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阐明荷兰肢带型肌营养不良症家系的遗传病因:27 年的探索历程。

Elucidation of the Genetic Cause in Dutch Limb Girdle Muscular Dystrophy Families: A 27-Year's Journey.

机构信息

Department of Neurology, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.

Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

出版信息

J Neuromuscul Dis. 2021;8(2):261-272. doi: 10.3233/JND-200585.

Abstract

BACKGROUND

A Dutch cohort of 105 carefully selected limb girdle muscular dystrophy (LGMD) patients from 68 families has been subject to genetic testing over the last 20 years. After subsequent targeted gene analysis around two thirds (45/68) of the families had received a genetic diagnosis in 2013.

OBJECTIVE

To describe the results of further genetic testing in the remaining undiagnosed limb girdle muscular dystrophy families in this cohort.

METHODS

In the families of the cohort for whom no genetic diagnosis was established (n = 23) further testing using Sanger sequencing, next generation sequencing with gene panel analysis or whole-exome sequencing was performed. In one case DNA analysis for facioscapulohumeral dystrophy type 1 was carried out.

RESULTS

In eight families no additional genetic tests could be performed. In 12 of the remaining 15 families in which additional testing could be performed a genetic diagnosis was established: two LGMDR1 calpain3-related families with CAPN3 mutations, one LGMDR2 dysferlin-related family with DYSF mutations, three sarcoglycanopathy families (LGMDR3-5 α-, β- and γ-sarcoglycan-related) with SGCA/SGCB/SGCG mutations, one LGMDR8 TRIM 32-related family with TRIM32 mutations, two LGMDR19 GMPPB-related families with GMPPB mutations, one family with MICU1-related myopathy, one family with FLNC-related myopathy and one family with facioscapulohumeral dystrophy type 1. At this moment a genetic diagnosis has been made in 57 of the 60 families of which DNA was available (95%).

CONCLUSION

A genetic diagnosis is obtained in 95% of the families of the original Dutch LGMD cohort of which DNA was available.

摘要

背景

经过 20 年的基因检测,荷兰的一个由 105 名精心挑选的肢带型肌营养不良症(LGMD)患者组成的队列,来自 68 个家系。2013 年,对随后的靶向基因分析显示,三分之二(45/68)的家系获得了基因诊断。

目的

描述对该队列中其余未确诊的肢带型肌营养不良症家系进行进一步遗传检测的结果。

方法

在队列中未建立遗传诊断的家系(n=23)中,采用 Sanger 测序、基因panel 分析或全外显子组测序进行进一步检测。在一个病例中进行了 1 型面肩肱型肌营养不良症的 DNA 分析。

结果

在 8 个家系中无法进行进一步的基因检测。在其余 15 个可进行进一步检测的家系中,有 12 个家系建立了遗传诊断:2 个 calpain3 相关的 LGMDR1 型肌钙蛋白 3 相关家系,存在 CAPN3 突变;1 个 dysferlin 相关的 LGMDR2 型肌营养不良症家系,存在 DYSF 突变;3 个 sarcoglycanopathy 家系(LGMDR3-5 α-, β- 和 γ-肌聚糖相关),存在 SGCA/SGCB/SGCG 突变;1 个 TRIM 32 相关的 LGMDR8 型肌营养不良症家系,存在 TRIM32 突变;2 个 GMPPB 相关的 LGMDR19 型肌营养不良症家系,存在 GMPPB 突变;1 个 MICU1 相关的肌病家系;1 个 FLNC 相关的肌病家系;1 个面肩肱型肌营养不良症 1 型家系。目前,对原始荷兰 LGMD 队列中 60 个可用 DNA 的家系中的 57 个(95%)家系进行了基因诊断。

结论

原始荷兰 LGMD 队列中,95%的可用 DNA 的家系获得了基因诊断。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f83c/9789482/9d7dfe1d1a90/jnd-8-jnd200585-g001.jpg

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