5 years ago

NEK1 genetic variability in a Belgian cohort of ALS and ALS-FTD patients

We evaluated the genetic impact of the amyotrophic lateral sclerosis (ALS) risk gene NIMA-related kinase 1 (NEK1) in a Belgian cohort of 278 patients with ALS (n=245) or ALS with frontotemporal dementia (ALS-FTD, n=33) and 609 control individuals. We identified two ALS patients carrying a loss-of-function (LOF) mutation, p.Leu854Tyrfs*2 and p.Tyr871Valfs*17, that were absent from the control group. A third LOF variant p.Ser1036* was present in two sibs with familial ALS, but also in an unrelated control person. Missense variants were common in both patients (3.6%) and controls (3.0%). The missense variant, p.Arg261His, which was previously associated with ALS risk, was detected with a minor allele frequency of 0.90% in patients compared to 0.33% in controls. Taken together, NEK1 LOF variants accounted for 1.1% of patients, although interpretation of pathogenicity and penetrance is complicated by the observation of occasional LOFs in unaffected individuals (0.16%). Furthermore enrichment of additional ALS gene mutations was observed in NEK1 carriers, suggestive of a ‘second hit’ model were NEK1 variants may modify disease presentation of driving mutations.

Publisher URL: www.sciencedirect.com/science

DOI: S0197458017302774

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