Given the high prevalence of TARDBP mutations in patients with a predominant UMN phenotype and the recent advancements in precision medicine and genetic therapies, we advocate for the consideration of genetic testing as a routine part of the diagnostic work-up for all patients with MNDs, including those displaying clinical features consistent with primary lateral sclerosis or, more broadly, prominent UMN involvement. The gene discussed is TARDBP; the disease is Primary lateral sclerosis.