Human Gene Module / Chromosome 2 / GPD2

GPD2glycerol-3-phosphate dehydrogenase 2

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
4 / 1
Aliases
GPD2, GDH2,  GPDM,  mGPDH
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
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.

Reports related to GPD2 (4 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 -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 19011903 Daoud H , et al. (2008)
- - copy_number_loss De novo NA 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)
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
3

Suggestive Evidence

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: Decreased from 4 to 3

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.

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 0.00010077478578954

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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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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