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.
Highlights
Motor neuron disease (MND) is a rapidly progressive and fatal neurodegenerative disorder, characterized by loss of motor neuron function
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
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
Summary
Motor neuron disease (MND) is a rapidly progressive and fatal neurodegenerative disorder, characterized by loss of motor neuron function. Presentations can include limb onset, bulbar onset, or cognitive/behavioural disease, reflecting variable involvement of the upper motor neurons, lower motor neurons and frontotemporal cortex (Turner and Swash, 2015). Age and site of onset, rate of disease progression and clinical syndrome vary considerably between cases, presenting difficulties for diagnosis and disease management. In Scotland, there is a predicted annual crude incidence of MND of 2.38 per 100,000 of the population (Forbes et al, 2007). Mean survival from symptom onset to death is 2.8 years (Forbes et al, 2007), albeit with a variable trajectory depending on the clinical syndrome
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