Genome sequencing as a first-line diagnostic test for hospitalized newborns

Purpose: SouthSeq, a translational research study to perform genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder, was conducted in NICUs in the Southeastern US. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas that are historically under-represented in genomic medicine research. Methods: GS and analysis were performed for 367 newborns to detect disease-causal genetic variation concurrent with standard of care clinical evaluation and testing. Results: Definitive diagnostic (DD) or likely diagnostic (LD) genetic findings were identified in 109 newborns (30%) and 51 (14%) were found to harbor an uncertain result. Only 39% of SouthSeq GS-detected DD/LD findings were identified via concurrent standard of care suggesting that GS testing is better for obtaining early genetic diagnosis. We also identified phenotypes that correlate with the likelihood of receiving a DD/LD finding, such as craniofacial, ophthalmologic, auditory, skin, and hair abnormalities. We did not observe any differences in diagnostic rates between racial/ethnic groups, although there did exist significant procedural differences such as in the numbers of variants requiring manual curation and orthogonal testing. Conclusion: We describe one of the largest to-date GS cohorts of ill newborns, recruited from across the Southeast US and enriched for African American and rural patients. Our results demonstrate the utility of GS as it provides early in life detection of clinically relevant genetic variation not identified via current standard clinical testing, particularly for newborns exhibiting certain phenotypic features.