Application of a targeted next generation sequencing panel for newborn screening

Abstract

Background: Newborn screening (NBS) programs are very important for appropriate management of susceptible neonates to prevent serious clinical problems. However, current biochemical screening programs can provide some rates of false-positive results. After total parenteral nutrition is completely off, repetitive NBS scheduled for neonates admitted in neonatal intensive care unit (NICU) results in delayed diagnosis. Therefore, confirmatory tests are required to precisely identify all affected neonates, and to diagnosis or rule out suspected diseases. Here, we propose a workflow to complement NBS using a targeted next-generation sequencing (TNGS) panel for the early diagnosis of inherited metabolic disorders and for ruling out suspected diseases in high-risk neonates. Material and Methods: The TNGS panel covered 198 genes associated with actionable genetic and metabolic diseases that are typically included in a NBS program in Korea, using tandem mass spectrometry. The panel was applied to 48 infants admitted to the NICU of Severance Children’s Hospital, Seoul, Korea, between May 2017 and September 2017. The infants were not selected for suspected metabolic disorders. Results: A total of 13 variants classified as likely pathogenic or pathogenic were detected in 11 (22.9%) neonates, including six genes (DHCR7, PCBD1, GAA, ALDOB, ATP7B and GBA) associated with metabolic diseases not covered in NBS. However, since these metabolic diseases are inherited as autosomal recessive, newborns with one variant have been identified as carriers. One of the 48 infants was diagnosed with an isobutyl-CoA dehydrogenase deficiency, and false positive results of tandem mass screening were confirmed in two infants using the TNGS panel. Conclusion: The proposed new workflow for the implementation of TNGS in conjunction with conventional NBS can allow for better management of and earlier diagnosis in susceptible infants, thus preventing the development of critical conditions in these infants.