Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients
Abstract Background Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatme...
Main Authors: | , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2020-01-01
|
Series: | Orphanet Journal of Rare Diseases |
Subjects: | |
Online Access: | https://doi.org/10.1186/s13023-019-1274-3 |
id |
doaj-9a7dc0be8c6041e5b97f74e6d93ed7cd |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Patrícia Varela Gianna Mastroianni Kirsztajn Fabiana L. Motta Renan P. Martin Lauro T. Turaça Henrique L. F. Ferrer Caio P. Gomes Priscila Nicolicht Maryana Mara Marins Juliana G. Pessoa Marion C. Braga Vânia D’Almeida Ana Maria Martins João B. Pesquero |
spellingShingle |
Patrícia Varela Gianna Mastroianni Kirsztajn Fabiana L. Motta Renan P. Martin Lauro T. Turaça Henrique L. F. Ferrer Caio P. Gomes Priscila Nicolicht Maryana Mara Marins Juliana G. Pessoa Marion C. Braga Vânia D’Almeida Ana Maria Martins João B. Pesquero Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients Orphanet Journal of Rare Diseases Fabry disease GLA gene Non-coding haplotypes Molecular diagnosis α-Galactosidase A activity DBS enzymatic activity |
author_facet |
Patrícia Varela Gianna Mastroianni Kirsztajn Fabiana L. Motta Renan P. Martin Lauro T. Turaça Henrique L. F. Ferrer Caio P. Gomes Priscila Nicolicht Maryana Mara Marins Juliana G. Pessoa Marion C. Braga Vânia D’Almeida Ana Maria Martins João B. Pesquero |
author_sort |
Patrícia Varela |
title |
Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients |
title_short |
Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients |
title_full |
Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients |
title_fullStr |
Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients |
title_full_unstemmed |
Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients |
title_sort |
correlation between gla variants and alpha-galactosidase a profile in dried blood spot: an observational study in brazilian patients |
publisher |
BMC |
series |
Orphanet Journal of Rare Diseases |
issn |
1750-1172 |
publishDate |
2020-01-01 |
description |
Abstract Background Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatment. The α-Galactosidase A enzymatic activity in dried blood spot (DBS) samples are widely used for screening purposes; however, even when values below the normal are found, new tests are required to confirm the diagnosis. Here we describe an analysis of GLA variants and their correlation with DBS α-Galactosidase A enzymatic activity in a large Brazilian population with Fabry disease symptoms. Results We analyzed GLA variants by DNA sequencing of 803 male patients with suspected Fabry disease or belonging to high-risk populations; in 179 individuals, 58 different exonic variants were detected. From these, 50 are variants described as pathogenic and eight described as variants of unknown significance. The other individuals presented complex non-coding haplotypes or had no variants. Interestingly, the enzymatic activity in DBS was different among pathogenic variants and the other genotypes, including variants of unknown significance; the first presented mean of 12% of residual activity, while the others presented levels above 70% of the activity found in healthy controls. Conclusion The activity of α-Galactosidase A in DBS was markedly reduced in males with known pathogenic variants when compared with subjects presenting variants of unknown significance, non-coding haplotypes, or without variants, indicating a possible non-pathogenic potential of these latter genotypes. These findings bring a better understanding about the biochemical results of α-Galactosidase A in DBS samples, as well as the possible non-pathogenic potential of non-coding haplotypes and variants of unknown significance in GLA gene. These results certainly will help clinicians to decide about the treatment of patients carrying variants in the gene causing this rare but life-threatening disease. |
topic |
Fabry disease GLA gene Non-coding haplotypes Molecular diagnosis α-Galactosidase A activity DBS enzymatic activity |
url |
https://doi.org/10.1186/s13023-019-1274-3 |
work_keys_str_mv |
AT patriciavarela correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT giannamastroiannikirsztajn correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT fabianalmotta correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT renanpmartin correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT laurotturaca correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT henriquelfferrer correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT caiopgomes correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT priscilanicolicht correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT maryanamaramarins correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT julianagpessoa correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT marioncbraga correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT vaniadalmeida correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT anamariamartins correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients AT joaobpesquero correlationbetweenglavariantsandalphagalactosidaseaprofileindriedbloodspotanobservationalstudyinbrazilianpatients |
_version_ |
1724317311347720192 |
spelling |
doaj-9a7dc0be8c6041e5b97f74e6d93ed7cd2021-01-31T12:17:22ZengBMCOrphanet Journal of Rare Diseases1750-11722020-01-0115111210.1186/s13023-019-1274-3Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patientsPatrícia Varela0Gianna Mastroianni Kirsztajn1Fabiana L. Motta2Renan P. Martin3Lauro T. Turaça4Henrique L. F. Ferrer5Caio P. Gomes6Priscila Nicolicht7Maryana Mara Marins8Juliana G. Pessoa9Marion C. Braga10Vânia D’Almeida11Ana Maria Martins12João B. Pesquero13Center for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloDivision of Nephrology – Department of Medicine, Federal University of São PauloCenter for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloCenter for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloCenter for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloCenter for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloCenter for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloCenter for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloCenter for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloCenter for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloDepartment of Psychobiology, Federal University of São PauloDepartment of Psychobiology, Federal University of São PauloReference Center in Inborn Errors of Metabolism, Pediatrics Department, Federal University of São PauloCenter for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Federal University of São PauloAbstract Background Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatment. The α-Galactosidase A enzymatic activity in dried blood spot (DBS) samples are widely used for screening purposes; however, even when values below the normal are found, new tests are required to confirm the diagnosis. Here we describe an analysis of GLA variants and their correlation with DBS α-Galactosidase A enzymatic activity in a large Brazilian population with Fabry disease symptoms. Results We analyzed GLA variants by DNA sequencing of 803 male patients with suspected Fabry disease or belonging to high-risk populations; in 179 individuals, 58 different exonic variants were detected. From these, 50 are variants described as pathogenic and eight described as variants of unknown significance. The other individuals presented complex non-coding haplotypes or had no variants. Interestingly, the enzymatic activity in DBS was different among pathogenic variants and the other genotypes, including variants of unknown significance; the first presented mean of 12% of residual activity, while the others presented levels above 70% of the activity found in healthy controls. Conclusion The activity of α-Galactosidase A in DBS was markedly reduced in males with known pathogenic variants when compared with subjects presenting variants of unknown significance, non-coding haplotypes, or without variants, indicating a possible non-pathogenic potential of these latter genotypes. These findings bring a better understanding about the biochemical results of α-Galactosidase A in DBS samples, as well as the possible non-pathogenic potential of non-coding haplotypes and variants of unknown significance in GLA gene. These results certainly will help clinicians to decide about the treatment of patients carrying variants in the gene causing this rare but life-threatening disease.https://doi.org/10.1186/s13023-019-1274-3Fabry diseaseGLA geneNon-coding haplotypesMolecular diagnosisα-Galactosidase A activityDBS enzymatic activity |