TBX15 is a T-box transcription factor primarily functioning as a developmental regulator of skeletal and craniofacial morphology 1. During embryogenesis, TBX15 is expressed in cranio-facial regions and developing limbs beginning at embryonic day 9.5 1. The gene controls mesenchymal precursor cell and chondrocyte numbers, with TBX15 knockout mice exhibiting significantly shorter faces, lower ear positioning, and reduced body/limb length 2. Beyond skeletal development, TBX15 regulates adipocyte differentiation and metabolic function. Overexpression impairs adipocyte differentiation and decreases mitochondrial respiration by 28% and ATP turnover by 45%, with 260-fold higher expression in subcutaneous versus visceral preadipocytes 3. Regulatory variants in TBX15 intron-1 affect both osteoporosis and obesity risk, with five SNPs showing identical trait-increasing alleles for both conditions 4. A deeply divergent haplotype in the TBX15/WARS2 region, likely introgressed from Denisovans, is under positive selection in Inuit populations and associates with altered TBX15 expression and DNA methylation 5. Clinically, TBX15 upregulation correlates with worse prognosis in gliomas through immunosuppressive mechanisms 6, while germline variants associate with Cousin syndrome. TBX15 remains implicated in craniofacial dysmorphology syndromes 1.