黏多糖贮积症 I 型中的“缺失突变”：通过 IDUA 特异性的内建 MLPA 分析鉴定两种新的拷贝数变异。

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

机构信息

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.

出版信息

Mol Genet Genomic Med. 2019 Sep;7(9):e00615. doi: 10.1002/mgg3.615. Epub 2019 Jul 18.

DOI:10.1002/mgg3.615

PMID:31319022

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6732313/

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.

摘要

背景

黏多糖贮积症 I 型（MPS I）是一种罕见的、隐性遗传的溶酶体贮积症，其特征是进行性多系统疾病。它是由双等位基因丧失功能的 IDUA 变异导致的 α-L-艾杜糖苷酸酶（IDUA）活性降低或缺失引起的。在 IDUA 中已经发现了超过 200 个致病变异。然而，仍有一部分 MPS I 患者仅检测到一个突变的 IDUA 等位基因。

方法

由于 MPS I 的基因检测通常基于测序方法，因此 IDUA 中的拷贝数变异（CNVs）可能会被遗漏，因此可能会被误诊。本研究的目的是使用 IDUA 特异性的多重连接依赖性探针扩增（MLPA）检测 CNVs。

结果

在仅检测到一个杂合 IDUA 突变 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.？）的情况下，对五个无关的 MPS I 患者样本进行了重新分析。我们检测到了一个新的剪接位点变异 c.973-7C>G（p.？），以及两个新的 CNVs，一个 IDUA 外显子 14 和 3'UTR 的大片段缺失 c.（1828+1_1829-1）（*1963？）del，以及一个从 IDUA 外显子 2 延伸到内含子 12 的大片段重复 c.（157+1_158-1）_（1727+1_1728-1）dup。