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How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutations, and compared them with those of a large series of sCJD cases. We identified six major groups of gCJD based on the combination PrP<jats:sup>Sc<\/jats:sup> type and codon 129 genotype on <jats:italic>PRNP<\/jats:italic> mutated allele, each showing distinctive histopathological characteristics, irrespectively of the <jats:italic>PRNP<\/jats:italic> associated mutation. Five gCJD groups, named M1, M2C, M2T, V1, and V2, largely reproduced those previously described in sCJD subtypes. The sixth group shared phenotypic traits with the V2 group and was only detected in patients carrying the E200K-129M haplotype in association with a PrP<jats:sup>Sc<\/jats:sup> type of intermediate size (\u201ci\u201d) between type 1 and type 2. Additional mutation-specific effects involved the pattern of PrP deposition (e.g., a \u201cthickened\u201d synaptic pattern in E200K carriers, cerebellar \u201cstripe-like linear granular deposits\u201d in\u00a0those with insertion mutations, and intraneuronal globular dots in E200K-V2 or -M\u201di\u201d). A few isolated cases linked to rare <jats:italic>PRNP<\/jats:italic> haplotypes (e.g., T183A-129M), showed atypical phenotypic features, which prevented their classification into the six major groups. The phenotypic variability of gCJD is mostly consistent with that previously found in sCJD. As in sCJD, the codon 129 genotype and physicochemical properties of PrP<jats:sup>Sc<\/jats:sup> significantly correlated with the phenotypic variability of gCJD. The most common mutations linked to CJD appear to have a variable and overall less significant effect on the disease phenotype, but they significantly influence disease susceptibility often in a strain-specific manner. The criteria currently used for sCJD subtypes can be expanded and adapted to gCJD to provide an updated classification of the disease with a molecular basis.<\/jats:p>","DOI":"10.1007\/s00401-021-02350-y","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T08:02:52Z","timestamp":1627545772000},"page":"707-728","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Phenotypic diversity of genetic Creutzfeldt\u2013Jakob disease: a histo-molecular-based classification"],"prefix":"10.1007","volume":"142","author":[{"given":"Simone","family":"Baiardi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Mammana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian S.","family":"Appleby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo A.","family":"Barria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignazio","family":"Cal\u00ec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierluigi","family":"Gambetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Gelpi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Giese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardino","family":"Ghetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Herms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ladogana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Mikol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suvankar","family":"Pal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane L.","family":"Ritchie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoria","family":"Ruf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otto","family":"Windl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Capellari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-9524","authenticated-orcid":false,"given":"Piero","family":"Parchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"2350_CR1","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1002\/ana.25300","volume":"84","author":"S Abu-Rumeileh","year":"2018","unstructured":"Abu-Rumeileh S, Redaelli V, Baiardi S, Mackenzie G, Windl O, Ritchie DL et al (2018) Sporadic fatal insomnia in europe: phenotypic features and diagnostic challenges. 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Non-financial interests: BSA is member of the board of directors for the CJD Foundation; the other authors declare they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was conducted according to the revised Declaration of Helsinki and Good Clinical Practice guidelines. All medical information was collected as part of national surveillance programs for prion diseases and approved by the local Institutional Review Board for each country\/participating center (CE-ISS 09\/266, May 2009). All patients\u2019 data and samples were coded to protect their identities. Written informed consent was given by study participants or the next of kin.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}