Fructose-1,6-Bisphosphatase Deficiency via the FBP1 Gene

Fructose-1,6-bisphosphatase (FBPase) deficiency (OMIM #229700) is a disorder of gluconeogenesis causing life-threatening episodes of hypoglycemia and lactic acidosis. FBPase is mainly expressed in the liver and kidneys and normally catalyzes the hydrolysis of fructose 1,6 bisphosphate to fructose-6-phosphate and inorganic phosphate. When hepatic glycogen stores are depleted, gluconeogenetic precursors such as lactate, glycerol, and pyruvate are used to maintain the blood glucose level. During periods of fasting and during febrile infectious diseases, a defect in FBPase can result in hypoglycemia, ketonuria, elevated lactate and alanine levels, and metabolic acidosis. In about half of affected patients, symptoms appear in the first week after birth; in the remaining patients, symptoms mainly occur in their first years of life (Asberg et al. J Inherit Metab Dis, Epub February 2010). The deficiency can be fatal in neonates and infants, and it has been suggested that patients with FBPase deficiency have been misdiagnosed with sudden infant death syndrome or Reye’s syndrome. Tolerance to fasting generally improves with age, and the prognosis is good with avoidance of fasting and use of an emergency regimen during infections (Dixon and Leonard. Arch Dis Child 67:1387-1391, 1992).

Fructose 1,6-bisphosphatase (FBPase) is encoded by exons 1-7 of the FBP1 gene (OMIM #611570) on chromosome 9q22.2-q22.3. FBPase deficiency is an inborn error of metabolism which shows autosomal recessive inheritance. Over 20 different FBP1 variants have been reported and are thought to affect the enzyme’s ability to bind to either the substrate fructose 1,6-bisphosphate, the competitive inhibitor fructose 2,6-bisphosphate, the allosteric inhibitor AMP, or metal ions. Reported variants include nonsense variants, missense changes, small insertions and deletions leading to frameshifts or amino acid duplication, deletion of exon 1, and whole gene deletion (Herzog et al. J Inherit Metab Dis 24:87-88, 2001; Faiyaz-Ul-Haque et al. Eur J Pediatr 168:1467-1471, 2009; Asberg et al. 2010). One variant, c.960_961insG, is common in the Japanese population (Kikawa et al. Am J Hum Genet 61:852-861, 1997).

The sensitivity of this test is currently unknown, as comprehensive assessments of sensitivity using direct sequencing methods have not been cited in the published literature for this rare disorder.

The sensitivity of duplication/deletion testing for this rare disorder is currently unknown. However, it should be noted that pathogenic gross deletions have been reported in the FBP1 gene.

This test provides full coverage of all coding exons of the FBP1 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).