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INTRODUCTION: Over 30 research groups and companies are exploring newborn screening using genomic sequencing (NBSeq), but the sensitivity of this approach is not well understood.METHODS: We identified individuals with treatable inherited metabolic disorders (IMDs) and ascertained the proportion whose DNA analysis revealed explanatory deleterious variants (EDVs). We examined variables associated with EDV detection and estimated the sensitivity of "DNA-first" NBSeq. We further predicted the annual rate of true positive and false negative NBSeq results in the United States for several conditions on the Recommended Uniform Screening Panel (RUSP).RESULTS: We identified 635 individuals with 80 unique IMDs. In univariate analyses, Black race (OR = 0.37, 95% CI: 0.16-0.89, p = 0.02) and public insurance (OR = 0.60, 95% CI: 0.39-0.91, p = 0.02) were less likely to be associated with finding EDVs. Had all individuals been screened with NBSeq, the sensitivity would have been 80.3%. We estimated that between 0 and 649.9 cases of RUSP IMDs would be missed annually by NBSeq in the United States.CONCLUSIONS: The overall sensitivity of NBSeq for treatable IMDs is estimated at 80.3%. That sensitivity will likely be lower for Black infants and those who are on public insurance.