In genetic prion diseases (gPrD), five genetic variants (E200K, V210I, V180I, P102L, and D178N) are responsible for about 85% of cases. The R208H is one of the several additional rare mutations and to date, only 16 cases carrying this mutation have been reported worldwide. To describe the phenotypic features of 5 affected patients belonging to apparently unrelated Sardinian (Italian) families with R208H gPrD, and provide evidence for a possible founder effect are the aims of this study. The R208H PRNP mutation has a much higher relative frequency in Sardinia than elsewhere in Italy (72% vs. 4.4% of gCJD cases). Our cohort shared similar phenotypic features to the previously described patients with R208H-129M haplotype with most patients showing the classical Creutzfeldt-Jakob disease (CJD) phenotype. The analysis of 10 controls and 5 patients by NGS sequencing identified 4 haplotypes, 3 associated with the wild type variant, and one (H1) shared by all patients carrying the 208His variant. This is the first report of a regional cluster for R208H mutation in gPrD and the first report of the presence of a common ancestor for this Sardinian R208H cluster, confirming the probable consequences of genetic isolation process even for rare diseases.

中文翻译：

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撒丁岛的克罗伊茨费尔特-雅各布遗传病：由于单个创始人效应，与PRNP R208H突变相关的病例系列。

在遗传性ion病毒疾病（gPrD）中，约有85％的病例是由五个遗传变异（E200K，V210I，V180I，P102L和D178N）引起的。R208H是其他几种罕见突变之一，迄今为止，全世界仅报道了16个携带该突变的病例。本研究的目的是描述属于R208H gPrD的明显不相关的撒丁岛（意大利）家族的5名受影响患者的表型特征，并为可能的创始人效应提供证据。R208H PRNP撒丁岛的突变相对频率比意大利其他地区高得多（72％比gCJD病例的4.4％）。我们的队列具有与先前描述的R208H-129M单倍型患者相似的表型特征，大多数患者表现出典型的Creutzfeldt-Jakob病（CJD）表型。通过NGS测序对10位对照和5位患者进行的分析确定了4个单倍型，3个与野生型变异体相关的单体型以及所有携带208His变异体的患者共享的一种（H1）。这是gPrD中R208H突变的区域性簇的首次报道，也是该撒丁岛R208H簇存在共同祖先的首次报道，这证实了遗传分离过程的可能后果，即使对于罕见疾病也是如此。