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

Autor:	In 't Groen SLM; Department of Pediatrics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., de Faria DOS; Department of Pediatrics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., Iuliano A; Department of Pediatrics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., van den Hout JMP; Department of Pediatrics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., Douben H; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., Dijkhuizen T; Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands., Cassiman D; Center for Metabolic Diseases, UZ and KU Leuven, 3000 Leuven, Belgium., Witters P; Center for Metabolic Diseases, UZ and KU Leuven, 3000 Leuven, Belgium., Barba Romero MÁ; Internal Medicine Department, Albacete University Hospital, 02006 Albacete, Spain., de Klein A; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., Somers-Bolman GM; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., Saris JJ; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., Hoefsloot LH; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., van der Ploeg AT; Department of Pediatrics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., Bergsma AJ; Department of Pediatrics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands., Pijnappel WWMP; Department of Pediatrics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2020 Jan 13; Vol. 17, pp. 337-348. Date of Electronic Publication: 2020 Jan 13 (Print Publication: 2020).
DOI:	10.1016/j.omtm.2019.12.016
Abstrakt:	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. (© 2020 The Author(s).)
Databáze:	MEDLINE
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