NEK1 mutations in familial amyotrophic lateral sclerosis

Sir, Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by adult-onset loss of motor neurons. Five to 10% of all ALS cases are familial ALS. To date, more than 20 genes have been implicated in causing familial ALS, with the discovery of mutations in CHCHD10 ( Bannwarth et al. , 2014 ) and TBK1 ( Cirulli et al. , 2015 ; Freischmidt et al. , 2015 ) representing the latest examples for monogenic causes of ALS. Most recently, whole exome sequencing of ALS patients suggested an association of heterozygous loss-of-function mutations in NEK1 with ALS. However, this observation was made in a cohort of mostly sporadic patients, and the result was only significant in a combined analysis of the discovery and the replication cohort ( Cirulli et al. , 2015 ), making further validation essential. To assess the association between NEK1 variants and familial ALS we analysed whole exome sequence data of 265 familial ALS index patients and 827 control individuals. A subset of these exome sequence data has recently led to the discovery of mutations in TBK1 as a cause for ALS in an exome-wide mutational burden analysis ( Freischmidt et al. , 2015 ). The patients with familial ALS were selected from families with two or more affected individuals from European countries (Germany, Sweden, Finland, Denmark, Switzerland, and Portugal) following a negative screen for SOD1 and C9orf72 mutations as described previously ( Freischmidt et al. , 2015 ). In-house control exomes ( n = 827) from Germany were used to compare the variant burden in NEK1 . All ALS patients were diagnosed according to the EFNS Consensus criteria ( Andersen et al. , 2012 ). Control subjects were comprised of healthy parents of children with various diseases, healthy control tissues of individuals with tumour diseases and 200 individuals of the KORA study. With informed written consent and approval by the national medical ethical review boards in accordance with the Declaration of Helsinki ( WMA, 2013 ), EDTA blood samples were drawn from control individuals, ALS patients and their healthy relatives. DNA was extracted from EDTA blood samples according to standard procedures ( Erdmann et al. , 2013 ). Sequencing, read mapping and variant calling was performed on HiSeq2000/2500 systems (Illumina) as described previously ( Freischmidt et al. , 2015 ).