Genetic epidemiology of motor neuron disease-associated variants in the Scottish population

Abstract

Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population.

Keywords: Amyotrophic lateral sclerosis; Motor neuron disease; NEK1; TBK1.

Fig. 1

Proportion of cases with a pathogenic or loss-of-function variant in genes on the MND gene panel or in C9orf72. (A): cases with a family history; (B): sporadic cases with no known family history. Each pie chart includes one digenic case that is counted for both of the genes in which a pathogenic or loss-of-function variant is found.

Fig. 2

Kaplan-Meier survival plot of MND cases grouped by genotype. C9orf72, pathogenic expansion identified; digenic, two pathogenic or loss-of-function variants identified; Nil, no pathogenic or loss-of-function variant identified; other, pathogenic or loss-of-function variant identified in TARDBP, TBK1, NEK1, or OPTN; SOD1, pathogenic SOD1 variant identified.