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Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more informatio...

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Autores principales: Beerepoot, Shanice, van Dooren, Silvy J.M., Salomons, Gajja S., Boelens, Jaap Jan, Jacobs, Edwin H., van der Knaap, Marjo S., van Kuilenburg, André B.P., Wolf, Nicole I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476914/
https://www.ncbi.nlm.nih.gov/pubmed/32632536
http://dx.doi.org/10.1007/s10048-020-00621-6
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author Beerepoot, Shanice
van Dooren, Silvy J.M.
Salomons, Gajja S.
Boelens, Jaap Jan
Jacobs, Edwin H.
van der Knaap, Marjo S.
van Kuilenburg, André B.P.
Wolf, Nicole I.
author_facet Beerepoot, Shanice
van Dooren, Silvy J.M.
Salomons, Gajja S.
Boelens, Jaap Jan
Jacobs, Edwin H.
van der Knaap, Marjo S.
van Kuilenburg, André B.P.
Wolf, Nicole I.
author_sort Beerepoot, Shanice
collection PubMed
description Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + ∗96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10048-020-00621-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-74769142020-09-21 Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients Beerepoot, Shanice van Dooren, Silvy J.M. Salomons, Gajja S. Boelens, Jaap Jan Jacobs, Edwin H. van der Knaap, Marjo S. van Kuilenburg, André B.P. Wolf, Nicole I. Neurogenetics Original Article Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + ∗96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10048-020-00621-6) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-07-07 2020 /pmc/articles/PMC7476914/ /pubmed/32632536 http://dx.doi.org/10.1007/s10048-020-00621-6 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Article
Beerepoot, Shanice
van Dooren, Silvy J.M.
Salomons, Gajja S.
Boelens, Jaap Jan
Jacobs, Edwin H.
van der Knaap, Marjo S.
van Kuilenburg, André B.P.
Wolf, Nicole I.
Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients
title Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients
title_full Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients
title_fullStr Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients
title_full_unstemmed Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients
title_short Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients
title_sort metachromatic leukodystrophy genotypes in the netherlands reveal novel pathogenic arsa variants in non-caucasian patients
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476914/
https://www.ncbi.nlm.nih.gov/pubmed/32632536
http://dx.doi.org/10.1007/s10048-020-00621-6
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