Broad variation in phenotypes for common GAA genotypes in Pompe disease

Hum Mutat. 2021 Nov;42(11):1461-1472. doi: 10.1002/humu.24272. Epub 2021 Sep 8.


Patients with the common c.-32-13T > G/null GAA genotype have a broad variation in age at symptom onset, ranging from early childhood to late adulthood. Phenotypic variation for other common GAA genotypes remains largely unexplored. Here, we analyzed variation in age at symptom onset for the most common GAA genotypes using the updated and extended Pompe GAA variant database. Patients with the c.2647-7G > A/null genotype invariably presented symptoms at adulthood, while the c.-32-13T > G/null, c.546G > T/null, c.1076-22T > G/null, c.2238G > C/null, and c.2173C > T/null genotypes led to presentations from early childhood up to late adulthood. The c.1309C > T/null genotype was associated with onset at early to late childhood. Symptom onset shifted toward higher ages in homozygous patients. These findings indicate that a broad variation in symptom onset occurs for various common GAA genotypes, suggesting the presence of modifying factors. We identified three new compound heterozygous c.-32-13T > G/null patients who carried the genetic modifier c.510C > T and who showed symptom onset at childhood. While c.510C > T acted by lowering GAA enzyme activity, other putative genetic modifiers did not at the group level, suggesting that these act in trans on processes downstream of GAA enzyme activity.

Keywords: GAA deficiency; Pompe disease; genotype-phenotype; glycogenosis type II; mutation database.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Enzyme Replacement Therapy
  • Genotype*
  • Glycogen Storage Disease Type II / genetics*
  • Glycogen Storage Disease Type II / therapy
  • Humans
  • Mutation
  • Phenotype*
  • alpha-Glucosidases / genetics*


  • GAA protein, human
  • alpha-Glucosidases