“Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assay
Abstract Background Mucopolysaccharidosis type I (MPS I) is a rare, recessively inherited lysosomal storage disorder, characterized by progressive multi‐systemic disease. It is caused by a reduced or absent alpha‐l iduronidase (IDUA) enzyme activity secondary to biallelic loss‐of‐function variants i...
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doaj-cec313b391b54b53b3d2c8c2a032f5052020-11-25T01:58:49ZengWileyMolecular Genetics & Genomic Medicine2324-92692019-09-0179n/an/a10.1002/mgg3.615“Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assayAmir Jahic0Sven Günther1Nicole Muschol2Barbro Fossøy Stadheim3Øivind Braaten4Hanne Kjensli Hyldebrandt5Gé‐Ann Kuiper6Karen Tylee7Frits A. Wijburg8Christian Beetz9Institute of Clinical Chemistry and Laboratory Diagnostics Jena University Hospital Jena GermanyInstitute of Clinical Chemistry and Laboratory Diagnostics Jena University Hospital Jena GermanyDepartment of Pediatrics University Medical Center Hamburg‐Eppendorf Hamburg GermanyDepartment of Clinical Genetics Oslo University Hospital Oslo NorwayDepartment of Clinical Genetics Oslo University Hospital Oslo NorwayDepartment of Clinical Genetics Oslo University Hospital Oslo NorwayPediatric Metabolic Diseases Amsterdam UMC University of AmsterdamAcademic Medical Center (AMC) Amsterdam NetherlandsManchester Center for Genomic Medicine St Mary's Hospital Manchester UKPediatric Metabolic Diseases Amsterdam UMC University of AmsterdamAcademic Medical Center (AMC) Amsterdam NetherlandsInstitute of Clinical Chemistry and Laboratory Diagnostics Jena University Hospital Jena GermanyAbstract Background Mucopolysaccharidosis type I (MPS I) is a rare, recessively inherited lysosomal storage disorder, characterized by progressive multi‐systemic disease. It is caused by a reduced or absent alpha‐l iduronidase (IDUA) enzyme activity secondary to biallelic loss‐of‐function variants in the IDUA. Over 200 causative variants in IDUA have been identified. Nevertheless, there is a fraction of MPS I patients with only a single mutated IDUA allele detectable. Methods As genetic testing of MPS I is usually based on sequencing methods, copy number variations (CNVs) in IDUA can be missed and therefore presumably remain underdiagnosed. The aim of this study was the detection of CNVs using an IDUA‐specific in house multiplex ligation‐dependent probe amplification (MLPA) assay. Results A total of five unrelated MPS I patient samples were re‐analyzed after only a single heterozygous IDUA mutation c.979G>C (p.A327P), c.1469T>C (p.L490P), c.1598C>G (p.P533R), c.1205G>A (p.W402X), c.973‐7C>G (p.?) could be identified. We detected a novel splice site variant c.973‐7C>G (p.?), as well as two novel CNVs, a large deletion of IDUA exon 14 and 3’UTR c.(1828 + 1_1829‐1)_(*1963_?)del, and a large duplication extending from IDUA exon 2 to intron 12 c.(157 + 1_158‐1)_(1727 + 1_1728‐1)dup. Conclusion Together with the CNVs we previously identified, a total of four pathogenic IDUA CNVs have now been reported.https://doi.org/10.1002/mgg3.615copy number variationsdeletionduplicationIDUAMLPA |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Amir Jahic Sven Günther Nicole Muschol Barbro Fossøy Stadheim Øivind Braaten Hanne Kjensli Hyldebrandt Gé‐Ann Kuiper Karen Tylee Frits A. Wijburg Christian Beetz |
spellingShingle |
Amir Jahic Sven Günther Nicole Muschol Barbro Fossøy Stadheim Øivind Braaten Hanne Kjensli Hyldebrandt Gé‐Ann Kuiper Karen Tylee Frits A. Wijburg Christian Beetz “Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assay Molecular Genetics & Genomic Medicine copy number variations deletion duplication IDUA MLPA |
author_facet |
Amir Jahic Sven Günther Nicole Muschol Barbro Fossøy Stadheim Øivind Braaten Hanne Kjensli Hyldebrandt Gé‐Ann Kuiper Karen Tylee Frits A. Wijburg Christian Beetz |
author_sort |
Amir Jahic |
title |
“Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assay |
title_short |
“Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assay |
title_full |
“Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assay |
title_fullStr |
“Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assay |
title_full_unstemmed |
“Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assay |
title_sort |
“missing mutations” in mps i: identification of two novel copy number variations by an idua‐specific in house mlpa assay |
publisher |
Wiley |
series |
Molecular Genetics & Genomic Medicine |
issn |
2324-9269 |
publishDate |
2019-09-01 |
description |
Abstract Background Mucopolysaccharidosis type I (MPS I) is a rare, recessively inherited lysosomal storage disorder, characterized by progressive multi‐systemic disease. It is caused by a reduced or absent alpha‐l iduronidase (IDUA) enzyme activity secondary to biallelic loss‐of‐function variants in the IDUA. Over 200 causative variants in IDUA have been identified. Nevertheless, there is a fraction of MPS I patients with only a single mutated IDUA allele detectable. Methods As genetic testing of MPS I is usually based on sequencing methods, copy number variations (CNVs) in IDUA can be missed and therefore presumably remain underdiagnosed. The aim of this study was the detection of CNVs using an IDUA‐specific in house multiplex ligation‐dependent probe amplification (MLPA) assay. Results A total of five unrelated MPS I patient samples were re‐analyzed after only a single heterozygous IDUA mutation c.979G>C (p.A327P), c.1469T>C (p.L490P), c.1598C>G (p.P533R), c.1205G>A (p.W402X), c.973‐7C>G (p.?) could be identified. We detected a novel splice site variant c.973‐7C>G (p.?), as well as two novel CNVs, a large deletion of IDUA exon 14 and 3’UTR c.(1828 + 1_1829‐1)_(*1963_?)del, and a large duplication extending from IDUA exon 2 to intron 12 c.(157 + 1_158‐1)_(1727 + 1_1728‐1)dup. Conclusion Together with the CNVs we previously identified, a total of four pathogenic IDUA CNVs have now been reported. |
topic |
copy number variations deletion duplication IDUA MLPA |
url |
https://doi.org/10.1002/mgg3.615 |
work_keys_str_mv |
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