Skip to main content
Top

Open Access 09-06-2024 | Amyotrophic Lateral Sclerosis | Original Communication

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

Authors: Danielle J. Leighton, Morad Ansari, Judith Newton, Elaine Cleary, Laura Stephenson, Emily Beswick, Javier Carod Artal, Richard Davenport, Callum Duncan, George H. Gorrie, Ian Morrison, Robert Swingler, Ian J. Deary, Mary Porteous, Siddharthan Chandran, Suvankar Pal, the Lothian Birth Cohorts Group, the CARE-MND Consortium

Published in: Journal of Neurology

Login to get access

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.
Appendix
Available only for authorised users
Literature
4.
6.
go back to reference Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med [Internet] 17(5):405–24. http://www.ncbi.nlm.nih.gov/pubmed/25741868. Accessed May 2015 Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med [Internet] 17(5):405–24. http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25741868. Accessed May 2015
12.
go back to reference Leighton D, Newton J, Colville S, Bethell A, Craig G, Cunningham L, et al (2019) Clinical audit research and evaluation of motor neuron disease (CARE-MND): a national electronic platform for prospective, longitudinal monitoring of MND in Scotland. Amyotroph Lateral Scler Front Degener [Internet] 20(3–4):242–50. http://www.ncbi.nlm.nih.gov/pubmed/30889975. Accessed 3 Apr 2019 Leighton D, Newton J, Colville S, Bethell A, Craig G, Cunningham L, et al (2019) Clinical audit research and evaluation of motor neuron disease (CARE-MND): a national electronic platform for prospective, longitudinal monitoring of MND in Scotland. Amyotroph Lateral Scler Front Degener [Internet] 20(3–4):242–50. http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​30889975. Accessed 3 Apr 2019
17.
19.
24.
go back to reference Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, et al (2014) Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet [Internet] 46(2):107–15. http://www.ncbi.nlm.nih.gov/pubmed/24362816. Accessed Feb 2014 Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, et al (2014) Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet [Internet] 46(2):107–15. http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​24362816. Accessed Feb 2014
25.
go back to reference Niven E, Newton J, Foley J, Colville S, Swingler R, Chandran S et al (2015) Validation of the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS): a cognitive tool for motor disorders. Amyotroph Lateral Scler Front Degener [Internet]. 16(3–4):172–179. https://doi.org/10.3109/21678421.2015.1030430. Accessed 27 Apr 2015CrossRef Niven E, Newton J, Foley J, Colville S, Swingler R, Chandran S et al (2015) Validation of the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS): a cognitive tool for motor disorders. Amyotroph Lateral Scler Front Degener [Internet]. 16(3–4):172–179. https://​doi.​org/​10.​3109/​21678421.​2015.​1030430. Accessed 27 Apr 2015CrossRef
27.
go back to reference R Core Team (2017) R: A Language and Environment for Statistical Computing [Internet]. R Foundation for Statistical Computing. Vienne, Austria: R Foundation for Statistical Computing, Vienna, Austria. http://www.r-project.org/ R Core Team (2017) R: A Language and Environment for Statistical Computing [Internet]. R Foundation for Statistical Computing. Vienne, Austria: R Foundation for Statistical Computing, Vienna, Austria. http://​www.​r-project.​org/​
31.
go back to reference Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol [Internet]. 11(4):323–30. http://www.ncbi.nlm.nih.gov/pubmed/22406228. Accessed Apr 2012 Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol [Internet]. 11(4):323–30. http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​22406228. Accessed Apr 2012
36.
42.
go back to reference Miltenberger-Miltenyi G, Conceição VA, Gromicho M, Pronto-Laborinho AC, Pinto S, Andersen PM, et al (2019) C9orf72 expansion is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry [Internet] 90(1):118–20. http://www.ncbi.nlm.nih.gov/pubmed/29661924. Accessed 16 Jan 2019 Miltenberger-Miltenyi G, Conceição VA, Gromicho M, Pronto-Laborinho AC, Pinto S, Andersen PM, et al (2019) C9orf72 expansion is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry [Internet] 90(1):118–20. http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​29661924. Accessed 16 Jan 2019
45.
Metadata
Title
Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland
Authors
Danielle J. Leighton
Morad Ansari
Judith Newton
Elaine Cleary
Laura Stephenson
Emily Beswick
Javier Carod Artal
Richard Davenport
Callum Duncan
George H. Gorrie
Ian Morrison
Robert Swingler
Ian J. Deary
Mary Porteous
Siddharthan Chandran
Suvankar Pal
the Lothian Birth Cohorts Group, the CARE-MND Consortium
Publication date
09-06-2024
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-024-12450-w