A genetic modifier of symptom onset in Pompe disease

Bergsma, Atze J.; In 't Groen, Stijn L. M.; van den Dorpel, Jan J. A.; van den Hout, Hannerieke J. M. P.; van der Beek, Nadine A. M. E.; Schoser, Benedikt; Toscano, Antonio; Musumeci, Olimpia; Bembi, Bruno; Dardis, Andrea; Morrone, Amelia; Tummolo, Albina; Pasquini, Elisabetta; van der Ploeg, Ans T. und Pijnappel, W. W. M. Pim (2019): A genetic modifier of symptom onset in Pompe disease. In: Ebiomedicine, Bd. 43: S. 553-561

Abstract

Background: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS I) variant/null ( i.e. fully deleterious) acid a-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset. Methods: We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays. Findings: In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing. Interpretation: c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. (C) 2019 The Authors. Published by Elsevier B.V.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2352-3964
• Sprache: Englisch