Human Gene Module / Chromosome 6 / DST

DSTDystonin

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 11
Rare Variants / Common Variants
27 / 0
Aliases
DST, RP3-361I14.2,  BP240,  BPA,  BPAG1,  CATX-15,  CATX15,  D6S1101,  DMH,  DT,  HSAN6,  MACF2
Associated Syndromes
-
Chromosome Band
6p12.1
Associated Disorders
-
Relevance to Autism

Five case-specific loss-of-function variants were identified in the DST gene following the sequencing of 215 synaptic genes in 147 cases with ASD, 273 cases with schizophrenia, and 287 controls (Kenny et al., 2013).

Molecular Function

Cytoskeletal linker protein that acts as an integrator of intermediate filaments, actin and microtubule cytoskeleton networks. Isoform 7 regulates the organization and stability of the microtubule network of sensory neurons to allow axonal transport. Defects in this gene are associated with hereditary sensory and autonomic neuropathy 6 (HSAN6) [MIM:614653], a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DST (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders Kenny EM , et al. (2013) Yes -
2 Support De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder Dong S , et al. (2014) 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 Support De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis Wang S , et al. (2018) No -
6 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
7 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
8 Support - Alonso-Gonzalez A et al. (2021) Yes -
9 Support - N.Y.) (07/2) No -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4830+4279A>G - intron_variant De novo - - 35982159 Zhou X et al. (2022)
c.4830+4687G>A - intron_variant De novo - - 35982159 Zhou X et al. (2022)
c.13347C>T p.Ala4449%3D synonymous_variant De novo - - 35901164 N.Y.) (07/2)
TA>T - frameshift_variant Unknown - Unknown 24126926 Kenny EM , et al. (2013)
c.5184+2751C>T - stop_gained Unknown - Unknown 24126926 Kenny EM , et al. (2013)
c.3865-153G>A - intron_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3086C>T p.Thr1029Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5184+4468C>T - intron_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.10705C>T p.Arg3569Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.10815G>C p.Glu3605Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4131A>G p.Glu1377%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.9213G>A p.Arg3071%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.12975A>G p.Leu4325%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.4831-2A>G - splice_site_variant Unknown - Unknown 24126926 Kenny EM , et al. (2013)
c.236G>A p.Arg79Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5662G>T p.Ala1888Ser stop_gained Unknown - Unknown 24126926 Kenny EM , et al. (2013)
c.6048+1>AG p.? splice_site_variant Unknown - Unknown 24126926 Kenny EM , et al. (2013)
c.13823G>T p.Gly4608Val missense_variant De novo - Simplex 30257206 Wang S , et al. (2018)
c.13296A>T p.Glu4432Asp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
11319+AAAC(delGTTT) 3773-! frameshift_variant De novo - Simplex 25284784 Dong S , et al. (2014)
c.1680-263del - frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.10954C>T p.Gln3652Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1779-264del - frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.13564C>A p.His4522Asn missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.512_513insCACCATCGC p.Pro171_Ala172insThrIleAla inframe_indel De novo - Simplex 30504930 Guo H , et al. (2018)
c.7538T>C p.Leu2513Ser missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.9776A>G p.Glu3259Gly missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Five case-specific loss-of-function variants were identified in the DST gene following the sequencing of 215 synaptic genes in 147 cases with ASD, 273 cases with schizophrenia, and 287 controls (Kenny et al., 2013); these variants were identified in two ASD cases and three SCZ cases and were not observed in the control cohort.

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

Five case-specific loss-of-function variants were identified in the DST gene following the sequencing of 215 synaptic genes in 147 cases with ASD, 273 cases with schizophrenia, and 287 controls (Kenny et al., 2013); these variants were identified in two ASD cases and three SCZ cases and were not observed in the control cohort.

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Five case-specific loss-of-function variants were identified in the DST gene following the sequencing of 215 synaptic genes in 147 cases with ASD, 273 cases with schizophrenia, and 287 controls (Kenny et al., 2013); these variants were identified in two ASD cases and three SCZ cases and were not observed in the control cohort.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Five case-specific loss-of-function variants were identified in the DST gene following the sequencing of 215 synaptic genes in 147 cases with ASD, 273 cases with schizophrenia, and 287 controls (Kenny et al., 2013); these variants were identified in two ASD cases and three SCZ cases and were not observed in the control cohort.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Five case-specific loss-of-function variants were identified in the DST gene following the sequencing of 215 synaptic genes in 147 cases with ASD, 273 cases with schizophrenia, and 287 controls (Kenny et al., 2013); these variants were identified in two ASD cases and three SCZ cases and were not observed in the control cohort.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Five case-specific loss-of-function variants were identified in the DST gene following the sequencing of 215 synaptic genes in 147 cases with ASD, 273 cases with schizophrenia, and 287 controls (Kenny et al., 2013); these variants were identified in two ASD cases and three SCZ cases and were not observed in the control cohort.

Reports Added
[De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.2018] [Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

Five case-specific loss-of-function variants were identified in the DST gene following the sequencing of 215 synaptic genes in 147 cases with ASD, 273 cases with schizophrenia, and 287 controls (Kenny et al., 2013); these variants were identified in two ASD cases and three SCZ cases and were not observed in the control cohort.

Reports Added
[Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014]
7/1/2015
icon
4

Increased from to 4

Description

Five case-specific loss-of-function variants were identified in the DST gene following the sequencing of 215 synaptic genes in 147 cases with ASD, 273 cases with schizophrenia, and 287 controls (Kenny et al., 2013); these variants were identified in two ASD cases and three SCZ cases and were not observed in the control cohort.

Krishnan Probability Score

Score 0.54929652142797

Ranking 1378/25841 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 0.99999999999999

Ranking 20/18225 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 0.92997999192357

Ranking 11308/18665 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 8

Ranking 222/461 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 0.13521668776383

Ranking 5453/20870 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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