Human Gene Module / Chromosome 2 / SPAST

SPASTSpastin

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
6 / 0
Aliases
SPAST, ADPSP,  FSP2,  KIAA1083,  SPG4
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
2p22.3
Associated Disorders
-
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).

Reports related to SPAST (8 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 -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1180delC p.Leu394fs frameshift_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
- - inversion De novo - - 22521361 Talkowski ME , et al. (2012)
c.657dupA p.Thr219fs frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1775T>G p.Ile592Arg missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
- - inversion Unknown Not maternal - 27841880 Redin C , et al. (2016)
c.1149_1150insGTGA;c.1245_1246insGTGA p.Tyr383fs;p.Tyr415fs frameshift_variant Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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).

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.

04-01-2017
2

Initial score established: 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).

CNVs associated with SPAST(1 CNVs)
2p22.3 28 Deletion-Duplication 46  /  220
Animal Models associated with SPAST(1 Models)
SPAST_1_KO_HM Genetic
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