Challenging traditional classifications: Gene penetrance in genetically transitional disease

Accurate estimates of gene penetrance are critical for evaluating disease risk, guiding clinical decision-making, supporting genetic counseling, and advancing research. Multiple methodologies have been developed to estimate penetrance, aiding in the classification of human genetic disorders. Penetrance estimating approaches for rare and low-frequency/common variants may vary. Building on these approaches, we suggest the adoption of quantitative thresholds to categorize variant penetrance as high (≥70%), moderate (30%–70%), or low (<30%). This penetrance stratification may approximately reflect the continuous influence of genetic variants on disease. Traditionally, human diseases have been classified dichotomously as monogenic or polygenic. Based on these models, high-penetrance variants are typically associated with Mendelian disorders, while low-penetrance variants contribute modestly to disease risk. Since the completion of the human genome project, there have been hundreds of thousands of genetic variants identified in the gray zone between monogenic and polygenic variants. To bridge the conceptual gap between monogenic and polygenic disorders, we previously proposed a novel framework termed genetically transitional disease. This concept highlights disorders influenced by genetic variants of low- to moderate-penetrance along with environment and aligns with the ClinGen Working Group's framework on risk alleles and low-penetrance variants. By overcoming the inadequacy and obstacle of a strictly binary classification of genetic disease and moving beyond, the genetically transitional disease model offers a refined and more advantageous approach to capturing genetic nuances and represents a potential paradigm shift in the interpretation of genetic variation, with more important and broader implications for both patient care and research.