Glycogen Storage Disease Type IX via the PHKA2 Gene

Glycogen storage disease (GSD) resulting from glycogen phosphorylase kinase deficiency (sometimes called GSD type IX) has several subtypes. This is because the phosphorylase kinase (Phk) enzyme is comprised of four subunits (αβγδ) and because there are tissue-specific forms of the subunits. GSD type IX is one of the most common types of GSD, involving ~25% of all GSD patients (Burwinkel et al. Hum Genet 102:423-429, 1998; Hendrickx et al. Am J Hum Genet 64:1541-1549, 1999). Defects in the liver alpha subunit of Phk (OMIM 306000) are by far the most common cause (~75%) of GSD type IX. Patients typically present in the first few months of life with hepatomegaly, growth retardation, elevated liver glycogen, and elevated serum triglycerides and cholesterol.

The PHKA2 gene encodes the liver alpha subunit of Phk. PHKA2 variants are inherited in an X-linked recessive fashion. Nearly all affected individuals are male. About 50 causative PHKA2 missense, nonsense, in-frame deletion, frameshift and splicing variants have been reported (Burwinkel et al. 1998; Hendrickx et al. 1999; Beauchamp et al. Molec Genet Metab 92:88-99, 2007). Causative variants are located throughout the length of the gene; no variants are predominant. Patients with missense variants may have normal or even elevated erythrocyte Phk activity (but reduced liver Phk activity). At least one multi-exon deletion has been reported (Fukao et al. Molec Genet Metab 92:179-182, 2007).

Sensitivity of this test has not been reported.

This test provides full coverage of all coding exons of the PHKA2 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).