The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration.

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to null mutations and expansion. In a total of 127 subjects ( = 74 mutations and = 53 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10-12 years earlier than heterozygous/wild type homozygous subjects. A replication study in negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (-5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in -driven disease.