Human Gene Module / Chromosome 15 / DMXL2

DMXL2Dmx-like 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 9
Rare Variants / Common Variants
9 / 0
Aliases
DMXL2, PEPNS,  RC3
Associated Syndromes
-
Chromosome Band
15q21.2
Associated Disorders
ADHD
Relevance to Autism

Two de novo missense variants in the DMXL2 gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Molecular Function

This gene encodes a protein with 12 WD domains; proteins with WD domains are involved in many functions including participation in signal transduction pathways. May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles and plays a role in the brain as a key controller of neuronal and endocrine homeostatic processes.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DMXL2 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
4 Support De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis Wang S , et al. (2018) No -
5 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
6 Support Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders Costain G , et al. (2019) Yes ADHD, behavioral problems
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Purvi Majethia et al. (2024) No -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4690G>A p.Glu1564Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial - Multi-generational 30732576 Costain G , et al. (2019)
c.6430C>T p.Arg2144Ter stop_gained De novo - Multiplex 30257206 Wang S , et al. (2018)
c.6137C>T p.Ala2046Val missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.7143G>A p.Met2381Ile missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.3455A>G p.Asp1152Gly missense_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.4987G>A p.Ala1663Thr missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.7229C>G p.Ser2410Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.352T>C p.Trp118Arg missense_variant Familial Both parents - 38374498 Purvi Majethia et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[New Scoring Scheme]
1/1/2019
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders.2019]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.2018] [Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
7/1/2015
icon
4

Increased from to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.07) (Iossifov et al., 2014; Krumm et al., 2015).

Krishnan Probability Score

Score 0.49789894636908

Ranking 2320/25841 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 0.99999999939593

Ranking 91/18225 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 0.91157623275033

Ranking 7744/18665 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 0.44564329131163

Ranking 962/20870 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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