Human Gene Module / Chromosome 1 / DPYD

DPYDdihydropyrimidine dehydrogenase

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 15
Rare Variants / Common Variants
26 / 3
Aliases
DPYD, DHP,  DPD,  MGC70799,  MGC132008
Associated Syndromes
-
Chromosome Band
1p21.3
Associated Disorders
DD/NDD, ID, ASD
Relevance to Autism

1p21.3 microdeletions affecting DPYD have been identified in individuals with ASD (Carter et al., 2011), intellectual disability (Willemsen et al., 2011), and syndromic obesity (D'Angelo et al., 2015); inherited missense variants in this gene have alo observed (Carter et al., 2011; Li et al., 2017).

Molecular Function

The encoded protein is a pyrimidine catabolic enzyme and participates in the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Biallelic mutations in this gene are responsible for dihydropyrimidine dehydrogenase (DPD) deficiency (OMIM 274270).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DPYD (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation A neonate with recurrent vomiting and generalized hypotonia diagnosed with a deficiency of dihydropyrimidine dehydrogenase Brussel W , et al. (2006) No -
2 Primary Structural variation of chromosomes in autism spectrum disorder Marshall CR , et al. (2008) Yes -
3 Support Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder Carter MT , et al. (2010) Yes -
4 Support Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability Willemsen MH , et al. (2011) No Autistic features
5 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
6 Positive Association Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Yes -
7 Support Two New Cases of 1p21.3 Deletions and an Unbalanced Translocation t(8;12) among Individuals with Syndromic Obesity D'Angelo CS , et al. (2015) No DD, ID, autistic features
8 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
9 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
10 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
11 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders Jiao Q , et al. (2019) No DD
12 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
13 Highly Cited Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity Diasio RB , et al. (1988) No -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (26)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 26279650 D'Angelo CS , et al. (2015)
- - copy_number_loss Unknown - - 26279650 D'Angelo CS , et al. (2015)
- - copy_number_loss De novo - - 22003227 Willemsen MH , et al. (2011)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss De novo - Simplex 21114665 Carter MT , et al. (2010)
GGGTAC>A - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_loss Familial Maternal - 21114665 Carter MT , et al. (2010)
- - copy_number_loss De novo - Multiplex 21114665 Carter MT , et al. (2010)
- - copy_number_loss De novo - Simplex 18252227 Marshall CR , et al. (2008)
c.91A>C p.Thr31Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial - Multiplex 22003227 Willemsen MH , et al. (2011)
- - copy_number_loss Familial Maternal Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Familial Paternal Unknown 23275889 Prasad A , et al. (2013)
c.1774C>T p.Arg592Trp missense_variant Unknown - - 30945278 Jiao Q , et al. (2019)
c.2897C>T p.Ser966Phe missense_variant Unknown - - 30945278 Jiao Q , et al. (2019)
c.704G>A p.Arg235Gln missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.3067C>A p.Pro1023Thr missense_variant Familial - - 21114665 Carter MT , et al. (2010)
c.2279C>T p.Thr760Ile missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2965T>A p.Cys989Ser missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2980A>G p.Ser994Gly missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1905+1G>A - splice_site_variant Familial Maternal - 21114665 Carter MT , et al. (2010)
c.5C>T p.Ala2Val missense_variant Familial Maternal - 21114665 Carter MT , et al. (2010)
c.1865G>A p.Cys622Tyr missense_variant Familial Paternal - 21114665 Carter MT , et al. (2010)
c.2378C>T p.Thr793Ile missense_variant Familial Paternal - 21114665 Carter MT , et al. (2010)
c.2580del p.Lys863AsnfsTer6 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1155_1156del p.Cys385Ter frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- T/C intergenic_variant - - - 23453885 Cross-Disorder Group of the Psychiatric Genomics Consortium (2013)
c.1906-30051G>A;c.1795-30051G>A;c.1690-30051G>A;c.1411-30051G>A - intron_variant - - - 29483656 Pardias AF , et al. (2018)
G>T - intergenic_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
2

Strong Candidate

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

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

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

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

Decreased from 4 to 4

Description

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

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

Decreased from 4 to 4

Description

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

Reports Added
[The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

Reports Added
[Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability.2011] [Two New Cases of 1p21.3 Deletions and an Unbalanced Translocation t(8;12) among Individuals with Syndromic Obesity.2015]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Hemizygous deletion in 4 individuals from 3 families (PMID: 21114665). Exonic deletion seen in 1 control (out of 5670 screened). Unclear how many autism samples screened to identify 4 individuals.

Krishnan Probability Score

Score 0.4080034034857

Ranking 22990/25841 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 4.1897224407905E-9

Ranking 16353/18225 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 0.94883655721706

Ranking 17846/18665 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 2

Ranking 379/461 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 0.007039987188777

Ranking 8456/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
FOS FBJ murine osteosarcoma viral oncogene homolog Human Protein Binding 2353 P01100
GOPC golgi-associated PDZ and coiled-coil motif containing Human Protein Binding 57120 Q9HD26
LXN latexin Human Protein Binding 56925 Q9BS40
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