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

Publication

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

Journal Paper/Review - Jan 28, 2022

Al Khleifat Ahmad, Iacoangeli Alfredo, Van Vugt Joke J F A, Bowles Harry, Moisse Matthieu, Zwamborn Ramona A J, van der Spek Rick A A, Shatunov Aleksey, Cooper-Knock Johnathan, Topp Simon, Byrne Ross P, Gellera Cinzia, López Victoria, Jones Ashley R, Opie-Martin Sarah, Vural Atay, Campos Yolanda, van Rheenen Wouter, Kenna Brendan, van Eijk Kristel R, Kenna Kevin, Weber Markus, Smith Bradley, Fogh Isabella, Silani Vincenzo, Morrison Karen E, Dobson Richard, van Es Michael A, McLaughlin Russell L, Vourc'h Patrick, Chio Adriano, Corcia Philippe, de Carvalho Mamede, Gotkine Marc, Panadés Monica P, Mora Jesus S, Shaw Pamela J, Landers John E, Glass Jonathan D, Shaw Christopher E, Başak Nazli, Hardiman Orla, Robberecht Wim, Van Damme Philip, van den Berg Leonard H, Veldink Jan H, Al-Chalabi Ammar

Citation

Al Khleifat A, Iacoangeli A, Van Vugt J, Bowles H, Moisse M, Zwamborn R, van der Spek R, Shatunov A, Cooper-Knock J, Topp S, Byrne R, Gellera C, López V, Jones A, Opie-Martin S, Vural A, Campos Y, van Rheenen W, Kenna B, van Eijk K, Kenna K, Weber M, Smith B, Fogh I, Silani V, Morrison K, Dobson R, van Es M, McLaughlin R, Vourc'h P, Chio A, Corcia P, de Carvalho M, Gotkine M, Panadés M, Mora J, Shaw P, Landers J, Glass J, Shaw C, Başak N, Hardiman O, Robberecht W, Van Damme P, van den Berg L, Veldink J, Al-Chalabi A. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis. NPJ Genom Med 2022; 7:8.

Type

Journal Paper/Review (English)

Journal

NPJ Genom Med 2022; 7

Publication Date

Jan 28, 2022

Issn Electronic

2056-7944

Brief description/objective

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.