Over 50 tandem repeat expansions are known to cause neurological disease including C9orf72 hexanucleotide repeat expansions in Amyotrophic Lateral Sclerosis (ALS). Through use of long-read sequencing technology, we identified a novel expansion in a variable number tandem repeat (VNTR) in the final intron of WD repeat domain 7 (WDR7). This VNTR is significantly longer in three independent cohorts of individuals with sporadic ALS compared with matched control individuals from Answer ALS, Quebec, and the Coriell Institute, suggesting that it acts as a risk factor for ALS. WDR7 encodes a protein that is involved in synaptic transmission and is associated with other proteins implicated in ALS, including UNC13A. We sought to evaluate functional consequences of the WDR7 repeat, including its role in forming RNA aggregates in a repeat-dependent manner. We tested for co-localization of WDR7 repeat RNA aggregates and protein markers of ALS and found co-localization of WDR7 RNA aggregates with TDP-43 but not FUS. Furthermore, each copy of the 69bp repeat forms a stem-loop structure which can generate microRNAs. We found that the 3’UTR of VPS53 contains 29 predicted microRNA binding sites for the WDR7 seed region – a 3-fold enrichment over any other 3’UTR – and that this 3’UTR region represses mRNA expression when incorporated into a luciferase reporter system. To ascertain the consequence of increased WDR7 repeat copy number we performed RNA-seq on HEK293 cells receiving constructs that express 0, 1, 27 or 36 copies of the WDR7 tandem repeat. Significant increases in immune-related genes and pathways were observed in cells receiving high versus low repeat copies, as were neuronal and synaptic genes like NEFH, RAB8A, and RAB11B-AS. These findings were corroborated with Answer ALS RNA-seq data from induced pluripotent cells differentiated into motor neurons (iMN), including analysis of 5 affected iMN lines with >30 repeat copies compared to 15 lines with <10 repeat copies. Finally, we continue to analyze the role of somatic and germline expansions of WDR7 and other tandem repeats in short and long-read sequence data in the context of ALS. Collectively our findings underscore the biological impact of tandem repeat expansions in modulating susceptibility to ALS.