Describe a Tunisian family carrier of the same rare mutation in TARDBP but developing different neurodegenerative disease with heterogenous features (age of onset and first symptoms) and explore the possible genetic modifiers leading to the observed intrafamilial phenotypic variability

The presence of the rare mutation p.G294A in TARDBP gene is associated to ALS/FTD spectrum, however, it is also linked to cognitive impairment in other neurodegenerative diseases (NDD). Additionally, the observed heterogeneity may be due to oligogenic profile and the interaction of TARDBP with other genes mutation. Such phenomenon is very likely to occur in the Tunisian population due to its high degree of inbreeding

Targeted next generation sequencing was used to analyze 48 genes associated to neurodegenerative diseases including TARDBP. Additional analysis for C9orf72 repeated expansion was performed by fragment length analysis and Repeat-primed PCR.

Genetic analysis identified TARDBP p.G294A mutation among in 4 members (1 ALS case, 2 patients with AD and 1 case with FTD-parkinsonism). However, only one patient with AD was not mutated TARDBP. The NGS analysis revealed additional mutations in ALS case harbored in GBA. While, the 3 cases of AD (TARDBP-mutated and non-mutated) were carriers of PRKN and GBA mutations.  Finally, the FTD-parkinsonism patient was mutated for LRRK2 p.G2019S that might increase his susceptibility to develop Parkinsonism spectrum.

The presence of rare genetic variants of TARDBP in this Tunisian family suggests that they may influence the clinical manifestation as well as be pathogenic variant in ALS case. Consequently, we suggest that other genetic and/or epigenetic modifiers must be responsible for disease variability in this TARDBP family case.