Human Gene Module / Chromosome 1 / CSMD2

CSMD2CUB and Sushi multiple domains 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
12 / 2
Aliases
-
Associated Syndromes
-
Chromosome Band
1p35.1
Associated Disorders
-
Relevance to Autism

A number of de novo variants in the CSMD2 gene, including a de novo loss-of-function variant and four de novo missense variants, have been identified in ASD probands from the Simons Simplex Collection, the SPARK cohort, the MSSNG cohort, a Chinese ASD cohort, and a Pakistani ASD cohort (Iossifov et al., 2014; Zhou et al., 2022; Yuan et al., 2023; Khan et al., 2024). A compound heterozygous mutation in the CSMD2 gene consisting of two inherited missense variants was reported in an ASD proband born to non-consanguineous parents (Tuncay et al., 2022). A de novo missense variant in this gene was also identified in an ADHD proband from a simplex family in Kim et al., 2017.

Molecular Function

The protein encoded by this gene is thought to be involved in the control of complement cascade of the immune system. Variants in this gene have been found to associate with adult ADHD (Lesch et al., 2008) and schizophrenia (Havik et al., 2011).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CSMD2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies Lesch KP , et al. (2008) No -
2 Positive Association - Bjarte HÃ¥vik et al. (2011) No -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support - Daniel Seung Kim et al. (2017) No -
5 Support - Tuncay IO et al. (2022) Yes DD
6 Support - Zhou X et al. (2022) Yes -
7 Support - Yuan B et al. (2023) Yes -
8 Primary - Hamid Khan et al. (2024) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.712+1G>T - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
- - upstream_gene_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2780C>T p.Ala927Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7903C>T p.Arg2635Cys missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.8925C>T p.Ser2975= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.8628C>T p.Phe2876= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.8713A>G p.Thr2905Ala missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5984G>A p.Arg1995Gln missense_variant De novo - Simplex 38649688 Hamid Khan et al. (2024)
c.6435C>T p.Phe2145= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2671A>G p.Ile891Val missense_variant De novo - Simplex 28332277 Daniel Seung Kim et al. (2017)
c.2107G>A p.Val703Met missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.9665G>A p.Arg3222His missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.920+23837C>A;c.800+23837C>A - intron_variant - - - 18839057 Lesch KP , et al. (2008)
c.1034-3332C>A;c.914-3332C>A - intron_variant - - - 21439553 Bjarte HÃ¥vik et al. (2011)
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.

7/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.49416273582401

Ranking 3800/25841 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
Iossifov Probability Score

Score 0.893

Ranking 154/239 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 (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.85174412627872

Ranking 3525/18665 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 0.34569674105013

Ranking 2073/20870 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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