3 research outputs found
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 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
Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening
Pompe disease is an inherited disorder caused by disease-associated variants in the acid α-glucosidase gene (GAA). The Pompe disease GAA variant database (http://www.pompevariantdatabase.nl) is a curated, open-source, disease-specific database, and lists disease-associated GAA variants, in silico predictions, and clinical phenotypes reported until 2016. Here, we provide an update to include 226 disease-associated variants that were published until 2020. We also listed 148 common GAA sequence variants that do not cause Pompe disease. GAA variants with unknown severity that were identified only in newborn screening programs were listed as a new feature to indicate the reason why phenotypes were still unknown. Expression studies were performed for common missense variants to predict their severity. The updated Pompe disease GAA variant database now includes 648 disease-associated variants, 26 variants from newborn screening, and 237 variants with unknown severity. Regular updates of the Pompe disease GAA variant database will be required to improve genetic counseling and the study of genotype–phenotype relationships