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Clinical evidence for genetic anticipation in C9orf72 pedigrees

Sara Van Mossevelde1, 2*, Julie Van Der Zee1, 2, Ilse Gijselinck1, 2, Anne Sieben1, 2, 3, Jan De Bleecker3, Tim Van Langenhove1, 2, 4, Adrian Ivanoiu5, Olivier Deryck6, Marleen Van Den Broeck1, 2, Maria Mattheijssens1, 2, Peeters Karin1, 2, Peter De Jonghe1, 2, 4, Peter De Deyn2, 7, Patrick Cras2, 4, Jean-Jacques Martin1, 2, Marc Cruts1, 2, Sebastiaan Engelborghs2, 7 and Christine Van Broeckhoven1, 2
  • 1 VIB, Department of Molecular Genetics, Belgium
  • 2 University of Antwerp, Institute Born-Bunge, Belgium
  • 3 University Hospital Ghent and University of Ghent, Department of Neurology, Belgium
  • 4 Antwerp University Hospital, Department of Neurology, Belgium
  • 5 Saint-Luc University Hospital and Institute of Neuroscience, Université Catholique de Louvain, Department of Neurology, Belgium
  • 6 General Hospital Sint-Jan Brugge-Oostende, Department of Neurology, Belgium
  • 7 Hospital Network Antwerp Middelheim and Hoge Beuken, Department of Neurology and Memory Clinic, Belgium

Pathological expansion of a repeat in the gene C9orf72 is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Patients carrying a repeat expansion mutation present with highly variable onset ages and wide onset age range from 29 to 75 suggesting the presence of modifying factors that are affecting the expression of the clinical phenotype. The majority of the C9orf72 repeat expansions are too large (> 80 repeat units and up to > 2100) to accurately define the actual number of repeat units preventing reliable correlation studies with onset age. However, we recently provided evidence for the presence in 6.5% of the patients of short repeat expansions (45-78 units) that were amendable for repeat sizing using a simple PCR-based assay (Gijselinck, I. et al. 2015). In one family we showed segregation of the 50-units repeat confirming the pathogenicity of these short C9orf72 expansions. Analysis of the repeat size versus onset age showed a significant inverse correlation (p=0.0006) indicating that C9orf72 repeat expansion leads to earlier onset age in the carriers. In one affected parent-offspring pair, we observed an increment of 1500 units confirming genetic anticipation. To further assess the occurrence of disease anticipation, we studied the onset ages of affected parent-offspring pairs (N = 22) in C9orf72 families. We also collected and reviewed the clinical data of family members in 31 C9orf72 families. The mean age at onset of all affected family members (N = 98) was 56.88 years ± 9.69 years (range 29-75 y). In 15 parent-offspring pairs, age at onset in the second generation was younger than in the first generation. The onset age in the second generation was on average 7.08 years earlier (SD 9.54) than in the first generation. Statistical analysis revealed a significant younger onset age in the second generation than in the first generation (p=0.004). The largest difference in onset age was seen in an affected parent-offspring pair where disease onset in the offspring was 25 years younger than in the parent. These results provide clinical and genetic evidence for disease anticipation based on increasing C9orf72 repeat expansion sizes. This finding is relevant for the clinical practice as it can help in predictions of clinical expectations in presymptomatic C9orf72 repeat expansion carriers.

References

Gijselinck I., Van Mossevelde S., van der Zee J., et al. The C9orf72 repeat size correlates with onset age of disease, hypermethylation and transcriptional downregulation of the promoter. Lancet Neurology 2015, submitted.

Keywords: C9orf72, repeat expansion size, anticipation, Onset age, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis

Conference: 11th National Congress of the Belgian Society for Neuroscience, Mons, Belgium, 22 May - 22 May, 2015.

Presentation Type: Oral or Poster presentation

Topic: Neuroscience

Citation: Van Mossevelde S, Van Der Zee J, Gijselinck I, Sieben A, De Bleecker J, Van Langenhove T, Ivanoiu A, Deryck O, Van Den Broeck M, Mattheijssens M, Karin P, De Jonghe P, De Deyn P, Cras P, Martin J, Cruts M, Engelborghs S and Van Broeckhoven C (2015). Clinical evidence for genetic anticipation in C9orf72 pedigrees. Front. Neurosci. Conference Abstract: 11th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2015.89.00070

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Received: 30 Apr 2015; Published Online: 05 May 2015.

* Correspondence: MD. Sara Van Mossevelde, VIB, Department of Molecular Genetics, Wilrijk, Antwerp, 2610, Belgium, sara.vanmossevelde@uantwerpen.be