Abstract
BackgroundMucopolysaccharidosis 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.MethodsAs 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.ResultsA 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.ConclusionTogether with the CNVs we previously identified, a total of four pathogenic IDUA CNVs have now been reported.
Highlights
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by biallelic loss‐of‐function variants in the IDUA (MIM #252800)
This study reports on a heterozygous deletion and a heterozygous duplication which partially affect the IDUA
We previously presented an MPS I patient who carried two distinct large IDUA deletions (Breen et al, )
Summary
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by biallelic loss‐of‐function variants in the IDUA (MIM #252800). Reduced or absent IDUA enzyme activity results in the lysosomal accumulation of GAGs and the onset of pathology in specific cells, tissues, and organs (Poletto, Pasqualim, Giugliani, Matte, & Baldo, ; Scott et al, ). The clinical diagnosis of MPS I is confirmed biochemically based on elevated GAGs in urine, and reduced or absent IDUA activity in leucocytes or skin fibroblasts (Beesley et al, ; Scott et al, ). In this study we used the same copy number screening tool as well as the Sanger‐based sequencing to re‐analyze five unrelated MPS I DNA samples, which were initially tested positive for a pathogenic variant on a single IDUA allele
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