• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
PDHA1 (HGNC:8806) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
pyruvate dehydrogenase E1 subunit alpha 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
PDHA
Alias symbols
E1alpha
%HI
35.05(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.99(Read more about gnomAD pLI score)
LOEUF
0.27(Read more about gnomAD LOEUF score)
Cytoband
Xp22.12
Genomic Coordinates
GRCh37/hg19: chrX:19362045-19379836 NCBI Ensembl UCSC
GRCh38/hg38: chrX:19343927-19361718 NCBI Ensembl UCSC
MANE Select Transcript
NM_000284.4 ENST00000422285.7 (Read more about MANE Select)
Function
The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle. {ECO:0000269|PubMed:19081061, ECO:0000269|PubMed:7782287}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-15840
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
09/27/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • pyruvate dehydrogenase deficiency Monarch
HI Evidence:
  • PUBMED: 21914562
    Imbard et al (2014) sequenced PDHA1 in 82 individuals with pyruvate dehydrogenase complex deficiency and identified 4 truncating variants in PDHA1 in three females (p.Ser312ArgfsX13, p.Arg304X, p.Gln84ThrfsX12) and one mosaic male (p.Arg283X). Affected individuals were all found to have reduced PDHc enzyme activity in fibroblasts. Two of the truncating variants detected in females were de novo. The inheritance of the other two variants was unknown. Two additional individuals were found to have large deletions (3.4 MB and 2.1 MB) containing PDHA1.
  • PUBMED: 33504798
    Martin et al (2021) analyzed exome sequencing data from 11,044 families in the Deciphering Developmental Disorders study to study the contribution of X-liked causes of developmental disorders in males and females. In this study they detected 2 de novo frameshift variants and 1 de novo nonsense variant in PDHA1 in female probands.
  • PUBMED: 18709504
    Ridout et al (2008) detected a mosaic splice site variant in a female with clinical features of pyruvate dehydrogenase complex deficiency, including brain abnormalities, developmental delay, and elevated lactate. Immunocytochemistry showed 40% of fibroblasts were deficient for E1alpha protein. Mutant cDNA was not detected suggesting the abnormal transcript was degraded. The splice site variant was not present in either parent.
  • PUBMED: 15384102
    Cameron et al (2004) detected a 4 basepair duplication in exon 9 of PDHA1 in a female with severe lactic acidosis, prenatal hydrocephalus, and died at 1 month of age. Western blot demonstrated reduced E1alph protein and very low PDHc enzyme activity was detected in fibroblasts. The variant was not present in an unaffected female sibling.
  • PUBMED: 20002125
    Barnerias et al (2010) reported a 4 basepair deletion in a female with encephalopathy, seizures, brain abnormalities, elevated lactate, and reduced PDHc activity.
HI Evidence Comments:
Pathogenic variants in PDHA1 are associated with Pyruvate dehydrogenase E1-alpha deficiency, an X-linked dominant disorder. Phenotypic findings commonly include developmental delay, lactic acidemia, hypotonia, epilepsy, brain abnormalities, and ataxia. Phenotype in females can be highly variable due to X inactivation. Affected males typically have hypomorphic alleles with some residual enzyme function.
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)