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Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

Pompe disease is an autosomal recessive lysosomal storage disorder caused by disease‐associated variants in the acid alpha‐glucosidase (GAA) gene. The current Pompe mutation database provides a severity rating of GAA variants based on in silico predictions and expression studies. Here, we extended t...

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Autores principales: Niño, Monica Y., in 't Groen, Stijn L.M., Bergsma, Atze J., van der Beek, Nadine A.M.E., Kroos, Marian, Hoogeveen‐Westerveld, Marianne, van der Ploeg, Ans T., Pijnappel, W.W.M. Pim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851659/
https://www.ncbi.nlm.nih.gov/pubmed/31254424
http://dx.doi.org/10.1002/humu.23854
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author Niño, Monica Y.
in 't Groen, Stijn L.M.
Bergsma, Atze J.
van der Beek, Nadine A.M.E.
Kroos, Marian
Hoogeveen‐Westerveld, Marianne
van der Ploeg, Ans T.
Pijnappel, W.W.M. Pim
author_facet Niño, Monica Y.
in 't Groen, Stijn L.M.
Bergsma, Atze J.
van der Beek, Nadine A.M.E.
Kroos, Marian
Hoogeveen‐Westerveld, Marianne
van der Ploeg, Ans T.
Pijnappel, W.W.M. Pim
author_sort Niño, Monica Y.
collection PubMed
description Pompe disease is an autosomal recessive lysosomal storage disorder caused by disease‐associated variants in the acid alpha‐glucosidase (GAA) gene. The current Pompe mutation database provides a severity rating of GAA variants based on in silico predictions and expression studies. Here, we extended the database with clinical information of reported phenotypes. We added additional in silico predictions for effects on splicing and protein function and for cross reactive immunologic material (CRIM) status, minor allele frequencies, and molecular analyses. We analyzed 867 patients and 562 GAA variants. Based on their combination with a GAA null allele (i.e., complete deficiency of GAA enzyme activity), 49% of the 422 disease‐associated variants could be linked to classic infantile, childhood, or adult phenotypes. Predictions and immunoblot analyses identified 131 CRIM negative and 216 CRIM positive variants. While disease‐associated missense variants were found throughout the GAA protein, they were enriched up to seven‐fold in the catalytic site. Fifteen percent of disease‐associated missense variants were predicted to affect splicing. This should be confirmed using splicing assays. Inclusion of clinical severity rating in the Pompe mutation database provides an invaluable tool for diagnosis, prognosis of disease progression, treatment regimens, and the future development of personalized medicine for Pompe disease.
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spelling pubmed-68516592019-11-18 Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity Niño, Monica Y. in 't Groen, Stijn L.M. Bergsma, Atze J. van der Beek, Nadine A.M.E. Kroos, Marian Hoogeveen‐Westerveld, Marianne van der Ploeg, Ans T. Pijnappel, W.W.M. Pim Hum Mutat Databases Pompe disease is an autosomal recessive lysosomal storage disorder caused by disease‐associated variants in the acid alpha‐glucosidase (GAA) gene. The current Pompe mutation database provides a severity rating of GAA variants based on in silico predictions and expression studies. Here, we extended the database with clinical information of reported phenotypes. We added additional in silico predictions for effects on splicing and protein function and for cross reactive immunologic material (CRIM) status, minor allele frequencies, and molecular analyses. We analyzed 867 patients and 562 GAA variants. Based on their combination with a GAA null allele (i.e., complete deficiency of GAA enzyme activity), 49% of the 422 disease‐associated variants could be linked to classic infantile, childhood, or adult phenotypes. Predictions and immunoblot analyses identified 131 CRIM negative and 216 CRIM positive variants. While disease‐associated missense variants were found throughout the GAA protein, they were enriched up to seven‐fold in the catalytic site. Fifteen percent of disease‐associated missense variants were predicted to affect splicing. This should be confirmed using splicing assays. Inclusion of clinical severity rating in the Pompe mutation database provides an invaluable tool for diagnosis, prognosis of disease progression, treatment regimens, and the future development of personalized medicine for Pompe disease. John Wiley and Sons Inc. 2019-07-29 2019-11 /pmc/articles/PMC6851659/ /pubmed/31254424 http://dx.doi.org/10.1002/humu.23854 Text en © 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Databases
Niño, Monica Y.
in 't Groen, Stijn L.M.
Bergsma, Atze J.
van der Beek, Nadine A.M.E.
Kroos, Marian
Hoogeveen‐Westerveld, Marianne
van der Ploeg, Ans T.
Pijnappel, W.W.M. Pim
Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity
title Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity
title_full Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity
title_fullStr Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity
title_full_unstemmed Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity
title_short Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity
title_sort extension of the pompe mutation database by linking disease‐associated variants to clinical severity
topic Databases
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851659/
https://www.ncbi.nlm.nih.gov/pubmed/31254424
http://dx.doi.org/10.1002/humu.23854
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