Center for Medical Research, Medical University of Graz, Graz, Austria.
J Neurol. 2012 Mar;259(3):515-23. doi: 10.1007/s00415-011-6213-8. Epub 2011 Sep 4.
Considerable non-allelic heterogeneity for autosomal recessively inherited Charcot-Marie-Tooth (ARCMT) disease has challenged molecular testing and often requires a large amount of work in terms of DNA sequencing and data interpretation or remains unpractical. This study tested the value of SNP array-based whole-genome homozygosity mapping as a first step in the molecular genetic diagnosis of sporadic or ARCMT in patients from inbred families or outbred populations with the ancestors originating from the same geographic area. Using 10 K 2.0 and 250 K Nsp Affymetrix SNP arrays, 15 (63%) of 24 CMT patients received an accurate genetic diagnosis. We used our Java-based script eHoPASA CMT-easy Homozygosity Profiling of SNP arrays for CMT patients to display the location of homozygous regions and their extent of marker count and base-pairs throughout the whole genome. CMT4C was the most common genetic subtype with mutations detected in SH3TC2, one (p.E632Kfs13X) appearing to be a novel founder mutation. A sporadic patient with severe CMT was homozygous for the c.250G > C (p.G84R) HSPB1 mutation which has previously been reported to cause autosomal dominant dHMN. Two distantly related CMT1 patients with early disease onset were found to carry a novel homozygous mutation in MFN2 (p.N131S). We conclude that SNP array-based homozygosity mapping is a fast, powerful, and economic tool to guide molecular genetic testing in ARCMT and in selected sporadic CMT patients.
常染色体隐性遗传性腓骨肌萎缩症（ARCMT）的非同等位基因异质性很大，这对分子检测提出了挑战，通常需要大量的 DNA 测序和数据解释工作，或者仍然不切实际。本研究测试了 SNP 芯片全基因组纯合性作图作为对来自近亲或具有相同地理起源祖先的散发性或 ARCMT 患者进行分子遗传学诊断的第一步的价值。使用 10 K 2.0 和 250 K Nsp Affymetrix SNP 芯片，24 名 CMT 患者中的 15 名（63%）获得了准确的遗传诊断。我们使用我们基于 Java 的脚本 eHoPASA CMT-easy SNP 芯片的 Homozygosity Profiling 来显示纯合区域的位置及其在整个基因组中的标记计数和碱基对的程度。CMT4C 是最常见的遗传亚型，在 SH3TC2 中检测到突变，一个（p.E632Kfs13X）似乎是一个新的创始突变。一名患有严重 CMT 的散发性患者纯合 c.250G > C（p.G84R）HSPB1 突变，该突变以前曾报道过导致常染色体显性 dHMN。两名发病较早的远缘 CMT1 患者被发现携带 MFN2 （p.N131S）的新型纯合突变。我们得出结论，SNP 芯片基于纯合性作图是一种快速、强大且经济的工具，可指导 ARCMT 和选定的散发性 CMT 患者的分子遗传学检测。
