Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

Stijn L. M. in't Groen, Douglas O. S. de Faria, Alessandro Iuliano, Johanna M. P. van den Hout, Hannie Douben, Trijnie Dijkhuizen, David Cassiman, Peter Witters, Miguel-Angel Barba Romero, Annelies de Klein, Galhana M. Somers-Bolman, Jasper J. Saris, Lies H. Hoefsloot, Ans T. van der Ploeg, Atze J. Bergsma, W. W. M. Pim Pijnappel*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid a-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5' UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient.

    Original languageEnglish
    Pages (from-to)337-348
    Number of pages12
    JournalMolecular therapy-Methods & clinical development
    Publication statusPublished - 12-Jun-2020



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