Abstract
Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-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 language | English |
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Pages (from-to) | 337-348 |
Number of pages | 12 |
Journal | Molecular Therapy - Methods and Clinical Development |
Volume | 17 |
DOIs | |
Publication status | Published - 12 Jun 2020 |
Bibliographical note
Funding Information:We thank the members of the Molecular Stem Cell Biology Group for the critical discussions. This work was funded through Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil), the Sophia Foundation for Medical Research (SSWO; project number s17 ‐ 32 ), and Metakids (project number 2016 ‐ 063 ). This project has received funding from the Ministry of Economic Affairs under TKI allowance under the TKI‐Programme Life Sciences & Health. The collaboration project is co-funded by the PPP Allowance made available by Health ∼ Holland, Top Sector Life Sciences & Health , to stimulate public-private partnerships (project numbers LSHM16008 and LSHM19015 ). The collaboration project is co-initiated by the Prinses Beatrix Spierfonds.
Funding Information:
We thank the members of the Molecular Stem Cell Biology Group for the critical discussions. This work was funded through Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil), the Sophia Foundation for Medical Research (SSWO; project number s17‐32), and Metakids (project number 2016 ‐ 063). This project has received funding from the Ministry of Economic Affairs under TKI allowance under the TKI‐Programme Life Sciences & Health. The collaboration project is co-funded by the PPP Allowance made available by Health ∼ Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships (project numbers LSHM16008 and LSHM19015). The collaboration project is co-initiated by the Prinses Beatrix Spierfonds.
Publisher Copyright:
© 2020 The Author(s)