Cytosolic Phosphoenolpyruvate Carboxykinase 1 Deficiency via the PCK1 Gene

Disorders of phosphoenolpyruvate carboxykinase (PEPCK) are thought to be a rare cause of childhood onset lactic acidemia. In humans, two PEPCK isozymes are found. One is located in the mitochodria and is encoded by the PCK2 gene. The second is found in the cytosol and is encoded by the PCK1 gene (Robinson 2014). A few early reports have described children with lactic acidemia, hypoglycemia, hypotonia, hepatomegaly and failure to thrive who were also found to have decreased PEPCK enzyme activity (Robinson 2014). More recently, two Ashkenazi Jewish siblings were reported to be homozygous for a missense variant in the PCK1 gene (Adams et al. 2014). Both siblings exhibited gross and fine motor delays, intellectual disability, illness-associated lethargy, fasting hypoglycemia, ketonuria, and metabolic acidosis. The stability of the cytosolic PEPCK enzyme was found to be greatly decreased in both siblings.

Mitochondrial PEPCK deficiency is thought to be inherited in an autosomal recessive manner, and is caused by pathogenic variants in the PCK1 gene (Adams et al. 2014). To date, only a single missense pathogenic variant has been reported in the PCK1 gene. The PCK1 gene is a nuclear encoded gene containing 9 coding exons and is located on chromosome 20 (20q13.31). The PEPCK enzyme plays a critical role in gluconeogenesis by catalyzing the conversion of oxaloacetate to phosphoenolpyruvate. The PCK1 gene is expressed primarily in the kidney and liver (Modaressi et al. 1998).

Clinical sensitivity cannot be estimated because only a very small number of patients have been reported (Adams et al. 2014; Robinson 2014). Analytical sensitivity may be high because the only reported pathogenic variant is detectable by sequencing.

To date, no large deletions or duplications have been described in the PCK1 gene.

This test provides full coverage of all coding exons of the PCK1 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).