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Predicting the phenotype of Pompe Disease from features of GAA variants

European Journal of Human Genetics volume 33, pages 688–691 (2025)Cite this article

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Abstract

As the management of Pompe disease depends on whether an individual has infantile onset Pompe disease (IOPD) or late onset Pompe disease (LOPD), the question of whether the phenotype can be predicted from specific pathogenic variants is becoming increasingly important. We reviewed published cases of Pompe disease in which IOPD versus LOPD and pathogenic GAA variants were assigned for specific individuals. We then compared variant types and locations versus phenotypes. We identified 115 cases, 42 with IOPD and 73 with LOPD. We found that two features of GAA variants can help predict phenotype: (1) presence of a splice variant on at least one allele and (2) ___location in specific protein domains. These findings help provide prognoses for newborns diagnosed with Pompe disease. Our analysis will also help expecting and prospective parents who pursue genetic testing as they consider therapeutic options that may be beneficial to implement soon after birth.

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Fig. 1: Diagram of the domains of acid alpha-glucosidase enzyme, with late onset Pompe disease (LOPD)-associated pathogenic variants shown as vertical lines above the diagram, and infantile onset Pompe disease (IOPD)-associated pathogenic variants shown as vertical lines below the diagram.

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All of our primary data are presented in the Supplement.

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Acknowledgements

No funding or in kind support was provided for this study.

Funding

The authors did not receive grants or any in kind support for this project. No funding or in kind support was provided for this study.

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Authors and Affiliations

  1. Medical School, University of Minnesota, Minneapolis, MN, USA

    Geetanjali Rajamani

  2. Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA

    Nishitha R. Pillai

  3. Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, MN, USA

    Seth A. Stafki, Peter I. Karachunski & Peter B. Kang

  4. Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA

    Seth A. Stafki, Peter I. Karachunski & Peter B. Kang

  5. Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA

    Peter B. Kang

Authors
  1. Geetanjali Rajamani
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  2. Nishitha R. Pillai
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  3. Seth A. Stafki
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  4. Peter I. Karachunski
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  5. Peter B. Kang
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Contributions

GR collected the primary data, conducted the analyses, and drafted the manuscript. NRP, SAS, and PIK critically reviewed the analyses and manuscript for important intellectual content. PBK supervised all aspects of the project, reviewed the data, and edited the manuscript.

Corresponding author

Correspondence to Peter B. Kang.

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The authors declare no competing interests.

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Ethical approval was not required as all cases reviewed were from the published literature.

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Rajamani, G., Pillai, N.R., Stafki, S.A. et al. Predicting the phenotype of Pompe Disease from features of GAA variants. Eur J Hum Genet 33, 688–691 (2025). https://doi.org/10.1038/s41431-024-01771-z

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