Phosphoglycerate Kinase Deficiency via the PGK1 Gene

Phosphoglycerate Kinase (PGK) deficiency is a metabolic disorder with patients presenting with variable nonspherocytic hemolytic anemia, myopathy, and central nervous system (CNS) disability. Age at onset is variable with patients primarily presenting with either nonspherocytic hemolytic anemia (60% of cases) or myopathy (30% of cases). Only a few cases have been reported with patients exhibiting both anemia and myopathy (10% of cases) (Beutler 2007; DiMauro et al. 1981). Anemia can result in pallor, jaundice, fatigue, and shortness of breath. Myopathy is characterized by exercise intolerance, myoglobinuria, cramps, myalgia, and muscle weakness. CNS symptoms occur in about half of PGK cases, irrespective of anemia or myopathy, and include seizures, intellectual disability, epilepsy, hemiplegic migraines, and ataxia. Genetic testing is helpful in the differential diagnosis of PGK deficiency from other forms of nonspherocytic hemolytic anemia and myopathic glycogen storage disorders. Iron supplements, blood transfusions as needed, and avoidance of strenuous exercise are standard treatment. In some severe cases, bone marrow transplantation and splenectomy have been shown to be beneficial (Beutler 2007).

PGK deficiency is inherited in an X-linked recessive manner through pathogenic variants in the PGK1 gene. Heterozygous females have been reported to have milder forms of hemolytic anemia, but are primarily asymptomatic. The majority of causative variants to date are missense variants resulting in reduced catalytic activity or protein stability. Complete loss of PGK function is thought to be incapable with life. Splice site variants and in-frame insertions/deletions resulting in functional but impaired PGK protein have also been described (Beutler 2007; Fermo et al. 2012; Noel et al. 2005). There is no clear genotype/phenotype correlation, but missense variants in the c-terminal domain near the substrate binding pocket are common for patients with myopathy. The PGK1 gene encodes the phosphoglycerate kinase which facilitates ATP generation during glycolysis. Anemia is typically seen as red blood cells rely on glycolysis for energy production and are unable to synthesize PGK lost due to protein instability (Chiarelli et al. 2012; Pey et al. 2013).

Only about 30 families have been reported to date with PGK deficiency. Analytical sensitivity should be high as all reported pathogenic variants in the PGK1 gene are detectable by sequencing. Clinical sensitivity cannot be estimated because only a small number of cases have been reported.

This test provides full coverage of all coding exons of the PGK1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).