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.

Dysregulation of AMPA receptor subunit expression in sporadic ALS post‐mortem brain

“…ALS post-mortem samples were obtained from the Medical Research Council (MRC) Edinburgh Brain Bank and had separately undergone whole genome sequencing for genetic identification [2]. Our study used three separate cases for each of C9orf72 repeat expansion, sporadic and SOD1 ALS cases.…”

“…The last 10 years has seen considerable progress in the genetic understanding of ALS with over 40 associated genes known to harbour genetic mutations associated with the disease. However, only a small proportion of total ALS cases (5-10%) are linked to hereditary mutations and the proportion of apparently sporadic ALS (sALS) cases having a genetic basis remains ∼10% [1,2]. In this regard, modelling sALS has been challenging and the majority of ALS research has been conducted on models based on genetic mutations including the C9orf72 repeat expansion (C9orf72 RE ) mutation and mutations to SOD1, which represent the two most frequent known familial and sporadic ALS mutations [1,2].…”

“…However, only a small proportion of total ALS cases (5-10%) are linked to hereditary mutations and the proportion of apparently sporadic ALS (sALS) cases having a genetic basis remains ∼10% [1,2]. In this regard, modelling sALS has been challenging and the majority of ALS research has been conducted on models based on genetic mutations including the C9orf72 repeat expansion (C9orf72 RE ) mutation and mutations to SOD1, which represent the two most frequent known familial and sporadic ALS mutations [1,2]. Whilst many mutations share general pathological features with sALS, including TDP-43 pathology [3], there is an appreciation that the diversity of mutated genes are also likely to reflect diverse pathways and mechanisms that underlie the degeneration of motor neurons in ALS [4,5].…”

OPTN p.Met468Arg and ATXN2 intermediate length polyQ extension in families with C9orf72 mediated amyotrophic lateral sclerosis and frontotemporal dementia

“…Importantly, however, gnomAD contains genetic information from individuals with a presumed non‐Mendelian form of ALS, and we are unable to discern whether this OPTN variant in gnomAD is carried by these individuals from the ALS cohort or other non‐ALS cohorts within gnomAD. In addition, we surveyed databases of diseased individuals, such as HGMD ( n = 197,952 submissions), ClinVar ( n = 442,835 submissions), and ALSoD ( n = 1,096 individuals) and observed the exact variant has been observed in two individuals with ALS, and deposited in ClinVar (Black et al, ).…”

Antisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1A

“…gov NCT01737398). An excellent recent review highlights a number of human disorders that are already underway or planned with ASO treatments in patients (11).…”