461G>A p.Arg154Gln missense_variant De novo - - 28135719 et al. (2017)
c.3721C>T p.Arg1241Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.4207C>T p.Arg1403Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1603C>T p.Arg535Ter stop_gained De novo - - 33596411 Radio FC et al. (2021)
c.2014C>T p.Arg672Ter stop_gained De novo - - 33596411 Radio FC et al. (2021)
c.2101G>T p.Glu701Ter stop_gained De novo - - 33596411 Radio FC et al. (2021)
c.3199C>T p.Gln1067Ter stop_gained De novo - - 33596411 Radio FC et al. (2021)
c.3508C>T p.Arg1170Ter stop_gained De novo - - 33596411 Radio FC et al. (2021)
c.3793C>T p.Arg1265Ter stop_gained De novo - - 33596411 Radio FC et al. (2021)
c.6058C>T p.Gln2020Ter stop_gained De novo - - 33596411 Radio FC et al. (2021)
c.7024C>T p.Arg2342Ter stop_gained De novo - - 33596411 Radio FC et al. (2021)
c.7324G>T p.Glu2442Ter stop_gained De novo - - 33596411 Radio FC et al. (2021)
c.382C>T p.Arg128Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.526C>T p.Arg176Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.577C>T p.Arg193Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.598C>G p.Arg200Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.686G>A p.Arg229Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.703C>T p.Arg235Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.727C>T p.Arg243Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4828C>T p.Gln1610Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.1475C>G p.Ala492Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1649G>A p.Arg550His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1649G>T p.Arg550Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1700C>A p.Ala567Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1703C>T p.Ala568Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1958G>C p.Arg653Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2137C>T p.Arg713Trp missense_variant De novo - - 33004838 Wang T et al. (2020)
c.2137C>T p.Arg713Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2341C>T p.Arg781Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2612G>A p.Arg871His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2959C>T p.Arg987Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4246C>T p.Arg1416Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4774C>T p.Arg1592Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4783C>A p.Gln1595Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5533G>A p.Glu1845Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6242G>A p.Arg2081Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6995G>A p.Arg2332His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.10301C>T p.Pro3434Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.10927G>A p.Ala3643Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6750C>T p.Pro2250%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.10864-1G>A - splice_site_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.5392C>T p.Gln1798Ter stop_gained De novo - Simplex 27525107 Yuen RK et al. (2016)
c.9502C>T p.Arg3168Ter stop_gained Familial Paternal - 33004838 Wang T et al. (2020)
c.5414del p.Leu1805Ter frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.6570dup p.Lys2191Ter frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.7492del p.Val2498Ter frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.986A>C p.Asp329Ala missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.7232C>A p.Ser2411Ter stop_gained De novo - Simplex 32094338 Husson T , et al. (2020)
c.460C>T p.Arg154Trp missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.923G>T p.Arg308Leu missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.1379G>A p.Arg460His missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.2429G>A p.Arg810Gln missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.6959_6963del p.Glu2320GlyfsTer37 frameshift_variant De novo - - 28135719 et al. (2017)
c.6960del p.Val2321TrpfsTer32 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.5392C>T p.Gln1798Ter stop_gained Unknown Not paternal - 33596411 Radio FC et al. (2021)
c.6799G>T p.Glu2267Ter stop_gained Unknown Not maternal - 33596411 Radio FC et al. (2021)
c.4651G>A p.Glu1551Lys missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.7373del p.Pro2458ArgfsTer2 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.4054G>A p.Asp1352Asn missense_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.7712C>T p.Ala2571Val missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.7796C>T p.Ser2599Leu missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1889G>A p.Arg630His missense_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.3029dup p.Asp1011GlyfsTer11 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.9950dup p.Ala3318GlyfsTer30 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.8492G>C p.Ser2831Thr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4801G>A p.Asp1601Asn missense_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.2294_2295del p.Ser765MetfsTer2 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.10953dup p.Asn3652GlnfsTer17 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.5086C>T p.Gln1696Ter stop_gained De novo - Simplex 33875846 Bertoli-Avella AM et al. (2021)
c.4441_4444del p.Glu1481ArgfsTer14 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.5392C>T p.Gln1798Ter stop_gained Unknown Not paternal Simplex 33004838 Wang T et al. (2020)
c.2262_2265dup p.Tyr756AlafsTer13 frameshift_variant Unknown - - 33596411 Radio FC et al. (2021)
c.2269_2272dup p.Arg758GlnfsTer11 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.2956_2959dup p.Arg987GlnfsTer36 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.6087_6088del p.Glu2029AspfsTer5 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.5806C>T p.Arg1936Ter stop_gained Familial Maternal Multiplex 33596411 Radio FC et al. (2021)
c.5013_5017del p.Glu1671AspfsTer16 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.6223_6227del p.Ser2075GlufsTer46 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.6226_6227del p.Lys2076GlufsTer46 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.6641_6642del p.Glu2214AlafsTer11 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.6974_6975del p.Leu2325ArgfsTer33 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.7338_7339dup p.Arg2447ThrfsTer14 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.7374_7381del p.Val2459ThrfsTer36 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.7380_7382del p.Pro2462del inframe_deletion De novo - Multiplex 38256266 Omri Bar et al. (2024)
c.10093C>T p.Pro3365Ser missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.10909_10910del p.His3638ProfsTer7 frameshift_variant De novo - - 33596411 Radio FC et al. (2021)
c.3029dup p.Asp1011GlyfsTer11 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.7080_7083del p.Asn2360LysfsTer42 frameshift_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.7328del p.Glu2443GlyfsTer17 frameshift_variant Familial Paternal Multiplex 33596411 Radio FC et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo likely gene-disruptive (LGD) variants in the SPEN gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2016) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SPEN as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo missense variants in SPEN have also been observed in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

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 likely gene-disruptive (LGD) variants in the SPEN gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2016) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SPEN as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo missense variants in SPEN have also been observed in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders2021]
1/1/2021
2
icon
2

Score remained at 2

Description

De novo likely gene-disruptive (LGD) variants in the SPEN gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2016) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SPEN as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo missense variants in SPEN have also been observed in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females2021]
10/1/2020
2
icon
2

Score remained at 2

Description

De novo likely gene-disruptive (LGD) variants in the SPEN gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2016) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SPEN as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo missense variants in SPEN have also been observed in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
2
icon
2

Score remained at 2

Description

De novo likely gene-disruptive (LGD) variants in the SPEN gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2016) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SPEN as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo missense variants in SPEN have also been observed in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

De novo likely gene-disruptive (LGD) variants in the SPEN gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2016) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SPEN as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo missense variants in SPEN have also been observed in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

De novo likely gene-disruptive (LGD) variants in the SPEN gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2016) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SPEN as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo missense variants in SPEN have also been observed in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
1/1/2019
icon
3

Increased from to 3

Description

De novo likely gene-disruptive (LGD) variants in the SPEN gene have been identified in two probands with ASD (Iossifov et al., 2014; Yuen et al., 2016) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SPEN as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo missense variants in SPEN have also been observed in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Krishnan Probability Score

Score 0.6124481364197

Ranking 170/25841 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 0.99999999999996

Ranking 22/18225 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 0.93

Ranking 110/239 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 0.58853014493696

Ranking 672/18665 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 0.31851542272344

Ranking 2464/20870 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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