Human Gene Module / Chromosome 6 / ENPP1

ENPP1ectonucleotide pyrophosphatase/phosphodiesterase 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
10 / 0
Aliases
ENPP1, ARHR2,  COLED,  M6S1,  NPP1,  NPPS,  PC-1,  PCA1,  PDNP1
Associated Syndromes
-
Chromosome Band
6q23.2
Associated Disorders
-
Relevance to Autism

Rare de novo non-coding variants in the ENPP1 gene have been identified in ASD probands in multiple studies (Yuen et al., 2017; Turner et al., 2017; Werling et al., 2018), while a de novo in-frame deletion variant in this gene was identified in a male ASD proband from a cohort of 100 Vietnamese children with ASD (Tran et al., 2020).

Molecular Function

This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ENPP1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
2 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
3 Support An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder Werling DM et al. (2018) Yes -
4 Primary Genetic landscape of autism spectrum disorder in Vietnamese children Tran KT et al. (2020) Yes -
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
TA>TGT p.? intron_variant De novo - Simplex 29700473 Werling DM et al. (2018)
c.1493G>A p.Arg498His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2444+191T>C - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.240+11572G>A - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.241-13097T>C - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.241-15028T>C - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.2230+545dup - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.2608-1402G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.522C>T p.Gly174%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1081_1083del p.Lys361del inframe_deletion De novo - Simplex 32193494 Tran KT et al. (2020)
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 0.49127783997684

Ranking 5674/25841 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 2.3098736123678E-5

Ranking 13815/18225 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 0.94144706962464

Ranking 14936/18665 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 -0.25034483443623

Ranking 16387/20870 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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