Recognized as a major influence factor to the neonatal death rates, the World Health Organization emphasizes the importance of medical screening to identify birth defects through three-level prevention, especially in developing countries. China has put great efforts in prenatal testing and newborn screening to control and reduce a proportion of birth defects during the last decades. So far, the national phenylketonuria screening program in China has achieved 85% covering rate of all infants. However, many infants were still undiagnosed due to the limitation of metabolic testing and small panel screening strategy, hence a comprehensive and scalable screening method for newborn is in need. In addition to birth defects, the reported number of adverse drug reactions (ADR) rise significantly in the last twenty years, representing a major health problem for Chinese population. In 2020, over 16 million ADR cases were collected by the National Medical Products Administration, and 10% of them were severe ADRs which could result in death. Previous studies have revealed that genetic factors and ethnic difference are crucial in predicting and preventing ADRs. Unlike the United States or European countries, China is lack of pharmacogenetic baseline dataset in order to facilitate new drug development and reduce ADRs through pre-emptive PGx profiling. Along with the rapid innovation and costs reduction, the next-sequencing technologies (NGS) have boosted the application of sequencing-based approaches in a wide range of clinical settings, including Mendelian diseases diagnosis, non-invasive prenatal testing for Trisomy 21, 13 and 18, as well as the precise medication for cancer patients. Recognizing the emerging role of NGS as a tool for population studies, we aim to evaluate the potential of WGS-based method in expanded newborn screening (NBS) and developing pharmacogenetic baseline dataset in Chinese population. Our study has demonstrated the clinical benefits of extended NBS using genomic sequencing to detect treatable or curable conditions in 321 unselected children. Furthermore, our research has developed by far the most comprehensive pharmacogenetic dataset from 2002 individuals using high-depth genomic sequencing, covering 31 administrative divisions. The results of our studies suggest WGS could be a suitable approach for newborn screening in a wide range of medical conditions, which could be further evaluated by large-scale, multi-center studies. In addition, a high-quality pharmacogenetic baseline dataset was set up using high-depth whole genome sequencing data, which could serve as a useful resource to guide pre-emptive PGx screening and facilitate new drug development in the future.