A Novel Splice Site Mutation in GRN (p.A237fs [A>T]) in a Large Italian Family With FTD From The Apulia-FTD Registry (P2.160)

OBJECTIVE: To assess genetics, clinical features of a large Italian family with FTD; to investigate whether GRN plasmatic levels can be used to detect p.A237fs [A>T] mutation carriers(GRN+) from non carriers(GRN-). BACKGROUND: 50[percnt] of FTD cases are familial. GRN Loss of function mutations (LoF) cause FTD through haploinsufficiency. GRN (p.A237fs [c.709-2A>G]) has been reported as causal in FTD families with predominant language impairment/parkinsonism at onset. Subjects with GRN mutations have significantly reduced GRN plasma levels. DESIGN/METHODS: Within an FTD population-based registry we identified a large FTD famil with an apparent autosomal dominant mode of inheritance. The diagnosis was made according to Neary. We collected blood samples from: 6 living FTD subjects, 19 unaffected first relatives, 28 unrelated controls. We screened for pathogenic mutations in FTD Mendelian genes (GRN, VCP, MAPT, TDP43) and for C9ORF72 repeat expansions. We measured plasma progranulin levels with ELISA. RESULTS: We found a novel pathogenic splice site mutation in GRN (p.A237fs [c.709-2A>T]), cosegregating with FTD and associated to predominant behavioural and personality changes at onset. The mutation was found also in 2 unaffected relatives. Mean plasma GRN levels were: 26.5 ng/ml in 4 affected GRN+ (2 were deceased meanwhile); 21.5 ng/ml in the 2 unaffected first-degree GRN+; 82.0 ng/ml in the 4 unaffected first-degree GRN-; 142.7 ng/ml in the 28 unrelated controls GRN-, (p=0.005, Kruskal Wallis). CONCLUSIONS: This family confirms that the clinical phenotype associated with spectrum of GRN mutations is heterogeneous. A gradient in the reduction of progranulin levels was identified with the highest levels in healthy unrelated controls and the lowest in the mutation carriers, while intermediate levels were found in the unaffected non-carriers relatives. Plasmatic progranulin levels may mirror LoF mutations in GRN, being a useful biomarker to identify GRN mutation carriers, to follow-up treatments response and to identify at risk relatives. Study Supported by: NA Disclosure: Dr. Capozzo has nothing to disclose. Dr. Sassi has nothing to disclose. Dr. Crews has nothing to disclose. Dr. Zecca has nothing to disclose. Dr. Arcuti has nothing to disclose. Dr. Copetti has nothing to disclose. Dr. Brescia has nothing to disclose. Dr. Singleton has nothing to disclose. Dr. Logroscino has received personal compensation for activities with Novartis, GlaxoSmithKline, and Boerhinger, and as a member of the Cohorts Project in Biomedicine. Dr. Logroscino has received personal compensation in an editorial capacity for Karger.