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Background: The aim of this study is to investigate potentially curable or treatable medical conditions in unselected newborns using genomic sequencing(GS). Methods: 321 newborns from a cohort of pregnant women from Qingdao, China, underwent high-depth GS (average 47.42 fold), with the approval of the ethics committee. 61 Mendelian Diseases, 151 Primary Immunodeficiency Diseases(PID) and 5 DPWG recommeded Essential pharmacogenetic(PGx) genes were analyzed. Results: 121 Mendelian pathogenic or likely pathogenic variants associated with 31 inherited diseases were detected, among these hearing loss, congenital hypothyroidism, methylmalonic acidemia, methylmalonic acidemia with homocystinuria, phenylketonuria(PKU) and benign hyperphenylalaninemia accounted for half of the carrier variants. Three children with compound heterozygous variants at GJB2 and PAH were confirmed by Sanger sequencing. Follow-up of the three families confirmed that one child was diagnosed with PKU and two children with GJB2 variants were scheduled to undergo hearing loss testing every six months after genetic counceling due to the nature of incomplete penetrance of hearing loss. 11 heterozygous pathogenic/ likely pathogenic variants in eight PID genes were identified in 11 infants. All 321 newborns carried at least one variant at the five DPGW recommended PGx genes. Codeine and clopidogrel require more attention in giving prescription for 25% and 8% of newborns have a decreased function of CYP2D6 and CYP2C19 enzymes respectively. Conclusions: Our study is the largest to date using GS to sequence unselected newborns. The results suggest that using GS may be a suitable method for screening newborns for variants in a large number of disease associated genes.