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

• Published in: Neurobiology of aging Vol. 61; pp. 255.e1 - 255.e7
• Main Authors: Nguyen, Hung Phuoc, Van Mossevelde, Sara, Dillen, Lubina, De Bleecker, Jan L., Moisse, Matthieu, Van Damme, Philip, Van Broeckhoven, Christine, van der Zee, Julie, Engelborghs, Sebastiaan, Crols, Roeland, De Deyn, Peter P., De Jonghe, Peter, Baets, Jonathan, Cras, Patrick, Mercelis, Rudy, Vandenberghe, Rik, Sieben, Anne, Santens, Patrick, Ivanoiu, Adrian, Deryck, Olivier, Vanopdenbosch, Ludo, Delbeck, Jean
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2018
• Subjects: Aged; Amyotrophic lateral sclerosis (ALS); Amyotrophic Lateral Sclerosis - genetics; Belgium; Cohort Studies; Female; Frontotemporal dementia (FTD); Frontotemporal Dementia - genetics; Gene Frequency; Genetic Association Studies; Genetic Variation - genetics; Humans; Loss of Function Mutation - genetics; Male; Middle Aged; NEK1; NIMA-related kinase 1; NIMA-Related Kinase 1 - genetics; Risk; NEK1; Amyotrophic lateral sclerosis (ALS); Frontotemporal dementia (FTD); NIMA-related kinase 1
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2017.08.021

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.