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. 2024 Aug;271(8):5256-5266.
doi: 10.1007/s00415-024-12450-w. Epub 2024 Jun 9.

Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland

Danielle J Leighton  1   2   3   4   5 , Morad Ansari  6 , Judith Newton  7   8   9 , Elaine Cleary  6 , Laura Stephenson  7 , Emily Beswick  8 , Javier Carod Artal  10 , Richard Davenport  7   8 , Callum Duncan  11 , George H Gorrie  7   12 , Ian Morrison  13 , Robert Swingler  7 , Ian J Deary  14 , Mary Porteous  6 , Siddharthan Chandran  7   8   9   15 , Suvankar Pal  7   8   9 ; Lothian Birth Cohorts Group, the CARE-MND Consortium
Collaborators, Affiliations

Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland

Danielle J Leighton et al. J Neurol. 2024 Aug.

Abstract

Background: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype-phenotype associations.

Methods: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology.

Results: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant.

Conclusions: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.

Keywords: Amyotrophic lateral sclerosis; C9orf72; Genetic epidemiology; Genotype-phenotype; Motor neuron disease; SOD1.

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Conflict of interest statement

The authors report no competing interests.

Figures

Fig. 1
Fig. 1
Summary of genetic epidemiology of incident MND cohort 2015–2017, VUS variant of uncertain clinical significance
See this image and copyright information in PMC

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