1. The role of exome sequencing in newborn screening for inborn errors of metabolism
- Author
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Aashish N. Adhikari, Pui-Yan Kwok, Joseph T. Shieh, Kunal Kundu, Mark N. Kvale, Barbara A. Koenig, Robert L. Nussbaum, Hao Tang, Robert J. Currier, Flavia Chen, Dedeepya Vaka, Rajgopal Srinivasan, Steven E. Brenner, Yaqiong Wang, Laia Bassaganyas, Yangyun Zou, Jeremy R. Sanford, Uma Sunderam, Savanna S. Randi, Renata C. Gallagher, George S. Amatuni, Sean D. Mooney, Jennifer M. Puck, and Neil Risch
- 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 - 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.
- Published
- 2019