Enlarging clinical spectrum of FALS with TARDBP gene mutations: S393L variant in an Italian family showing phenotypic variability and relevance for genetic counselling

Objective: The present study was aimed to enlarge the Italian ALS sample analysed for TARDBP gene mutations. Methods: Genomic DNA from 47 patients, 70 FTD patients and 158 controls was extracted from peripheral blood samples according to a standard protocol. The five coding exons (2-6) of the TARDBP gene and the flanking exon-intron boundaries were analysed by direct sequencing. Using ClustalW2 human TDP-43, protein sequence was aligned with TDP-43 protein sequence of different species. Results: A heterozygous c.1178 C -> T transition that leads to a change p.S393L was observed in a 75-years-old male patient and in his two affected siblings. A patient's brother had died at 69 years of age after a two-year history of ALS. In FTD patients no mutations were found. Conclusions: We describe a further Italian family with FALS, in which a variant (p.S393L) of the TARDBP gene was identified. Clinical course and phenotypic variability in three affected siblings is presented and relevance for genetic counselling of patients and their families is underlined. At the present state of knowledge, we suggest that the same guidelines established for SOD1 molecular testing could be proposed also for TARDBP analysis in FALS.