Founder effect and estimation of the age of the Progranulin Thr272fs mutation in 14 Italian pedigrees with frontotemporal lobar degeneration

Progranulin (PGRN) mutations have been recognized to be monogenic causes of frontotemporal lobar degeneration (FTLD). PGRN Thr272fs mutation in the Italian population has been previously identified. In the present study, we evaluated the occurrence of a founder effect studying 8 polymorphic microsatellite markers flanking the PGRN gene in 14 apparently unrelated families. We identified a common haplotype associated with PGRN Thr272fs carriers, assuming common ancestry. The inferred age analysis (range between 260 [95% credible set: 227-374] and 295 [95% credible set: 205-397] generations) places the introduction of the mutation back to the Neolithic era when the Celts, the population of that period, settled in Northern Italy. PGRN Thr272fs mutation appears to be as either behavioral frontotemporal dementia (80%) or primary progressive aphasia (20%), it was equally distributed between male and female, and the mean age at onset was 59.6 ± 5.9 (range 53-68). In 14 families, autosomal dominant pattern of inheritance was present in 64.2% of cases. No clinical predictors of disease onset were demonstrated. The identification of a large cohort of frontotemporal lobar degeneration (FTLD) patients with homogeneous genetic background well may be used in the search of disease modulators to elucidate genotype-phenotype correlations of progranulopathies.