Human Gene Module / Chromosome 2 / DPYSL5

DPYSL5dihydropyrimidinase like 5

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
1 / 3
Rare Variants / Common Variants
9 / 0
Aliases
-
Associated Syndromes
Ritscher-Schinzel syndrome 4, DD, ID
Chromosome Band
2p23.3
Associated Disorders
-
Relevance to Autism

Desprez et al., 2025 reported six different missense variants in the DPYSL5 gene (including the previously identified p.Glu41Lys recurrent variant that was experimentally confirmed as a loss-of-function variant in Jeanne et al., 2021) in three male fetuses and six individuals aged up to 10 years old; all living participants in this cohort had developmental delay (6/6), predominantly in language (5/6), and mild to severe intellectual disability (5/5), while four of these individuals had autism spectrum disorder. Subsequent functional assays of novel DPYSL5 missense variants in differentiating mouse or human neuronal cultures in Desprez et al., 2025 revealed impairments in dendritic arborization, axonal elongation, and synaptic density. Of the nine individuals with Ritscher-Schinzel syndrome 4 reported in Jeanne et al., 2021, ASD was reported in one and stereotypic movements were reported in two others. A de novo missense variant in the DPYSL5 gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Molecular Function

This gene encodes a member of the CRMP (collapsing response mediator protein) family thought to be involved in neural development. Antibodies to the encoded protein were found in some patients with neurologic symptoms who had paraneoplastic syndrome. Heterozygous variants in the DPYSL5 gene are responsible for Ritscher-Schinzel syndrome 4 (OMIM 619435), a disorder characterized by a constellation of congenital anomalies, including dysmorphic craniofacial features and structural brain anomalies, associated with global developmental delay and impaired intellectual development (Jeanne et al., 2021).

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Reports related to DPYSL5 (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support - Médéric Jeanne et al. (2021) No ASD, stereotypy, epilepsy/seizures
3 Primary - Florence Desprez et al. () No ASD
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1090G>A p.Val364Ile missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.73G>A p.Glu25Lys missense_variant De novo - Simplex 41286434 Florence Desprez et al. ()
c.121G>A p.Glu41Lys missense_variant De novo - Simplex 41286434 Florence Desprez et al. ()
c.757G>T p.Ala253Ser missense_variant De novo - Simplex 41286434 Florence Desprez et al. ()
c.692G>A p.Arg231His missense_variant Unknown - Unknown 41286434 Florence Desprez et al. ()
c.121G>A p.Glu41Lys missense_variant De novo - - 33894126 Médéric Jeanne et al. (2021)
c.1060C>T p.Arg354Cys missense_variant De novo - Simplex 41286434 Florence Desprez et al. ()
c.1562G>A p.Arg521Gln missense_variant De novo - Simplex 41286434 Florence Desprez et al. ()
c.139G>A p.Gly47Arg missense_variant De novo (germline mosaicism) - Multiplex 33894126 Médéric Jeanne et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

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.

10/1/2025
3

Initial score established: 3

Krishnan Probability Score

Score 0.54996990577967

Ranking 1374/25841 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 0.9983321007664

Ranking 1209/18225 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 0.93856620118012

Ranking 13907/18665 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 -0.35770783678244

Ranking 17911/20870 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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