Al Khleifat, AhmadIacoangeli, Alfredovan Vugt, Joke J F ABowles, HarryMoisse, MatthieuZwamborn, Ramona A Jvan der Spek, Rick A AShatunov, AlekseyCooper-Knock, JohnathanTopp, SimonByrne, RossGellera, CinziaLópez-Alonso, VictoriaJones, Ashley ROpie-Martin, SarahVural, AtayCampos, Yolandavan Rheenen, WouterKenna, BrendanVan Eijk, Kristel RKenna, KevinWeber, MarkusSmith, BradleyFogh, IsabellaSilani, VincenzoMorrison, Karen EDobson, Richardvan Es, Michael AMcLaughlin, Russell LVourc'h, PatrickChio, AdrianoCorcia, Philippede Carvalho, MamedeGotkine, MarcPanades, Monica PMora, Jesus SShaw, Pamela JLanders, John EGlass, Jonathan DShaw, Christopher EBasak, NazliHardiman, OrlaRobberecht, WimVan Damme, Philipvan den Berg, Leonard HVeldink, Jan HAl-Chalabi, Ammar2023-04-272023-04-272022-01-28NPJ Genom Med. 2022 Jan 28;7(1):8.http://hdl.handle.net/20.500.12105/15907There 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.engVoRhttp://creativecommons.org/licenses/by/4.0/Genome sequencesAmyotrophic lateral sclerosis (ALS)Atribución 4.0 Internacional3509164871810.1038/s41525-021-00267-92056-7944NPJ genomic medicineopen access