Human Gene Module / Chromosome 2 / GPD2

GPD2glycerol-3-phosphate dehydrogenase 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
5 / 1
Aliases
GPD2, GDH2,  GPDM,  mGPDH
Associated Syndromes
-
Chromosome Band
2q24.1
Associated Disorders
DD/NDD
Relevance to Autism

A 25-year-old female patient with intellectual disability, mildly unusual face, and a pervasive developmental disorder was found to carry a compound heterozygous mutation involving the GPD2 gene: a de novo 298 kb deletion containing the NR4A2 and GPD2 genes; and a maternally-inherited missense variant (c.614C>T; p.Pro205Leu) that abolished enzymatic activity (Barge-Schaapveld et al., 2013).

Molecular Function

The protein encoded by this gene localizes to the inner mitochondrial membrane and catalyzes the conversion of glycerol-3-phosphate to dihydroxyacetone phosphate, using FAD as a cofactor. Along with GDP1, the encoded protein constitutes the glycerol phosphate shuttle, which reoxidizes NADH formed during glycolysis.

SFARI Genomic Platforms
Reports related to GPD2 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Haploinsufficiency of the GPD2 gene in a patient with nonsyndromic mental retardation Daoud H , et al. (2008) No -
2 Primary Intellectual disability and hemizygous GPD2 mutation Barge-Schaapveld DQ , et al. (2013) No PDD (pervasive developmental disorder)
3 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
4 Positive Association Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population Kuo PH , et al. (2015) Yes -
5 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 19011903 Daoud H , et al. (2008)
- - copy_number_loss De novo - Simplex 23554088 Barge-Schaapveld DQ , et al. (2013)
c.1640C>T p.Thr547Ile missense_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
c.614C>T p.Pro205Leu missense_variant Familial Maternal Simplex 23554088 Barge-Schaapveld DQ , et al. (2013)
c.1920del p.Gly641AlafsTer12 frameshift_variant 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 - - - 26398136 Kuo PH , et al. (2015)
SFARI Gene score
2

Strong Candidate

A 25-year-old female patient with intellectual disability, mildly unusual face, and a pervasive developmental disorder was found to carry a compound heterozygous mutation involving the GPD2 gene: a de novo 298 kb deletion containing the NR4A2 and GPD2 genes; and a maternally-inherited missense variant (c.614C>T; p.Pro205Leu) that abolished enzymatic activity (Barge-Schaapveld et al., 2013). A rare maternally-inherited heterozygous missense variant that was predicted to be pathogenic was identified in both affected siblings in a multiplex ASD family in Toma et al., 2014. A SNP within 100kb of the GPD2 gene (rs3916984, T allele) showed association with ASD (P = 2.25E-05) in a case-control analysis in the Taiwanese Han population in Kuo et al., 2015.

Score Delta: Score remained at 2

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

A 25-year-old female patient with intellectual disability, mildly unusual face, and a pervasive developmental disorder was found to carry a compound heterozygous mutation involving the GPD2 gene: a de novo 298 kb deletion containing the NR4A2 and GPD2 genes; and a maternally-inherited missense variant (c.614C>T; p.Pro205Leu) that abolished enzymatic activity (Barge-Schaapveld et al., 2013). A rare maternally-inherited heterozygous missense variant that was predicted to be pathogenic was identified in both affected siblings in a multiplex ASD family in Toma et al., 2014. A SNP within 100kb of the GPD2 gene (rs3916984, T allele) showed association with ASD (P = 2.25E-05) in a case-control analysis in the Taiwanese Han population in Kuo et al., 2015.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A 25-year-old female patient with intellectual disability, mildly unusual face, and a pervasive developmental disorder was found to carry a compound heterozygous mutation involving the GPD2 gene: a de novo 298 kb deletion containing the NR4A2 and GPD2 genes; and a maternally-inherited missense variant (c.614C>T; p.Pro205Leu) that abolished enzymatic activity (Barge-Schaapveld et al., 2013). A rare maternally-inherited heterozygous missense variant that was predicted to be pathogenic was identified in both affected siblings in a multiplex ASD family in Toma et al., 2014. A SNP within 100kb of the GPD2 gene (rs3916984, T allele) showed association with ASD (P = 2.25E-05) in a case-control analysis in the Taiwanese Han population in Kuo et al., 2015.

Reports Added
[New Scoring Scheme]
10/1/2018
icon
4

Increased from to 4

Description

A 25-year-old female patient with intellectual disability, mildly unusual face, and a pervasive developmental disorder was found to carry a compound heterozygous mutation involving the GPD2 gene: a de novo 298 kb deletion containing the NR4A2 and GPD2 genes; and a maternally-inherited missense variant (c.614C>T; p.Pro205Leu) that abolished enzymatic activity (Barge-Schaapveld et al., 2013). A rare maternally-inherited heterozygous missense variant that was predicted to be pathogenic was identified in both affected siblings in a multiplex ASD family in Toma et al., 2014. A SNP within 100kb of the GPD2 gene (rs3916984, T allele) showed association with ASD (P = 2.25E-05) in a case-control analysis in the Taiwanese Han population in Kuo et al., 2015.

Krishnan Probability Score

Score 0.41062899345969

Ranking 22621/25841 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.
ExAC Score

Score 0.0001007747857895

Ranking 13080/18225 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
Sanders TADA Score

Score 0.9399506640762

Ranking 14392/18665 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).
Larsen Cumulative Evidence Score

Score 12

Ranking 159/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.42456217966136

Ranking 1181/20870 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.
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