A Systematic Review of Genotype–Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS

Owen Connolly, Laura Le Gall, Gavin McCluskey, Colette Donaghy, William Duddy, Stephanie Duguez

Research output: Contribution to journalReview articlepeer-review

36 Citations (Scopus)
79 Downloads (Pure)


Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease characterised by progressive deterioration of upper and lower motor neurons that eventually culminates in severe muscle atrophy, respiratory failure and death. There is a concerning lack of understanding regarding the mechanisms that lead to the onset of ALS and as a result there are no reliable biomarkers that aid in the early detection of the disease nor is there an effective treatment. This review first considers the clinical phenotypes associated with ALS, and discusses the broad categorisation of ALS and ALS-mimic diseases into upper and lower motor neuron diseases, before focusing on the genetic aetiology of ALS and considering the potential relationship of mutations of different genes to variations in phenotype. For this purpose, a systematic review is conducted collating data from 107 original published clinical studies on monogenic forms of the disease, surveying the age and site of onset, disease duration and motor neuron involvement. The collected data highlight the complexity of the disease’s genotype–phenotype relationship, and thus the need for a nuanced approach to the development of clinical assays and therapeutics.
Original languageEnglish
Article number58
Pages (from-to)1-27
Number of pages27
JournalJournal of Personalized Medicine
Issue number3
Early online date29 Jun 2020
Publication statusPublished (in print/issue) - 30 Sept 2020

Bibliographical note

Funding Information:
This work was financed by the European Union Regional Development Fund (ERDF) EU Sustainable Competitiveness Programme for Northern Ireland, Northern Ireland Public Health Agency (HSC R&D) and Ulster University (PI: A Bjourson). L.L.G. was a recipient of an ArSLA PhD fellowship, O.C. was a recipient of a PhD DELL fellowship and G.M. was a recipient of an IICN fellowship.

Publisher Copyright:
© 2020 by the authors.

Copyright 2020 Elsevier B.V., All rights reserved.


  • ALS
  • ALS genes
  • ALS variants
  • Genotype–phenotype
  • MND


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