Human Gene Module / Chromosome 8 / DPYSL2

DPYSL2dihydropyrimidinase like 2

Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 12
Rare Variants / Common Variants
2 / 0
DPYSL2, CRMP-2,  CRMP2,  DHPRP2,  DRP-2,  DRP2,  N2A3,  ULIP-2,  ULIP2
Associated Syndromes
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
Associated Disorders
Relevance to Autism

De novo missense variants that were predicted in silico to be damaging were identified in the DPYSL2 gene in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified DPYSL2 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Multiple studies have reported an association between the DPYSL2 gene and schizophrenia (Nakata et al., 2003; Fallin et al., 2005; Fallin et al., 2011; Liu et al., 2014; Lee et al., 2015), as well as evidence suggesting that the DPYSL2 gene links mTOR signaling and schizophrenia (Liu et al., 2014; Pham et al., 2016).

Molecular Function

This gene encodes a member of the collapsin response mediator protein family. Collapsin response mediator proteins form homo- and hetero-tetramers and facilitate neuron guidance, growth and polarity. The encoded protein promotes microtubule assembly and is required for Sema3A-mediated growth cone collapse, and also plays a role in synaptic signaling through interactions with calcium channels. This gene has been implicated in multiple neurological disorders, and hyperphosphorylation of the encoded protein may play a key role in the development of Alzheimer's disease.

Reports related to DPYSL2 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association The human dihydropyrimidinase-related protein 2 gene on chromosome 8p21 is associated with paranoid-type schizophrenia. Nakata K , et al. (2003) No -
2 Negative Association An investigation of the dihydropyrimidinase-like 2 (DPYSL2) gene in schizophrenia: genetic association study and expression analysis. Zhao X , et al. (2005) No -
3 Positive Association Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Fallin MD , et al. (2005) No -
4 Negative Association A two-stage case-control association study of the dihydropyrimidinase-like 2 gene (DPYSL2) with schizophrenia in Japanese subjects. Koide T , et al. (2010) No -
5 Positive Association Linkage and association on 8p21.2-p21.1 in schizophrenia. Fallin MD , et al. (2011) No -
6 Primary Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
7 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
8 Positive Association Functional variants in DPYSL2 sequence increase risk of schizophrenia and suggest a link to mTOR signaling. Liu Y , et al. (2014) No -
9 Positive Association Changes in Dpysl2 expression are associated with prenatally stressed rat offspring and susceptibility to schizophrenia in humans. Lee H , et al. (2015) No -
10 Support The DPYSL2 gene connects mTOR and schizophrenia. Pham X , et al. (2016) No -
11 Recent Recommendation Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
12 Recent Recommendation An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders. Chen S , et al. (2018) No -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1312C>A p.His438Asn missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1801C>T p.Arg601Cys missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score

Suggestive Evidence



Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4.4 + acc2

Initial score established: 4.4 + acc2



Krishnan Probability Score

Score 0.49980804518459

Ranking 2131/25841 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: A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at
ExAC Score

Score 0.9955582887691

Ranking 1485/18225 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 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: aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.817

Ranking 220/239 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 ( The list of probability scores can be found here: /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.44687204718797

Ranking 347/18665 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
Zhang D Score

Score 0.38912946624899

Ranking 1571/20870 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.
CNVs associated with DPYSL2(1 CNVs)
8p21.2 9 Deletion-Duplication 17  /  217
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