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The role of exome sequencing in newborn screening for inborn errors of metabolism
- Source :
- Nat Med, Nature medicine, vol 26, iss 9
- Publication Year :
- 2019
-
Abstract
- Public health newborn screening (NBS) programs provide population-scale ascertainment of rare, treatable conditions that require urgent intervention. Tandem mass spectrometry (MS/MS) is currently used to screen newborns for a panel of rare inborn errors of metabolism (IEMs)1–4. The NBSeq project evaluated whole-exome sequencing (WES) as an innovative methodology for NBS. We obtained archived residual dried blood spots and data for nearly all IEM cases from the 4.5 million infants born in California between mid-2005 and 2013 and from some infants who screened positive by MS/MS, but were unaffected upon follow-up testing. WES had an overall sensitivity of 88% and specificity of 98.4%, compared to 99.0% and 99.8%, respectively for MS/MS, although effectiveness varied among individual IEMs. Thus, WES alone was insufficiently sensitive or specific to be a primary screen for most NBS IEMs. However, as a secondary test for infants with abnormal MS/MS screens, WES could reduce false-positive results, facilitate timely case resolution and in some instances even suggest more appropriate or specific diagnosis than that initially obtained. This study represents the largest, to date, sequencing effort of an entire population of IEM-affected cases, allowing unbiased assessment of current capabilities of WES as a tool for population screening. Whole-exome sequencing is not sensitive or specific enough to replace the gold standard of tandem mass spectrometry screening of rare inborn errors of metabolism, but can help to reduce false positives and facilitate the timely resolution of ambiguous cases.
- Subjects :
- 0301 basic medicine
Pediatrics
medicine.medical_specialty
Immunology
Medical and Health Sciences
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
0302 clinical medicine
Neonatal Screening
Clinical Research
Tandem Mass Spectrometry
Infant Mortality
Exome Sequencing
Genetics
medicine
False positive paradox
Humans
Exome
Genetic Testing
Dried blood
Exome sequencing
Genetic testing
Pediatric
screening and diagnosis
Newborn screening
Entire population
medicine.diagnostic_test
business.industry
Inborn Errors
Prevention
Infant, Newborn
Infant
General Medicine
Gold standard (test)
Perinatal Period - Conditions Originating in Perinatal Period
Newborn
Detection
Metabolism
030104 developmental biology
030220 oncology & carcinogenesis
4.4 Population screening
Population screening
business
Metabolism, Inborn Errors
4.2 Evaluation of markers and technologies
Subjects
Details
- ISSN :
- 1546170X
- Volume :
- 26
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Nature medicine
- Accession number :
- edsair.doi.dedup.....ccb833efbb18add6c94e90befc9a4bfd