Human Gene Module / Chromosome X / PDHA1

PDHA1pyruvate dehydrogenase E1 subunit alpha 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
9 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xp22.12
Associated Disorders
-
Relevance to Autism

Li et al., 2023 determined that a de novo coding-synonymous variant in the PDHA1 gene originally identified in a Japanese ASD proband in Takata et al., 2018 was a non-canonical splicing variant; subsequent functional analysis by minigene splicing assays demonstrated that this variant resulted in deletion of 23 base pairs from exon 14 of this gene. A frameshift variant in the PDHA1 gene had previously been identified in a female ASD proband from the ASPIRE cohort (Callaghan et al., 2019).

Molecular Function

The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to PDHA1 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
2 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
3 Primary - Kuokuo Li et al. (2024) Yes -
4 Support - M Cecilia Poli et al. () No -
5 Support - Purvi Majethia et al. (2024) No DD
6 Support - Alistair T Pagnamenta et al. (2024) No -
7 Support - Axel Schmidt et al. (2024) No Epilepsy/seizures
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1149G>A p.Trp383Ter stop_gained De novo - - 38177409 M Cecilia Poli et al. ()
c.*1776C>T - 3_prime_UTR_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
- - inversion Unknown Not maternal - 38776926 Alistair T Pagnamenta et al. (2024)
c.642G>T p.Trp214Cys missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.738C>T p.Gly246= synonymous_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.379C>T p.Arg127Trp missense_variant De novo - - 38374498 Purvi Majethia et al. (2024)
- - copy_number_gain Unknown Not maternal - 38776926 Alistair T Pagnamenta et al. (2024)
c.1058_*3dup - frameshift_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.852C>T p.Gly284= synonymous_variant De novo - Simplex 29346770 Takata A , et al. (2018)
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.

4/1/2024
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.42579686453636

Ranking 20991/25841 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 0.99209013913194

Ranking 1706/18225 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 0.86602763773972

Ranking 4113/18665 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 -0.17886588505888

Ranking 14928/20870 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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