Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1461-1472 |
| Number of pages | 12 |
| Journal | Human Mutation |
| Volume | 42 |
| Issue number | 11 |
| Early online date | 18 Aug 2021 |
| DOIs | |
| Publication status | Published - Nov 2021 |
Bibliographical note
Funding Information:We thank Dr. Arnold J. J. Reuser for his critical review of the manuscript?and Ton Verkerk for his invaluable assistance with generating the database. We thank Philip Lijnzaad for his help with the statistical analysis. This study was supported by grants from the Administrative Department of Science, Technology and Innovation (Colciencias, Colombia) and Sanofi Genzyme. The collaboration project is co-funded by the PPP Allowance made available by Health-Holland, Top Sector Life Sciences & Health, to the Prinses Beatrix Spierfonds to stimulate public?private partnerships (project numbers: LSHM17075 and LSHM19015). Research on Pompe disease at Erasmus MC is financially supported by ?Prinses Beatrix Spierfonds? (project numbers: W.OR13-21, W.OR15-10, W.OR16-07); Tex Net; Sophia Foundation for Medical Research (SSWO) (project number: s17-32); Metakids (project number: 2016-063); Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico??National Counsil of Technological and Scientific Development,? Brasil (grant number: 234407/2014-0); Colciencias and Sanofi Genzyme. Ans T. van der Ploeg has provided consulting services for various industries in the field of Pompe disease under an agreement between these industries and Erasmus MC, Rotterdam, The Netherlands.
Funding Information:
We thank Dr. Arnold J. J. Reuser for his critical review of the manuscript and Ton Verkerk for his invaluable assistance with generating the database. We thank Philip Lijnzaad for his help with the statistical analysis. This study was supported by grants from the Administrative Department of Science, Technology and Innovation (Colciencias, Colombia) and Sanofi Genzyme. The collaboration project is co‐funded by the PPP Allowance made available by Health‐Holland, Top Sector Life Sciences & Health, to the Prinses Beatrix Spierfonds to stimulate public–private partnerships (project numbers: LSHM17075 and LSHM19015). Research on Pompe disease at Erasmus MC is financially supported by “Prinses Beatrix Spierfonds” (project numbers: W.OR13‐21, W.OR15‐10, W.OR16‐07); Tex Net; Sophia Foundation for Medical Research (SSWO) (project number: s17‐32); Metakids (project number: 2016‐063); Conselho Nacional de Desenvolvimento Científico e Tecnológico–“National Counsil of Technological and Scientific Development,” Brasil (grant number: 234407/2014‐0); Colciencias and Sanofi Genzyme. Ans T. van der Ploeg has provided consulting services for various industries in the field of Pompe disease under an agreement between these industries and Erasmus MC, Rotterdam, The Netherlands.
Publisher Copyright:
© 2021 The Authors. Human Mutation published by Wiley Periodicals LLC