Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), yet the mechanisms underlying selective neuronal vulnerability remain unclear. A major challenge in identifying consistent transcriptomic changes across C9orf72 patient-derived neuron lines has been heterogeneous differentiations, lack of isogenic controls and low sequencing depth. To overcome these challenges, we generated homogeneous cortical neuron (iCNs) cultures from multiple isogenic C9orf72 patient iPSCs pairs and performed RNA deep sequencing. We identified robust and reproducible gene expression and splicing alterations in pathways related to cytoskeletal organization, extracellular matrix adhesion and synaptic signaling. Notably, we observed exon 30 skipping in the cytoskeletal regulator Filamin B (FLNB), leading to the loss of its hinge domain. This was accompanied by altered FLNB localization, disrupted actin crosslinking and impaired mechano-transduction pathways. These findings reveal convergent transcriptomic and functional disruptions across multiple isogenic C9orf72 patient derived iCNs offering new insights into ALS/FTD pathogenesis. Building on these findings, we tested the cytoskeletal- microtubule-stabilizing agent Paclitaxel (Taxol) for its therapeutic potential in C9orf72 iCNs. In one patient line, Taxol improved neurite density, supporting the functional relevance of cytoskeletal dysregulation. However, bulk RNA sequencing in additional patient lines revealed minimal transcriptomic rescue, suggesting Taxol may act downstream of transcription or has variable effects across patient backgrounds. Altogether, this study establishes an isogenic iPSC-based neuronal platform that integrates transcriptomic and functional analysis to uncover reproducible disease mechanisms and further evaluate candidate therapeutic strategies for ALS/FTD.