Triosephosphate Isomerase Deficiency via the TPI1 Gene

Triosephosphate isomerase (TPI) deficiency has been reported in less than 100 individuals. TPI deficiency is a metabolic disorder due to impairment of the glycolytic pathway. Patients present in early childhood with life threatening chronic hemolytic anemia and progressive neuromuscular impairment. Additional symptoms can include cardiomyopathy, susceptibility to chronic infections, splenomegaly, dyspnea, jaundice and fatigue (Orosz et al. 2006). Genetic testing can be helpful in the differential diagnosis of TPI deficiency from other forms of hemolytic anemia including thalassemia, spherocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and acquired and immune hemolytic anemias. There are no curative therapies for TPI deficiency, but supportive care includes blood transfusions and assisted ventilation (Orosz et al. 2009).

TPI deficiency is inherited in an autosomal recessive manner through pathogenic variants in the TPI1 gene. The TPI1 gene encodes triosephosphate isomerase which is a glycolytic enzyme that regulates dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate equilibrium. TPI functions as a homodimer and when disrupted, leads to DHAP accumulation which is metabolized to toxic methylglyoxal. The c.315G>C (p.Glu105Asp), also referred to as p.Glu104Asp using legacy nomenclature, is the most prevalent pathogenic variant and accounts for about 80% of causative alleles (Daar et al. 1986; Orosz et al. 2009, Watanabe et al. 1996). Other missense variants have also been reported through the coding region which impair TPI dimer formation (Orosz et al. 2006). Nonsense, small insertions and deletions have also been reported in a minority of cases (Valentin et al. 2000). TPI deficiency is fully penetrant with symptom onset occurring during infancy (Orosz et al. 2009).

Clinical sensitivity cannot be estimated because only a small number of cases have been reported to date. Analytical sensitivity should be high because all pathogenic variants to date are detected by this method.

This test provides full coverage of all coding exons of the TPI1 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).