Human Gene Module / Chromosome 8 / DDHD2

DDHD2DDHD domain containing 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
5 / 1
Aliases
DDHD2, SAMWD1,  SPG54,  iPLA(1)gamma
Associated Syndromes
-
Chromosome Band
8p11.23
Associated Disorders
-
Relevance to Autism

Genome-wide association analysis of 6222 ASD case-pseudocontrol pairs from the SPARK cohort in Matoba et al., 2020 identified a novel genome-wide significant locus (rs60527016 at chr8:38.19M-38.45M); subsequent massively parallel reporter assay (MPRA) identified a putative casual variant within this novel locus (rs7001340), and expression quantitative trait loci data demonstrated an association between the risk allele of rs7001340 and decreased expression of DDHD2 in both adult and prenatal brain tissue. DDHD2 had previously been shown in Parikshak et al., 2016 to be significantly downregulated in post-mortem cortex of individuals with autism compared to controls (logFC -0.28, P-value 5.67E-05, FDR 0.013), and Hall et al., 2020 demonstrated via transcriptome-wide association studies (TWAS) of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, major depressive disorder, and schizophrenia that genetic predictors of reduced expression of DDHD2 were significantly (P < 0.05) associated with all five tested neuropsychiatric conditions.

Molecular Function

This gene encodes a phospholipase enzyme containing sterile-alpha-motif (SAM), WWE, and DDHD domains. This protein participates in membrane trafficking between the endoplastic reticulum and the Golgi body. Mutations in this gene can cause autosomal recessive spastic paraplegia 54.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DDHD2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Transmission disequilibrium of small CNVs in simplex autism Krumm N , et al. (2013) Yes -
2 Support Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism Parikshak NN et al. (2016) Yes -
3 Positive association Cis-effects on gene expression in the human prenatal brain associated with genetic risk for neuropsychiatric disorders Hall LS et al. (2020) Yes -
4 Primary Common genetic risk variants identified in the SPARK cohort support DDHD2 as a candidate risk gene for autism Matoba N et al. (2020) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Cirnigliaro M et al. (2023) Yes -
7 Support - Isaac O Akefe et al. (2024) No -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Paternal Simplex 24035194 Krumm N , et al. (2013)
c.1946A>G p.Asn649Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1382C>T p.Ala461Val missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.634C>T p.Gln212Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.815G>A p.Trp272Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intergenic_variant - - - 32747698 Matoba N et al. (2020)
SFARI Gene score
2

Strong Candidate

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
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.49201280637681

Ranking 4826/25841 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 3.0963982375012E-8

Ranking 15952/18225 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 0.94879477840909

Ranking 17829/18665 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 0.56143724358566

Ranking 201/20870 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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