Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Ahmad Al Khleifat, Alfredo Iacoangeli, Joke J.f.a. Van Vugt, Harry Bowles, Ramona A.J. Zwamborn, Matthieu Moisse, Ramona A.J. Zwamborn, Johnathan Cooper-Knock, Aleksey Shatunov, Ashley Jones, Wouter van Rheenen, Sarah Opie-Martin, Isabella Fogh, Simon Topp, Bradley Smith, Richard Dobson, Christopher Shaw, Adriano Chiò, Monica P. Panades, Jesus S MoraPamela J. Shaw, John E. Landers, Jonathan D. Glass, A. Nazli Başak, Orla Hardiman, Wim Robberecht, Philip Van Damme, Leonard H van den Berg, Jan H. Veldink, Ammar Al-Chalabi

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There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.
Original languageEnglish
JournalNPJ Genomic medicine
Publication statusPublished - 19 Oct 2021


  • ALS (Amyotrophic Lateral Sclerosis)
  • MND
  • WGS
  • Structural variants
  • bioinformatics


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