ClinGen Dosage Sensitivity Curation Page

PIGA

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.