Predicting the phenotype of Pompe Disease from features of GAA variants

Geetanjali Rajamani; Nishitha R Pillai; Seth A Stafki; Peter I Karachunski; Peter B Kang

doi:10.1038/s41431-024-01771-z

Predicting the phenotype of Pompe Disease from features of GAA variants

Eur J Hum Genet. 2025 Jan 7. doi: 10.1038/s41431-024-01771-z. Online ahead of print.

Authors

Geetanjali Rajamani¹, Nishitha R Pillai², Seth A Stafki^{3

4}, Peter I Karachunski^{3

4}, Peter B Kang^{5

6

7}

Affiliations

¹ Medical School, University of Minnesota, Minneapolis, MN, USA.
² Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
³ Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, MN, USA.
⁴ Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.
⁵ Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, MN, USA. [email protected].
⁶ Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA. [email protected].
⁷ Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA. [email protected].

PMID: 39775060
DOI: 10.1038/s41431-024-01771-z

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.