Submission Details

Glycogen storage disease type 4 (GSD IV) is a clinically heterogeneous autosomal recessive disease caused by deficiency of the glycogen branching enzyme (GBE) encoded by the GBE1 gene. Abnormally long chains of glycogen known as polyglucosan bodies accumulate in various tissues of the body resulting in hepatic, cardiac and neurological disease. The severity of disease is correlated with residual activity of the GBE enzyme. Severe prenatal presentations can include fetal akinesia deformation sequence, decreased fetal movements, polyhydramnios, and fetal hydrops. Neonates have profound hypotonia, respiratory distress, and dilated cardiomyopathy, with death typically in early infancy. A historical subtype system used to classify patients along the GSD IV spectrum based on severity and age of onset is no longer favored, as all individuals with GBE deficiency have homozygous or compound heterozygous pathogenic variants in the GBE1 gene. OMIM currently lists two separate disease entities for GBE1: #232500 for GSD IV and #263570 for adult polyglucosan body disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity, glycogen storage disease due to glycogen branching enzyme deficiency (MONDO: 0009292)

We have curated 26 variants in GBE1 (missense, nonsense, frameshift, large deletion) reported in 17 probands across 7 publications (PMIDs: 8613547, 15452297, 15019703, 17662246, 15520786, 16278887, 12913206). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. The gene-disease association is also supported by experimental evidence showing reduced GBE expression and activity in patient cells, reduced GBE activity in COS-7 cells transfected with specific GBE1 variants, multiple animal models including three separate mouse models that mimic varying disease severities with GBE1 gene alterations, and finally partial rescue of activity using a peptide designed to increase protein stability (PMIDs: 8613547, 9851430, 15452297, 11817063, 17257876, 21075835, 21856731, 26385640, 26199317).

In summary, the GBE1 gene is definitively associated with autosomal recessive GBE IV. 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 Prenatal GCEP on the meeting date August 23, 2023 (SOP Version 9).