LRFN5 (leucine rich repeat and fibronectin type III domain containing 5) is a synaptic cell adhesion molecule that mediates homophilic cell-cell adhesion in a calcium-independent manner and promotes neurite outgrowth in hippocampal neurons. At the molecular level, LRFN5 regulates synaptic development and function 1, with expression dynamically controlled by transcriptional factors including POLR2A and RAD21 2. The gene is uniquely located within a large, mammalian-specific conserved topologically associating domain on chromosome 14, suggesting complex regulatory architecture 1. LRFN5 has significant disease relevance across multiple neuropsychiatric and systemic conditions. LRFN5 dysregulation is implicated in autism susceptibility, particularly in males, with locus structural variations influencing disease risk 1. The risk allele of rs1950834 reduces LRFN5 expression specifically in the nucleus accumbens of major depressive disorder (MDD) patients, and knockdown induces depression-like behaviors while overexpression confers stress resilience 2. Serum LRFN5 levels are elevated in drug-naive MDD patients and decrease with antidepressant treatment, serving as a potential diagnostic biomarker 3. Additionally, LRFN5 is identified as a differential marker in pancreatic delta cells 4 and shows promise as part of a methylation-based biomarker panel for pancreatic cancer detection 5. Gene-based analyses associate LRFN5 with depressive symptoms in aging populations 6 and ocular perfusion pressure in glaucoma 7.