Human Gene Module / Chromosome 2 / SPAST

SPASTSpastin

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
12 / 17
Rare Variants / Common Variants
16 / 0
EAGLE Score
8.1
Moderate Learn More
Aliases
SPAST, ADPSP,  FSP2,  KIAA1083,  SPG4
Associated Syndromes
-
Chromosome Band
2p22.3
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (Talkowski et al., 2012). This BCA-disrupted gene was also individually implicated by case-control CNV burden or by a minimum of 3 CNVs in neuodevelopmental disorder (NDD) cases with none in controls in a follow-up study in the same report. This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Molecular Function

ATP-dependent microtubule severing protein. Microtubule severing may promote reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and for completion of the abscission stage of cytokinesis. May also play a role in axon growth and the formation of axonal branches. Defects in SPAST are the cause of spastic paraplegia autosomal dominant type 4 (SPG4).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SPAST (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
2 Primary Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries Talkowski ME , et al. (2012) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
6 Recent Recommendation Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
7 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
8 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
9 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
10 Support Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients Balicza P , et al. (2019) Yes -
11 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
12 Support - Kwong AK et al. (2021) No -
13 Support - Yap CX et al. (2021) Yes -
14 Support - Abe-Hatano C et al. (2021) No -
15 Support - Yuan B et al. (2023) Yes -
16 Support - Wang J et al. (2023) Yes -
17 Support - Karthika Ajit Valaparambil et al. () No -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 33568206 Yap CX et al. (2021)
- - inversion De novo - - 22521361 Talkowski ME , et al. (2012)
- - inversion Unknown Not maternal - 27841880 Redin C , et al. (2016)
c.983T>C p.Ile328Thr missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.586+23A>T - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.586+24T>C - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.281G>T p.Gly94Val missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1250_1252del p.Glu417del inframe_deletion De novo - - 33446253 Kwong AK et al. (2021)
c.1625A>G p.Asp542Gly missense_variant Familial Maternal - 31134136 Balicza P , et al. (2019)
c.1496G>A p.Arg499His missense_variant Familial - Unknown 33624935 Abe-Hatano C et al. (2021)
c.1496G>A p.Arg499His missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.1180del p.Ala394GlnfsTer2 frameshift_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.657dup p.Cys220MetfsTer24 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1492_1493del p.Arg498AlafsTer13 frameshift_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.1775T>G p.Ile592Arg missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
NM_199436.1:c.1149_1153insGTGA;c.1245_1249insGTGA p.Pro384ValfsTer11 frameshift_variant Unknown - Simplex 28263302 C Yuen RK et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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
1
icon
1

Score remained at 1

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

Reports Added
[Exome sequencing in paediatric patients with movement disorders2021]
1/1/2021
1
icon
1

Score remained at 1

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

Reports Added
[Analysis of common genetic variation and rare CNVs in the Australian Autism Biobank2021] [Whole genome sequencing of 45 Japanese patients with intellectual disability2021]
1/1/2020
1
icon
1

Score remained at 1

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

Reports Added
[New Scoring Scheme]
7/1/2019
2
icon
2

Decreased from 2 to 2

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

Reports Added
[Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients.2019]
1/1/2019
2
icon
2

Decreased from 2 to 2

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
4/1/2017
2
icon
2

Decreased from 2 to 2

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

Reports Added
[Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
10/1/2016
2
icon
2

Decreased from 2 to 2

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

Reports Added
[The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
1/1/2016
2
icon
2

Decreased from 2 to 2

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

Reports Added
[Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
10/1/2015
3
icon
2

Decreased from 3 to 2

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768). This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

1/1/2015
3
icon
3

Decreased from 3 to 3

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768).

Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
6
icon
3

Decreased from 6 to 3

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD. Two de novo LoF variants in the SPAST gene (both frameshift) have been identified in ASD probands (PMIDs 22495311, 25363768).

7/1/2014
No data
icon
6

Increased from No data to 6

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD.

4/1/2014
No data
icon
6

Increased from No data to 6

Description

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed that there is no significant burden (P=0.27) of SPAST CNVs in individuals with NDD.

Krishnan Probability Score

Score 0.52194958044536

Ranking 1670/25841 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 0.99707471255289

Ranking 1357/18225 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 0.982

Ranking 42/239 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 0.022256429756575

Ranking 35/18665 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 362/461 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 0.36983984625133

Ranking 1789/20870 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
Submit New Gene

Report an Error