SHC2 (SHC adaptor protein 2) is a signaling adapter protein that couples activated growth factor receptors to downstream signaling pathways, particularly in neuronal contexts 1. The protein functions as a receptor tyrosine kinase-binding adapter involved in cell surface receptor signaling and interacts with focal adhesion kinase in cellular density-dependent mechanisms 2. Clinically, SHC2 is associated with multiple system atrophy (MSA), a progressive neurodegenerative α-synucleinopathy characterized by autonomic failure and motor symptoms. Copy number loss of SHC2 in the 19p13.3 subtelomeric region was identified as a disease-specific alteration, occurring in affected monozygotic twins discordant for MSA and in 32% of Japanese MSA patients, with statistical significance suggesting a causal link (odds ratio = 89.8) 1. However, this association shows population-specific heterogeneity; a subsequent US cohort study found no SHC2 deletions in 105 well-characterized MSA patients, indicating genetic background influences disease mechanisms 3. Additionally, SHC2 has been identified as a candidate loss-of-function gene in familial cholesteatoma across multiple families 4 and as a potential Alzheimer disease-associated gene variant when restricting analysis to functional coding sequence variants 5. These findings suggest SHC2 dysfunction contributes to multiple neurodegenerative and otologic disorders through impaired signaling adapter function.