Background/Objectives: Gaucher disease (GD) is characterized by significant phenotypic heterogeneity, even among patients with identical GBA1 genotypes, suggesting the role of genetic and/or epigenetic modifiers. The enzymatic defect and pathological accumulation of glucosylceramide (GlcCer) lead to chronic metabolic inflammation, potentially interacting with other biological pathways to influence disease expression. Methods: This study leveraged one of the world’s most deeply phenotyped cohorts of GD patients, drawn from a major tertiary referral center, with prolonged longitudinal follow-up. Whole exome sequencing (WES) was conducted on 275 extensively characterized patients, focusing on those exhibiting complex phenotypes. Results: Eighteen patients (6.5%) presented with atypical manifestations not fully explained by GD. WES revealed additional genetic diagnoses, including hereditary hemochromatosis (n=5), Familial Mediterranean Fever (n=4), homozygous MSH6 mutation-associated hereditary cancer predisposition (n=2), and others. These concurrent genetic diseases can modify GD presentation and complicate clinical management. Conclusions: This work underscores the importance of recognizing complex phenotypes in GD, identifying modifier genes, and informing precision medicine strategies for improved patient outcomes.