Human Gene Module / Chromosome X / ENOX2

ENOX2ecto-NOX disulfide-thiol exchanger 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 2
Rare Variants / Common Variants
1 / 4
Aliases
-
Associated Syndromes
-
Chromosome Band
Xq26.1
Associated Disorders
-
Relevance to Autism

An X-chromosome-wide association (XWAS) study of 6,873 individuals with autism from MSSNG, SSC, and SPARK (5,639 males and 1,234 females) and 8,981 controls (3,911 males and 5,070 females) in Mendes et al., 2024 identified four intronic SNPs in the ENOX2 gene that reached the significance threshold for association (P < 1.07E-05) in a sex-stratified female-XWAS analysis; three of these SNPs also reached the significance threshold for association in an XWAS meta-analysis. Furthermore, rare predicted damaging SNVs (<0.1% frequency in gnomAD) in the ENOX2 gene were found to have a higher frequency in male ASD cases from MSSNG, SSC, and SPARK compared to other family members, while rare CNV deletions (<1% frequency in gnomAD) overlapping at least one exon of the ENOX2 gene were found to be enriched in ASD cases (female and both sexes combined) from these three cohorts compared to unaffected family members.

Molecular Function

This gene is a tumor-specific member of the ECTO-NOX family of genes that encode cell surface NADH oxidases. The encoded protein has two enzymatic activities: catalysis of hydroquinone or NADH oxidation, and protein disulfide interchange. The protein also displays prion-like properties.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ENOX2 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Ashlesha Gogate et al. (2024) Yes -
2 Primary - Marla Mendes et al. (2025) Yes -
Rare Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.818G>A p.Arg273His missense_variant Familial Maternal Multiplex 39632905 Ashlesha Gogate et al. (2024)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.97+2748C>T - intron_variant - - - 39706197 Marla Mendes et al. (2025)
c.-38-19370T>C - intron_variant - - - 39706197 Marla Mendes et al. (2025)
c.-182-39395A>G - intron_variant - - - 39706197 Marla Mendes et al. (2025)
c.-183+58785del - intron_variant - - - 39706197 Marla Mendes et al. (2025)
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.

4/1/2025
3

Initial score established: 3

Krishnan Probability Score

Score 0.45611520328318

Ranking 9930/25841 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 0.0031455506957032

Ranking 10948/18225 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 0.93824780679085

Ranking 13798/18665 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 0.003590712596412

Ranking 8578/20870 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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