The triple code model for advancing research in rare and undiagnosed diseases beyond the base pairs

Rare and undiagnosed diseases pose significant challenges for understanding their mechanisms, diagnosis, and treatment. The Triple Code Model, an integrative paradigm described here, considers the combined influence of the genetic code, epigenetic code, and nuclear structure (an emerging code), as fundamental biochemical mechanisms underlying many rare diseases. Studies demonstrate dysfunctional membrane and cytoplasmic signals instruct the epigenome to ultimately impact the 3D structure and dynamics of the nucleus, highlighting their close interrelationships. Consequently, this model offers a holistic perspective on rare and undiagnosed diseases by moving beyond a solely genetic view. We propose that this integrated framework will efficiently guide rare disease research by taking it 'Beyond the Base Pairs,' leading to improved diagnostics and personalized treatments.