Human Gene Module / Chromosome 8 / CSMD3

CSMD3CUB and Sushi multiple domains 3

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
9 / 10
Rare Variants / Common Variants
30 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
8q23.3
Associated Disorders
-
Relevance to Autism

CSMD3 was initially proposed as an autism candidate gene based on the identification of de novo balanced translocations with breakpoints near this gene in two patients diagnosed with autistic disorder (Floris et al., 2008). Whole-genome sequencing of 32 Chinese ASD trios in Wu et al., 2018 identified a statistically significant enrichment in transmitted damaging missense variants in CSMD3 vs. non-transmitted damaging missense variants (6 transmitted vs. 1 non-transmitted, P-value 0.00049). De novo coding variants in this gene, including a damaging missense variant, have been identified in ASD probands (Iossifov et al., 2014; Takata et al., 2018; Satterstrom et al., 2020). Song et al., 2022 identified rare and potentially deleterious missense variants in CSMD3 in Chinese patients with neurodevelopmental disorders (NDDs), including ASD, intellectual disability, schizophrenia, and epileptic encephalopathy; in the same report, disruption of Csmd3 in mice resulted in NDD-related behaviors, abnormal neuronal developmental and cortical lamination, and abnormal dendritic arborization and spine organization in cortical neurons.

Molecular Function

Predicted to be involved in regulation of dendrite development. Predicted to be located in plasma membrane. Overexpression of CSMD3 in cultured hippocampal neurons has been shown to induce dendritic branching (Mizukami et al., 2012).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CSMD3 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary - Floris C et al. (2008) Yes Epilepsy/seizures
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support - Mizukami T et al. (2016) No -
4 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
5 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
6 Support Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing Wu J , et al. (2018) Yes -
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
8 Recent Recommendation - behavior (Song) Yes ID, SCZ, epilepsy/seizures
9 Support - Zhou X et al. (2022) Yes -
10 Support - Xi K et al. (2023) Yes -
Rare Variants   (30)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 18270536 Floris C et al. (2008)
c.4217A>G p.Tyr1406Cys missense_variant Unknown - - 35245678 behavior (Song)
c.7166G>A p.Gly2389Asp missense_variant De novo - - 35245678 behavior (Song)
c.8750A>C p.Tyr2917Ser missense_variant Unknown - - 35245678 behavior (Song)
c.1475C>A p.Pro492Gln missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.6355A>T p.Ser2119Cys missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.8468T>C p.Ile2823Thr missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.2218C>T p.Arg740Trp missense_variant Familial Paternal - 35245678 behavior (Song)
c.10347A>G p.Glu3449%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3853G>A p.Gly1285Arg missense_variant Familial Paternal - 35245678 behavior (Song)
c.4898C>T p.Ser1633Leu missense_variant Familial Paternal - 35245678 behavior (Song)
c.5476G>T p.Asp1826Tyr missense_variant Familial Paternal - 35245678 behavior (Song)
c.5996C>G p.Pro1999Arg missense_variant Familial Maternal - 35245678 behavior (Song)
c.6949T>C p.Tyr2317His missense_variant Familial Maternal - 35245678 behavior (Song)
c.7856G>T p.Gly2619Val missense_variant Familial Maternal - 35245678 behavior (Song)
c.7997A>G p.Tyr2666Cys missense_variant Familial Maternal - 35245678 behavior (Song)
c.2511G>C p.Gln837His missense_variant Familial - Simplex 30392784 Wu J , et al. (2018)
c.2666A>G p.Asn889Ser missense_variant Familial - Simplex 30392784 Wu J , et al. (2018)
c.3104C>T p.Ser1035Leu missense_variant Familial - Simplex 30392784 Wu J , et al. (2018)
c.4724G>A p.Arg1575Gln missense_variant Familial - Simplex 30392784 Wu J , et al. (2018)
c.6500A>C p.Asn2167Thr missense_variant Familial - Simplex 30392784 Wu J , et al. (2018)
c.7466G>A p.Arg2489His missense_variant Familial - Simplex 30392784 Wu J , et al. (2018)
c.5525T>C p.Leu1842Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.6448C>T p.His2150Tyr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.8866G>T p.Gly2956Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3551A>T p.Asp1184Val missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.5115C>T p.Gly1705%3D synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.7110A>T p.Leu2370%3D synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.178+59943_178+59944insGATA - intron_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1932C>T p.Asp644%3D synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
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 0.5702996941682

Ranking 940/25841 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 0.99999999592205

Ranking 122/18225 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 0.95079131403608

Ranking 18630/18665 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 0.28364027966126

Ranking 2975/20870 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
Submit New Gene

Report an Error