PHKB

Inheritance Pattern: AR

Disease ID:MONDO:0009868

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0009868

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009868

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009868

Submitter: ClinGen

The gene *PHKB* which codes for subunit b of Phosphorylase b kinase (Phk) has been definitively associated with Glycogen Storage Disease 9B (GSD 9B or GSD IXB) according to the gene-disease validity curation process (Standard Operating Procedures Version 10) of ClinGen. Context for *PHKB*: Phk’s functional role is to activate glycogen phosphorylase through phosphorylation. Glycogen phosphorylase hydrolyzes glycogen thereby releasing free glucose for utilization under fasting conditions. Therefore improper activation of glycogen phosphorylase can result in glycogen buildup in the liver, hypoglycemia, exercise intolerance and progressive muscle weakness. The hexadecameric structure of Phk is created by the association of four copies of each of the α-, β-, ɣ-, and δ-subunits. The regulatory subunits are α, β and δ, while ɣ contains the active site. Subunit α is encoded *PHKA1* and *PHKA2* are found on the X-chromosome and encode the muscle and liver isoform of the subunit. Pathogenic mutations in *PHKA2* cause the most frequent type of GSD 9. *PHKB* is found on chromosome 16 and can be alternatively spliced to produce tissue isoforms. *PHKG1* and *PHKG2* encode the muscle and liver isoforms of ɣ, respectively, and are found on chromosomes 7 and 16. Mutations in *PHKG1* and *PHKG2* are associated with the more severe version GSD 9c. *CALM1*, *CALM2*, and *CALM3* are three separate genes that encode the δ subunit. Mutations in these genes have not been linked to the disease. Phk has widespread tissue distribution but primarily causes disease in the liver and muscle. *PHKB* performs a regulatory role in Phk and is similar to the α subunit. In an autosomal recessive manner mutations in this subunit have been associated with hepatomegaly, hypoglycemia only after prolonged fasting and in some cases mild muscle hypotonia and growth retardation. Manifestation can be highly variable ranging from mild to aggressive.(PMID: 33858366) The average age of onset is 3.8 years.(PMID: 33858366) Most all patients present with hepatomegaly and elevated hepatic transaminase. Less than half of reported cases have reported hypoglycemia.(PMID: 33858366) And only about 15% of cases report short stature. Liver cirrhosis has also been reported in one case.(PMID: 33858366) Most variants reported to date affect primarily the liver with no symptoms of muscle involvement being reported. While symptoms improve with age, individuals should be monitored life-long for complications such as liver fibrosis. There is a predominance of severe, null mutations (nonsense, frameshift and splice site mutations identified in the PHKB gene of the six reported probands). Summary of Case Level Data (12): 6 probands were scored and 12 unique variants were identified (7 of which are predicted or proven null). Summary of Experimental Evidence (2.5): This gene disease relationship is also supported by experimental evidence of a mouse model that replicates the disease and .5 points for the biochemical function of Phk matching expected phenotypes.

Inheritance Pattern: AR

Disease ID:MONDO:0009868

Submitter: Orphanet