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Genet Med. 2015 May;17(5):337-47. doi: 10.1038/gim.2014.117. Epub 2014 Sep 25.

Development of DNA confirmatory and high-risk diagnostic testing for newborns using targeted next-generation DNA sequencing.

Author information

1
Parabase Genomics, Boston, Massachusetts, USA.
2
Omicia, Oakland, California, USA.
3
Clinic for Special Children, Strasburg, Pennsylvania, USA.
4
Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
5
1] Parabase Genomics, Boston, Massachusetts, USA [2] Division of Genetics, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA.

Abstract

PURPOSE:

Genetic testing is routinely used for second-tier confirmation of newborn sequencing results to rule out false positives and to confirm diagnoses in newborns undergoing inpatient and outpatient care. We developed a targeted next-generation sequencing panel coupled with a variant processing pipeline and demonstrated utility and performance benchmarks across multiple newborn disease presentations in a retrospective clinical study.

METHODS:

The test utilizes an in silico gene filter that focuses directly on 126 genes related to newborn screening diseases and is applied to the exome or a next-generation sequencing panel called NBDx. NBDx targets the 126 genes and additional newborn-specific disorders. It integrates DNA isolation from minimally invasive biological specimens, targeted next-generation screening, and rapid characterization of genetic variation.

RESULTS:

We report a rapid parallel processing of 8 to 20 cases within 105 hours with high coverage on our NBDx panel. Analytical sensitivity of 99.8% was observed across known mutation hotspots. Concordance calls with or without clinical summaries were 94% and 75%, respectively.

CONCLUSION:

Rapid, automated targeted next-generation sequencing and analysis are practical in newborns for second-tier confirmation and neonatal intensive care unit diagnoses, laying a foundation for future primary DNA-based molecular screening of additional disorders and improving existing molecular testing options for newborns.

PMID:
25255367
DOI:
10.1038/gim.2014.117
[Indexed for MEDLINE]

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