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[P4–071]: EXOME SEQUENCING IN ATYPICAL FRONTOTEMPORAL DEMENTIA WITH PERI‐ROLANDIC ATROPHY SUGGESTS A ROLE FOR MATRIX METALLOPROTEINASES IN FRONTOTEMPORAL DEMENTIA
Author(s) -
Zee Julie,
Nguyen Hung Phuoc,
Mendonca Alexandre,
Guerreiro Manuela,
BaradaranHeravi Yalda,
Dillen Lubina,
Van Broeckhoven Christine,
EarlyOnset Dementia Consortium European
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.1936
Subject(s) - frontotemporal dementia , exome sequencing , dementia , genetics , exome , biology , gene , medicine , mutation , disease , pathology
impact of NEK1 genetic variability on ALS risk, we performed massive parallel resequencing of the NEK1 coding region in a Belgian cohort of 280 patients with ALS (n1⁄4248) and FTD-ALS (n1⁄432) and 609 matched control individuals. Results:We identified two premature termination codon (PTC) mutations (p.Leu854Tyrfs*2 and p.Tyr871Valfs*17) in two isolated ALS patients (onset ages 63 and 61 years) that were absent from the control group. One nonsense mutation (p.Ser1036*) was present in one familial ALS patient (disease onset 47 years) but also in an unaffected control (aged 54 years). Transcript analysis confirmed loss of the mutated transcript by nonsense-mediated RNA decay for all three PTC mutations. Overall this represented a mutation frequency for NEK1 LOF mutations of 1.07% (3/280) in patients compared to 0.16% (1/609) in controls. Missense mutations were common in both patients (11/280 or 3.9%) and controls (18/609, or 3.0%), though one (p.Arg232Cys) was only found in one isolated FTD-ALS patient (onset age 45 years). The missense variant, p.Arg261His, was previously associated with increased risk for ALS. In our study, we detected this variant with a minor allele frequency of 1.07% in patients compared to 0.25% in controls, which did not reach statistical significance, possibly due to the smaller sample size. Conclusions: In our Belgian study population of 280 ALS and FTD-ALS patients we observedNEK1 LOFmutations in about 1% of patients, in line with previous reports, although interpretation of pathogenicity and penetrance is complicated by the observation of occasional LOFs in unaffected individuals.