ClinGen Dosage Sensitivity Curation Page

PIGA

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24706016 Kato, et al., 2014, report four male patients with early-onset epileptic encephalopathy. Three had maternally inherited missense changes. One had a nonsense mutation in the last exon (maternal testing not done) that results in an intact protein. No mutations were found in 6500 control exomes from NHLBI or from 573 laboratory control specimens. This same nonsense mutation had previously been reported by Johnston, et al, 2012, in males of a family showing X-linked inheritance who had dysmorphic features and early-onset epileptic encephalopathy. The female carriers in this family were phenotypically normal and showed skewed X-inactivation.
24357517 Belet, et al., 2014, report a frameshift mutation in exon 2 in a 24-year old male who, at age 6 months, had onset of myoclonic seizures with arrest of development and axial hypotonia (described in Claes et al, 1997, PMID:9307258). Affect maternal uncles died in infancy of respiratory infections or status epilepticus. Female carriers were all normal. The authors showed that the mutation results in the likely use of an alternate start codon leading to a hypomorphic N-truncated protein.

Haploinsufficiency phenotype comments:

Additional missense mutations and an in-frame deletion are reported (PMIDs: 24259184, 24259288, 24259184). The clinical features associated with partial loss of function of PIGA (phosphatidylinositol glycan class A) have been termed multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2), an X-linked recessive neurodevelopmental disorder characterized by: hypotonia, refractory seizures, growth abnormalities, alveolar ridge abnormalities, dental anomalies, and mild facial dysmorphic features. The phenotype shows clinical variability that can be classified into 2 types, severe and less severe, which correlate with the degree of PIGA activity reduction caused by the mutations [summary by Johnston et al., 2012 (PMID 22305531), Belet et al., 2014 (PMID 24357517), Kato et al., 2014 (PMID 24706016)]. Of note, the males in the family described by Swoboda et al., 2014 (PMID:24259288) also had the unique features of iron overload and cutaneous manifestations. Based on mouse models and the available human data, it is likely that complete loss of PIGA gene expression is not compatible with life in a male. Additionally, acquired somatic mutations in PIGA have been associated with paroxysmal nocturnal hemoglobinuria (PNH). PNH is an uncommon acquired hemolytic anemia that often manifests with hemoglobinuria, abdominal pain, smooth muscle dystonias, fatigue, and thrombosis (see OMIM #300818).

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.