Human Gene Module / Chromosome 1 / ASPM

ASPMabnormal spindle microtubule assembly

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 15
Rare Variants / Common Variants
63 / 0
Aliases
ASPM, ASP,  Calmbp1,  MCPH5
Associated Syndromes
-
Chromosome Band
1q31.3
Associated Disorders
DD/NDD, EPS
Relevance to Autism

A de novo missense variant in the ASPM gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Rare inherited loss-of-function and damaging missense variants in the ASPM gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015 and in a cohort of Chinese ASD probands in Guo et al., 2017. Subsequent Transmission and De Novo Association (TADA) analysis in Guo et al., 2017 identified ASPM as an ASD candidate gene, with a PTADA of 0.001826 in the Chinese ASD case-control cohort and a PTADA of 0.001356 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

Molecular Function

This gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. Studies in mouse also suggest a role of this gene in mitotic spindle regulation, with a preferential role in regulating neurogenesis. Biallelic mutations in the ASPM gene are responsible for a form of autosomal recessive primary microcephaly (MCPH5; OMIM 608716), a disorder associated with intellectual disability and speech delay (Bond et al., 2002; Bond et al., 2003).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ASPM (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited ASPM is a major determinant of cerebral cortical size Bond J , et al. (2002) No -
2 Support Protein-truncating mutations in ASPM cause variable reduction in brain size Bond J , et al. (2003) No -
3 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
5 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 -
6 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No DD, epilepsy/seizures
7 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
8 Support A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons Garrett L , et al. (2020) No -
9 Support - Woodbury-Smith M et al. (2022) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Wang J et al. (2023) Yes -
12 Support - Cirnigliaro M et al. (2023) Yes -
13 Support - Maria C Mannino et al. (2023) No -
14 Support - Ayyappan Anitha et al. (2024) Yes -
15 Support - Hosneara Akter et al. () No -
Rare Variants   (63)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1468C>T p.Arg490Cys missense_variant Familial - - 28831199 Li J , et al. (2017)
c.1880G>A p.Arg627His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3395A>G p.Glu1132Gly missense_variant Familial - - 28831199 Li J , et al. (2017)
c.5000G>A p.Arg1667His missense_variant Familial - - 28831199 Li J , et al. (2017)
c.5849C>T p.Ala1950Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2977A>G p.Lys993Glu missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.4066-5305_4066-5304del - frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.1567A>C p.Ser523Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2353C>T p.Leu785Phe missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.4066-5522T>G - stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2672del p.Leu891CysfsTer44 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.4296A>C p.Arg1432Ser missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
C>A p.Ala663Ser missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
C>A p.Ala663Ser missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.4066-7430G>T - missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.4066-7458G>A - missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.4066-8871G>A - missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3599-2A>G - splice_site_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.4669T>C p.Cys1557Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
C>T p.Ala1877Thr missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
C>T p.Ala1877Thr missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
C>T p.Arg1264His missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1592_1595del p.Val531GlufsTer17 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.7782_7783del p.Lys2595SerfsTer6 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.4786C>T p.Arg1596Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.4066-5025dup - frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.4066-5164del - frameshift_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.4066-5302del - frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.4066-6024C>T - stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.5810_5811insC p.Arg1938LysfsTer9 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.3796G>T p.Glu1266Ter stop_gained Familial Both parents - 30842647 Boonsawat P , et al. (2019)
c.1987G>T p.Ala663Ser missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2047C>T p.Pro683Ser missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2267A>G p.Tyr756Cys missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2275C>T p.Arg759Trp missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2300G>A p.Arg767His missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2339A>C p.Lys780Thr missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2612C>T p.Pro871Leu missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2621A>G p.Tyr874Cys missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2746G>A p.Asp916Asn missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2824C>T p.Arg942Cys missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.3091A>G p.Ile1031Val missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3395A>T p.Glu1132Val missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3406G>A p.Val1136Met missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3497C>T p.Thr1166Ile missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3624G>T p.Glu1208Asp missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3791G>A p.Arg1264His missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.3791G>A p.Arg1264His missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.3829T>C p.Trp1277Arg missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.4892G>A p.Arg1631Lys missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.710T>A p.Leu237Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4423C>T p.Gln1475Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4066-6166_4066-6165del - frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2094del p.Lys698AsnfsTer10 frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.4066-5303_4066-5302del - frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1632_1636del p.Leu545AsnfsTer8 frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.6562_6565del p.Lys2188CysfsTer24 frameshift_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.3485_3486del p.Cys1162SerfsTer22 frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2267A>G p.Tyr756Cys missense_variant De novo - Multiplex (monozygotic twins) 39038432 Ayyappan Anitha et al. (2024)
c.6591_6594del p.Ser2198ThrfsTer14 frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.6686_6689del p.Arg2229ThrfsTer10 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4066-4953_4066-4950del - frameshift_variant Familial Paternal Multiplex (monozygotic twins) 31398340 Ruzzo EK , et al. (2019)
c.4528del p.Arg1510GlufsTer6 frameshift_variant Familial Paternal Multiplex (monozygotic twins) 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo missense variant in the ASPM gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Rare inherited loss-of-function and damaging missense variants in the ASPM gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015 and in a cohort of Chinese ASD probands in Guo et al., 2017. Subsequent Transmission and De Novo Association (TADA) analysis in Guo et al., 2017 identified ASPM as an ASD candidate gene, with a PTADA of 0.001826 in the Chinese ASD case-control cohort and a PTADA of 0.001356 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ASPM gene are responsible for a form of autosomal recessive primary microcephaly (MCPH5; OMIM 608716), a disorder associated with intellectual disability and speech delay (Bond et al., 2002; Bond et al., 2003).

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.

1/1/2020
2
icon
2

Score remained at 2

Description

A de novo missense variant in the ASPM gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Rare inherited loss-of-function and damaging missense variants in the ASPM gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015 and in a cohort of Chinese ASD probands in Guo et al., 2017. Subsequent Transmission and De Novo Association (TADA) analysis in Guo et al., 2017 identified ASPM as an ASD candidate gene, with a PTADA of 0.001826 in the Chinese ASD case-control cohort and a PTADA of 0.001356 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ASPM gene are responsible for a form of autosomal recessive primary microcephaly (MCPH5; OMIM 608716), a disorder associated with intellectual disability and speech delay (Bond et al., 2002; Bond et al., 2003).

Reports Added
[A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons.2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo missense variant in the ASPM gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Rare inherited loss-of-function and damaging missense variants in the ASPM gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015 and in a cohort of Chinese ASD probands in Guo et al., 2017. Subsequent Transmission and De Novo Association (TADA) analysis in Guo et al., 2017 identified ASPM as an ASD candidate gene, with a PTADA of 0.001826 in the Chinese ASD case-control cohort and a PTADA of 0.001356 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ASPM gene are responsible for a form of autosomal recessive primary microcephaly (MCPH5; OMIM 608716), a disorder associated with intellectual disability and speech delay (Bond et al., 2002; Bond et al., 2003).

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

Decreased from 3 to 3

Description

A de novo missense variant in the ASPM gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Rare inherited loss-of-function and damaging missense variants in the ASPM gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015 and in a cohort of Chinese ASD probands in Guo et al., 2017. Subsequent Transmission and De Novo Association (TADA) analysis in Guo et al., 2017 identified ASPM as an ASD candidate gene, with a PTADA of 0.001826 in the Chinese ASD case-control cohort and a PTADA of 0.001356 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ASPM gene are responsible for a form of autosomal recessive primary microcephaly (MCPH5; OMIM 608716), a disorder associated with intellectual disability and speech delay (Bond et al., 2002; Bond et al., 2003).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo missense variant in the ASPM gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Rare inherited loss-of-function and damaging missense variants in the ASPM gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015 and in a cohort of Chinese ASD probands in Guo et al., 2017. Subsequent Transmission and De Novo Association (TADA) analysis in Guo et al., 2017 identified ASPM as an ASD candidate gene, with a PTADA of 0.001826 in the Chinese ASD case-control cohort and a PTADA of 0.001356 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ASPM gene are responsible for a form of autosomal recessive primary microcephaly (MCPH5; OMIM 608716), a disorder associated with intellectual disability and speech delay (Bond et al., 2002; Bond et al., 2003).

Reports Added
[Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.2019]
7/1/2017
icon
3

Increased from to 3

Description

A de novo missense variant in the ASPM gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Rare inherited loss-of-function and damaging missense variants in the ASPM gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015 and in a cohort of Chinese ASD probands in Guo et al., 2017. Subsequent Transmission and De Novo Association (TADA) analysis in Guo et al., 2017 identified ASPM as an ASD candidate gene, with a PTADA of 0.001826 in the Chinese ASD case-control cohort and a PTADA of 0.001356 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ASPM gene are responsible for a form of autosomal recessive primary microcephaly (MCPH5; OMIM 608716), a disorder associated with intellectual disability and speech delay (Bond et al., 2002; Bond et al., 2003).

Krishnan Probability Score

Score 0.30674905847446

Ranking 25468/25841 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 6.1643899194663E-26

Ranking 18110/18225 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 0.94956491538216

Ranking 18142/18665 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 -0.27106089455813

Ranking 16747/20870 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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