A genetic modifier of symptom onset in Pompe disease

Atze J. Bergsma, Stijn L. M. in 't Groen, Jan J. A. van den Dorpel, Hannerieke J. M. P. van den Hout, Nadine A. M. E. van der Beek, Benedikt Schoser, Antonio Toscano, Olimpia Musumeci, Bruno Bembi, Andrea Dardis, Amelia Morrone, Albina Tummolo, Elisabetta Pasquini, Ans T. van der Ploeg, W. W. M. Pim Pijnappel

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1)variant/null (i.e. fully deleterious)acid α-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 c.510C>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. Fund: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17–32)and Metakids (2016–063).
Original languageEnglish
Pages (from-to)553-561
JournalEBioMedicine
Volume43
DOIs
Publication statusPublished - 1 May 2019
Externally publishedYes

Cite this

Bergsma, A. J., in 't Groen, S. L. M., van den Dorpel, J. J. A., van den Hout, H. J. M. P., van der Beek, N. A. M. E., Schoser, B., ... Pijnappel, W. W. M. P. (2019). A genetic modifier of symptom onset in Pompe disease. EBioMedicine, 43, 553-561. https://doi.org/10.1016/j.ebiom.2019.03.048
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. ; Pijnappel, W. W. M. Pim. / A genetic modifier of symptom onset in Pompe disease. In: EBioMedicine. 2019 ; Vol. 43. pp. 553-561.
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abstract = "Background: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1)variant/null (i.e. fully deleterious)acid α-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 c.510C>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. Fund: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17–32)and Metakids (2016–063).",
author = "Bergsma, {Atze J.} and {in 't Groen}, {Stijn L. M.} and {van den Dorpel}, {Jan J. A.} and {van den Hout}, {Hannerieke J. M. P.} and {van der Beek}, {Nadine A. M. E.} and Benedikt Schoser and Antonio Toscano and Olimpia Musumeci and Bruno Bembi and Andrea Dardis and Amelia Morrone and Albina Tummolo and Elisabetta Pasquini and {van der Ploeg}, {Ans T.} and Pijnappel, {W. W. M. Pim}",
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Bergsma, AJ, in 't Groen, SLM, van den Dorpel, JJA, van den Hout, HJMP, van der Beek, NAME, Schoser, B, Toscano, A, Musumeci, O, Bembi, B, Dardis, A, Morrone, A, Tummolo, A, Pasquini, E, van der Ploeg, AT & Pijnappel, WWMP 2019, 'A genetic modifier of symptom onset in Pompe disease' EBioMedicine, vol. 43, pp. 553-561. https://doi.org/10.1016/j.ebiom.2019.03.048

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.; Pijnappel, W. W. M. Pim.

In: EBioMedicine, Vol. 43, 01.05.2019, p. 553-561.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A genetic modifier of symptom onset in Pompe disease

AU - Bergsma, Atze J.

AU - in 't Groen, Stijn L. M.

AU - van den Dorpel, Jan J. A.

AU - van den Hout, Hannerieke J. M. P.

AU - van der Beek, Nadine A. M. E.

AU - Schoser, Benedikt

AU - Toscano, Antonio

AU - Musumeci, Olimpia

AU - Bembi, Bruno

AU - Dardis, Andrea

AU - Morrone, Amelia

AU - Tummolo, Albina

AU - Pasquini, Elisabetta

AU - van der Ploeg, Ans T.

AU - Pijnappel, W. W. M. Pim

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Background: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1)variant/null (i.e. fully deleterious)acid α-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 c.510C>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. Fund: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17–32)and Metakids (2016–063).

AB - Background: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1)variant/null (i.e. fully deleterious)acid α-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 c.510C>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. Fund: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17–32)and Metakids (2016–063).

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30922962

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Bergsma AJ, in 't Groen SLM, van den Dorpel JJA, van den Hout HJMP, van der Beek NAME, Schoser B et al. A genetic modifier of symptom onset in Pompe disease. EBioMedicine. 2019 May 1;43:553-561. https://doi.org/10.1016/j.ebiom.2019.03.048