We evaluated the genetic impact of the amyotrophic lateral sclerosis (ALS) risk gene never in mitosis gene a–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 2 ALS patients carrying a loss-of-function (LOF) mutation, p.Leu854Tyrfs*2 and p.Tyr871Valfs*17, that was absent in the control group. A third LOF variant p.Ser1036* was present in 2 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 LOF variants 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.
Nguyen, H. P., Van Mossevelde, S., Dillen, L., De Bleecker, J. L., Moisse, M., Van Damme, P., … Delbeck, J. (2018). NEK1 genetic variability in a Belgian cohort of ALS and ALS-FTD patients. Neurobiology of Aging, 61, 255.e1-255.e7. https://doi.org/10.1016/j.neurobiolaging.2017.08.021