Submission Details

PHKG2 was first reported in relation to autosomal recessive glycogen storage disease (GSD) IXc in 1996 (Maichele et al., PMID: 8896567). PHKG2 is the hepatic and testis isoform of the phosphorylase b kinase (PhK) gamma subunit, which activates glycogen phosphorylase. Since glycogen phosphorylase activation is necessary for glycogen breakdown, PHKG2 dysfunction leads to GSD IXc, an inborn error of glycogenolysis. Patients with GSD IXc usually present with elevated transaminases, hypertriglyceridemia, hepatomegaly, and fasting hypoglycemia. Clinical manifestations also include hypercholesterolemia, hypotonia, and growth and/or developmental delay (PMID: 34876562). After childhood, symptoms can improve with proper management. However, it is possible for patients to develop severe hepatic phenotypes such as cirrhosis or fibrosis (PMID: 32697758). There are currently no alternative diseases in the literature associated with PHKG2.

14 variants (5 missense, 2 in-frame indel, 3 nonsense, 4 frameshift) that have been reported in 10 probands in 9 publications (PMID: 6962066, 8896567, 9384616, 35549678, 34876562, 24389071, 32697758, 25266922, 21646031) are included in this curation. At least 7 patients were shown to have a variant that leads to significantly reduced or absent PhK activity (PMID: 6962066, 8896567, 9384616, 35549678, 24389071, 25266922, 21646031). This disease does not appear to disproportionately affect any specific population. Patients included in this curation have ancestry in Europe, East Asia, South Asia, Africa, and the Middle East. One variant of interest (c.643G>A [p.Asp215Asn]) seen in one patient (PMID: 25266922) is interestingly the same variant observed in the rat model, as discussed below (PMID: 8896567). The mechanism of pathogenicity is known to be LOF.

This gene-disease relationship is also supported by experimental evidence including biochemical assays and animal models (PMID: 34083142, 10487978, 30659246, 8896567). First, biochemical experiments demonstrating the function of PHKG2 in glycogen metabolism are consistent with the phenotypes of elevated liver glycogen and hypoglycemia seen in patients (PMID: 10487978). Next, PHKB encodes a protein with a similar function to PHKG2, as PHKB is also a subunit (beta) of phosphorylase b kinase. PHKB is implicated in a similar disease, GSD IXb, and was classified as definitive by the General IEM GCEP (PMID: 30659246). GTEx analysis showed PHKG2 highly expressed in the testis, but not more highly expressed in the liver compared to other tissues. Although this evidence was evaluated for expression evidence A, it was not scored due to lack of increased expression in hepatic tissues (PMID: 23715323). Maichele et al. published a rat model in 1996 with the p.D215N variant. This model organism demonstrated a variety of GSD-related phenotypes also seen in humans including hepatomegaly, elevated liver glycogen, and impaired glycogen mobilization during fasting (PMID: 8896567). Finally, Gibson et al. published a mouse model in 2021 developed through a targeted Phkg2 knockout. Similarly to the rat model from Maichele et al., these mice showed increased liver glycogen in addition to decreased liver PhK enzyme activity, increased liver body weight ratio (hepatomegaly), and early perisinusoidal liver fibrosis (PMID: 34083142).

In summary, PHKG2 is definitively associated with autosomal recessive glycogen storage disease IXc. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date [03/08/2024] (SOP Version 10).