An arrhythmogenic pathogenetic pathway for SIDS from patient genotype to clinical phenotype. The figure denotes the pathogenic pathway from genotype to clinical phenotype, with environmental influences noted. The genetic abnormality, in this instance a polymorphism in the cardiac Na⁺ channel SCN5A, causes a molecular phenotype of increased late Na⁺ current (I_Na) under the influence of environmental factors such as acidosis. Interacting with other ion currents that may themselves be altered by genetic and environmental factors, the late Na⁺ current causes a cellular phenotype of prolonged action potential duration as well as early afterdepolarizations. Prolonged action potential in the cells of the ventricular myocardium and further interaction with environmental factors such as autonomic innervation, which in turn may be affected by genetic factors, produce a tissue/organ phenotype of a prolonged QT interval on the ECG and torsade de pointes arrhythmia in the whole heart. If this is sustained or degenerates to ventricular fibrillation, the clinical phenotype of SIDS results. Environmental and multiple genetic factors may interact at many different levels to produce the characteristic phenotypes at the molecular, cellular, tissue, organ, and clinical levels. The study by Bowers et al. in this issue of the JCI (8) demonstrates the importance of environmental influences, in this case acidosis, in the pathogenetic pathway of SIDS.