"Missing mutations" in MPS I: Identification of two novel copy number variations by an IDUA-specific in house MLPA assay.

Autor: Jahic A; Institute of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, Jena, Germany.; Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany., Günther S; Institute of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, Jena, Germany., Muschol N; Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Fossøy Stadheim B; Department of Clinical Genetics, Oslo University Hospital, Oslo, Norway., Braaten Ø; Department of Clinical Genetics, Oslo University Hospital, Oslo, Norway., Kjensli Hyldebrandt H; Department of Clinical Genetics, Oslo University Hospital, Oslo, Norway., Kuiper GA; Pediatric Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, Netherlands., Tylee K; Manchester Center for Genomic Medicine, St Mary's Hospital, Manchester, UK., Wijburg FA; Pediatric Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, Netherlands., Beetz C; Institute of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, Jena, Germany.; Centogene AG, Rostock, Germany.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2019 Sep; Vol. 7 (9), pp. e00615. Date of Electronic Publication: 2019 Jul 18.
DOI: 10.1002/mgg3.615
Abstrakt: 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.
(© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje