Human Gene Module / Chromosome 8 / UNC5D

UNC5Dunc-5 netrin receptor D

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
7 / 0
Aliases
UNC5D, PRO34692,  Unc5h4
Associated Syndromes
-
Chromosome Band
8p12
Associated Disorders
-
Relevance to Autism

A homozygous deletion adjacent to the UNC5D gene that overlapped with a non-coding epigenetic mark was identified in an ASD proband born to consanguineous parents from the HMCA cohort (Schmitz-Abe et al., 2020). A region of homozygosity (ROH) segment overlapping the UNC5D gene had previously been identified in four ASD probands from the Simons Simplex Collection and no unaffected siblings (Gamsiz et al. 2013), and rare inherited intergenic deletions upstream of UNC5D that overlapped a human expressed sequence tag (EST) had previously been observed in four unrelated ASD probands in Walker and Scherer, 2013.

Molecular Function

Receptor for the netrin NTN4 that promotes neuronal cell survival. Plays a role in cell-cell adhesion and cell guidance. Receptor for netrin involved in cell migration. Plays a role in axon guidance by mediating axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding. May play a role in apoptosis in response to DNA damage. It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand. Mediates cell-cell adhesion via its interaction with FLRT3 on an adjacent cell.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
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Reports related to UNC5D (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Intellectual disability is associated with increased runs of homozygosity in simplex autism Gamsiz ED et al. (2013) Yes -
2 Support Identification of candidate intergenic risk loci in autism spectrum disorder Walker S and Scherer SW (2013) Yes -
3 Primary Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder Schmitz-Abe K et al. (2020) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.184G>A p.Asp62Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2102G>A p.Cys701Tyr missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Simplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_loss Familial Paternal Simplex 23879678 Walker S and Scherer SW (2013)
c.2366G>A p.Arg789His missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Both parents Simplex 32820185 Schmitz-Abe K et al. (2020)
c.1285C>A p.Gln429Lys missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

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.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49509643422044

Ranking 3213/25841 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 0.84920186128347

Ranking 3623/18225 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 0.85239593299825

Ranking 3549/18665 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 0.28190631792371

Ranking 3003/20870 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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