Glycogen Storage Disease Type IV via the GBE1 Gene

Glycogen storage disease (GSD) type IV (OMIM 232500), also known as Andersen disease, is a rare, severe disorder caused by a deficiency of glycogen branching enzyme encoded by the GBE1 gene. Clinical features for GSD type IV vary widely. Some research groups bin patients into two groups: those presenting with liver disease and those presenting with neuromuscular symptoms (see OMIM; http://www.emedicine.com/ped/topic97.htm; Bao et al. J Clin Invest 97:941-948, 1996; and Bruno et al. Neurology 63:1053-1058, 2004). In most liver disease cases, failure to thrive is observed during the first 18 months. Hepatosplenomegaly and liver cirrhosis then develop, leading to death by 5 years. Non-progressive hepatic forms have also been described. The neuromuscular forms of the disease range from a lethal neonatal form with hypotonia, muscle wasting, and cardiomyopathy to an adult onset form, sometimes called adult polyglucosan body disease (APBD; OMIM 263570) characterized by neurodegenerative features. For additional information, see the web sites for the Association for Glycogen Storage Disease (www.agsdus.org) and the APBD Research Foundation (www.apbdrf.org).

Both GSD Type IV and APBD are autosomal recessive disorders. Variants in the GBE1 gene are the only known cause of both of these disorders. About 20 different causative variants have been reported. The variants are about equally split between missense and nonsense or frameshift. Variants are located throughout the length of the gene. APBD appears to be more common in people with Ashkenazi Jewish ancestry than other populations. Few connections have been made between genotype and phenotype, although there are indications that some missense variants may lead to partial enzymatic activity and less severe phenotypes.

Sensitivity of this test has not been reported but should be relatively high for patients with low enzyme activity.

This test provides full coverage of all coding exons of the GBE1 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.

This testing also includes coverage for the deep intronic variant c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT (Akman et al. 2015).