Thus, we have applied WES to screen Mendelian dementia and neuronal ceroid lipofuscinosis genes in 100 familial and apparently sporadic patients from 6 small and isolated towns and villages in Apulia displaying a heterogeneous FTD-like phenotype. By contrast, whole exome sequencing (WES) is a powerful tool to investigate the genetic landscape underlying complex syndromes 11, 12, 13. Given the rare frequency of the pathogenic variants and the lack of large multigenerational pedigrees, GWA and linkage studies are unlikely to effectively detect such variants. It is likely that very rare, Mendelian, coding and private mutations may explain some of the remaining genetic component of FTD.
On the other hand, a growing body of evidence pointed to likely shared pathogenic mechanisms between frontal dementing syndromes with extrapyramidal signs and neuronal ceroid lipofuscinosis (NCL) 7, 8, 9, 10. Nevertheless, a large fraction of FTD families and apparently sporadic cases with late-onset disease does not carry mutations in these genes. Less frequently, mutations in the genes encoding TAR DNA-binding protein 43 ( TDP-43), valosin containing protein ( VCP), and the charged multivesicular body protein 2B ( CHMP2B), Ubiquilin 2 ( UBQLN2), prion protein ( PRNP) and Triggering Receptor Expressed on Myeloid Cells 2 ( TREM2) have been reported 3, 4, 5, 6 and 16 pathogenic mutations in these genes have been detected in Italian FTD patients and explain part of the disease heritability (Table S1, Fig. Hexanucleotide repeat expansions in the non-coding region of chromosome 9 open reading frame ( C9orf72) underlie approximately 10% of all cases of FTD. Mutations in granulin (GRN) and microtubule-associated tau ( MAPT) most typically cause early-onset (< 55 years) apparently Mendelian FTD. 40–50% of FTD patients report a positive family history for disease 2. Genetics plays a pivotal role in the aetiology of FTD. FTD is the second leading cause of early-onset dementia, after Alzheimer’s disease (AD) 1.
In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.įrontotemporal dementia (FTD) refers to a clinical spectrum of disorders that are genetically, clinically, and neuropathologically heterogeneous. By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders.
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