ClinGen Dosage Sensitivity Curation Page

PDHA1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
1907799 Chun et al. (1991) found a de novo 20 bp deletion in PDHA1 that resulted in a frameshift and premature stop codon in a female patient with severe PDH deficiency. Enzyme activity was ~22% as compared to controls.
9686362 De Meirleir et al. (1998) found a 36 bp insertion in a brother and sister with PDH deficiency. The mother was a normal carrier and was shown to have the the insertion and normal alleles at 50:50, while the daughter had 95:5 ratio (insertion:normal alleles).
10679936 Lissens et al. (2000) reported a summary of mutations in PDHA1 in 130 patients (61 female and 69 male from 123 families), including 36 missense mutations, 1 nonsense mutation, and 39 in/del mutations.

Haploinsufficiency phenotype comments:

Mutations in PDHA1 are associated with Pyruvate dehydrogenase E1-alpha deficiency, an X-linked dominant disorder and Leigh syndrome, an X-linked recessive disorder. There is a wide spectrum of phenotypic severity.

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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

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.