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PHKG2 encodes the gamma catalytic subunit of phosphorylase b kinase, a key regulator of glycogenolysis. Pathogenic variants in PHKG2 underlie Glycogen storage disease type IXc, a rare autosomal recessive hepatic glycogenosis presenting with early childhood hepatomegaly, elevated transaminases, and metabolic disturbances.
An 18-month series from Pakistan described 10 Pakistani children from seven unrelated families with PHKG2-related liver phosphorylase kinase deficiency (10 probands) (PMID:32697758). All patients exhibited early hepatomegaly, growth delay, hypoglycemia, and elevated liver enzymes under a recessive inheritance model. One family included compound heterozygous siblings segregating two distinct PHKG2 alleles (one additional affected sibling) (PMID:32697758).
A separate neonatal case report detailed a single patient with jaundice, hypoglycemia, growth retardation, and transaminase elevation. Genetic testing identified two novel PHKG2 alleles: c.698T>C (p.Phe233Ser) and a frameshift leading to p.Arg320AspfsTer5 (11th proband) (PMID:35549678).
Across all reports, PHKG2 variant classes include five loss-of-function alleles (c.226C>T (p.Arg76Ter), c.454C>T (p.Arg152Ter), c.958C>T (p.Arg320Ter), c.913dup (p.Arg305fs), c.557-3C>G), one missense (c.107C>T (p.Ser36Phe)), one splice site, and one novel missense (c.698T>C (p.Phe233Ser)) [PMID:32697758; PMID:35549678].
Functional assays of patient-derived variants confirmed that p.Phe233Ser and p.Arg320AspfsTer5 markedly reduce phosphorylase b kinase activity in vitro, consistent with a loss-of-function mechanism (PMID:35549678).
Collectively, 11 probands across eight families with segregation data and concordant functional studies support a Strong ClinGen gene–disease association. PHKG2 sequencing is clinically indicated in infants with unexplained hepatomegaly, hypoglycemia, and elevated transaminases. Key Take-home: loss-of-function PHKG2 variants cause autosomal recessive Glycogen storage disease type IXc, with responsive metabolic management guiding diagnosis and therapy.
Gene–Disease AssociationStrong11 probands across eight families with segregation and concordant functional data Genetic EvidenceStrong11 probands (10 in multi‐patient series, 1 neonatal case), compound heterozygosity and sib segregation Functional EvidenceModerateIn vitro assays demonstrate loss of phosphorylase b kinase activity for p.Phe233Ser and p.Arg320AspfsTer5 |