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Project

Onset age variability in GRN-associated frontotemporal lobar degeneration: a high-throughput assay to identify functional onset age modifying variants.

Frontotemporal lobar degeneration (FTLD) is the most common cause of neurodegenerative dementia at young age after Alzheimer's disease. Loss-of-function (LOF) mutations in the granulin gene (GRN) are a major cause of FTLD, accounting for up to 11.2% of patients. Most GRN mutation carriers present clinically with frontotemporal dementia (FTD), but clinical phenotypes are diverse and also include Alzheimer's dementia and Parkinson's disease in rare occasions. Another striking feature is the wide variability of onset age, which can span up to 40 years within one family. Asymptomatic mutation carriers older than 80 years of age have been reported. The pronounced onset age heterogeneity points to the existence of modifiers affecting the onset age of GRN-associated neurodegeneration. Identifying these factors is of importance as they might represent targets for disease-delaying therapies. This is particularly important given that there are currently no cures for FTLD patients. Given that GRN-related FTLD is characterized by great variability in onset age, modifier studies now represent a challenging and important avenue in the field of FTLD genetics. We have applied a family-based approach to identify onset age modifiers, starting from an extended Belgian founder family segregating the GRN IVS1+5 G>C null mutation. Patients of the family present with disease at highly variable onset ages ranging from 45 to 80 years. In this family, we have identified a quantitative trait locus (QTL) for onset age. Variants in this locus were also associated with onset age in a cohort of unrelated FTD patients without GRN LOF mutation. Now we aim to investigate this region in detail, to identify the functional gene and variant underlying the onset age variability. We will employ a combination of technologies to identify the genetic modifier, starting with whole-genome and whole exome sequencing data of GRN founder mutation carriers to identify variants in the QTL. We will use a high-throughput in vitro assay to identify functional QTL variants. We will evaluate the effect of each variant on onset age in the founder family. The extended pedigree, including 85 patients and 40 at risk mutation carriers, offers a powerful setting for this analysis. We further will evaluate the functional effect of candidate modifier variants using reporter gene assays. This will result in a list of variants that have a functional, biological effect and show to modify the onset age of the patients. Identifying genetic modifiers of onset age might be a first step towards a disease-modifying or -delaying therapy. The modifiers might also enhance our understanding of the pathomechanisms of FTLD. Furthermore, this information could be relevant in the context of disease prognosis and genetic counseling.
Date:1 Apr 2020 →  31 Mar 2021
Keywords:FRONTOTEMPORAL LOBAR DEGENERATION, ONSET AGE MODIFIER
Disciplines:Genetics, Molecular and cell biology not elsewhere classified