Dokumentdetails
ID
doi:10.1007/s00415-024-12450-w...
Autor
Leighton, Danielle J. Ansari, Morad Newton, Judith Cleary, Elaine Stephenson, Laura Beswick, Emily Carod Artal, Javier Davenport, Richard Duncan, Callum Gorrie, George H. Morrison, Ian Swingler, Robert Deary, Ian J. Porteous, Mary Chandran, Siddharthan Pal, Suvankar the Lothian Birth Cohorts Group, the CARE-MND ConsortiumLangue
enEditor
Springer
Kategorie
Medicine & Public Health
Jahr
2024
Auflistungsdatum
12.06.2024
Schlüsselwörter
motor neuron disease amyotrophic lateral sclerosis genetic epidemiology genotype-phenotype sod1 c9orf72 mnd using variant sod1 pathogenic genetic expansion c9orf72Zusammenfassung
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.
Leighton, Danielle J.,Ansari, Morad,Newton, Judith,Cleary, Elaine,Stephenson, Laura,Beswick, Emily,Carod Artal, Javier,Davenport, Richard,Duncan, Callum,Gorrie, George H.,Morrison, Ian,Swingler, Robert,Deary, Ian J.,Porteous, Mary,Chandran, Siddharthan,Pal, Suvankar,the Lothian Birth Cohorts Group, the CARE-MND Consortium, 2024, Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland, Springer
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