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Genetic Creutzfeldt-Jakob disease in Sardinia: a case series linked to the PRNP R208H mutation due to a single founder effect

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Abstract

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.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article. If needed, further data that support the findings of this study are available from the corresponding author, [MM], upon reasonable request.

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Authors and Affiliations

  1. SC Neurologia AOU Policlinico di Monserrato, Cagliari, Sardinia, Italy

    Marta Melis, Gianluca Floris & Giovanni Defazio

  2. SC Neurologia e Stroke Unit AOB, Cagliari, Italy

    Andrea Molari, Giovanni Cossu & Maurizio Melis

  3. Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università degli Studi di Cagliari, Cagliari, Italy

    Sarah Vascellari

  4. Genetica Medica, Dipartimento di Scienze Mediche e Sanità Pubblica, Università di Cagliari, Caligria, Italy

    Luisa Balestrino & Sandro Orrù

  5. Department of Neuroscience, Istituto Superiore di Sanità, 00161, Rome, Italy

    Anna Ladogana & Anna Poleggi

  6. IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139, Bologna, Italy

    Piero Parchi

  7. Department of Experimental Diagnostic and Specialty Medicine (DIMES), Università di Bologna, 40138, Bologna, Italy

    Piero Parchi

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  1. Marta Melis
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  2. Andrea Molari
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  3. Gianluca Floris
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Correspondence to Marta Melis.

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Melis, M., Molari, A., Floris, G. et al. Genetic Creutzfeldt-Jakob disease in Sardinia: a case series linked to the PRNP R208H mutation due to a single founder effect. Neurogenetics 21, 251–257 (2020). https://doi.org/10.1007/s10048-020-00618-1

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