A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats

Julie van der Zee, Ilse Gijselinck, Lubina Dillen, Tim Van Langenhove, Jessie Theuns, Sebastiaan Engelborghs, Stéphanie Philtjens, Mathieu Vandenbulcke, Kristel Sleegers, Anne Sieben, Veerle Bäumer, Githa Maes, Ellen Corsmit, Barbara Borroni, Alessandro Padovani, Silvana Archetti, Robert Perneczky, Janine Diehl-Schmid, Alexandre de Mendonça, Gabriel Miltenberger-MiltenyiSónia Pereira, José Pimentel, Benedetta Nacmias, Silvia Bagnoli, Sandro Sorbi, Caroline Graff, Huei Hsin Chiang, Marie Westerlund, Raquel Sanchez-Valle, Albert Llado, Ellen Gelpi, Isabel Santana, Maria Rosário Almeida, Beatriz Santiago, Giovanni Frisoni, Orazio Zanetti, Cristian Bonvicini, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Ludger Schöls, Michael T. Heneka, Frank Jessen, Radoslav Matej, Eva Parobkova, Gabor G. Kovacs, Thomas Ströbel, Stayko Sarafov, Ivailo Tournev, Albena Jordanova, Adrian Danek, Thomas Arzberger, Gian Maria Fabrizi, Silvia Testi, Eric Salmon, Patrick Santens, Jean Jacques Martin, Patrick Cras, Rik Vandenberghe, Peter Paul De Deyn, Marc Cruts, Christine Van Broeckhoven, Alfredo Ramirez, Delia Kurzwelly, Carmen Sachtleben, Wolfgang Mairer, Clara Firmo, Anna Antonell, Jose Molinuevo, Charlotte Forsell, Lena Lillius, Anne Kinhult Ståhlbom, Håkan Thonberg, Inger Nennesmo, Anne Börjesson-Hanson, Valentina Bessi, Irene Piaceri, Maria Helena Ribeiro, Catarina Oliveira, João Massano, Carolina Garret, Paula Pires, Adrian Danel, Sergio Ferrari, Tiziana Cavallaro

Research output: Contribution to journalArticlepeer-review


We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P <0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.

Original languageEnglish
Pages (from-to)363-373
Number of pages11
JournalHuman Mutation
Issue number2
Publication statusPublished - Feb 2013


  • C9orf72
  • European Early-Onset Dementia consortium
  • FTLD
  • Intermediate alleles
  • Repeat expansion

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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