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 Ángel 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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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 languageEnglish
Pages (from-to)337-348
Number of pages12
JournalMolecular Therapy - Methods and Clinical Development
Volume17
DOIs
Publication statusPublished - 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)

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