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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年6月9日

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  • 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,
  • Andrew Bethell,
  • Susan Byrne,
  • Myles Connor,
  • Gillian Craig,
  • Ondrej Dolezal,
  • Moira Flett,
  • Louise Gardiner,
  • Jessica Gill,
  • Isaac Chau,
  • Janice Hatrick,
  • Micheala Johnson,
  • Katja Lassak,
  • Juan Larraz,
  • Helen Lennox,
  • Pauline MacDonald,
  • Laura Marshall,
  • Dympna McAleer,
  • Alison McEleney,
  • Kitty Millar,
  • Louise Murrie,
  • David Perry,
  • Gowri Saravanan,
  • David Simpson,
  • Susan Stewart,
  • Dorothy Storey,
  • Gill Stott,
  • David Thompson,
  • Carol Thornton,
  • Carolyn Webber,
  • Michael Wong,
  • Sarah Harris,
  • James Prendergast,
  • Tom Russ,
  • Adele Taylor,
  • Ian Deary

摘要

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.