Yonsei Med J.  2018 Jul;59(5):652-661. 10.3349/ymj.2018.59.5.652.

A New Integrated Newborn Screening Workflow Can Provide a Shortcut to Differential Diagnosis and Confirmation of Inherited Metabolic Diseases

Affiliations
  • 1Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.
  • 2SD Genomics Co., Ltd., Seoul, Korea.
  • 3Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea. KAL1119@yuhs.ac
  • 4Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
  • 5Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. kimjw@skku.edu

Abstract

PURPOSE
We developed a new workflow design which included results from both biochemical and targeted gene sequencing analysis interpreted comprehensively. We then conducted a pilot study to evaluate the benefit of this new approach in newborn screening (NBS) and demonstrated the efficiency of this workflow in detecting causative genetic variants.
MATERIALS AND METHODS
Ten patients in Group 1 were diagnosed clinically using biochemical assays only, and 10 newborns in Group 2 were diagnosed with suspected inherited metabolic disease (IMD) in NBS. We applied NewbornDiscovery (SD Genomics), an integrated workflow design that encompasses analyte-phenotype-gene, single nucleotide variant/small insertion and deletion/copy number variation analyses along with clinical interpretation of genetic variants related to each participant's condition.
RESULTS
A molecular genetic diagnosis was established in 95% (19/20) of individuals. In Group 1, 13 and 7 of 20 alleles were classified as pathogenic and likely pathogenic, respectively. In Group 2, 11 and 6 of 17 alleles with identified causative variants were pathogenic and likely pathogenic, respectively. There were no variants of uncertain significance. For each individual, the NewbornDiscovery and biochemical analysis results reached 100% concordance, since the single newborn testing negative for causative genetic variant in Group 2 showed a benign clinical course.
CONCLUSION
This integrated diagnostic workflow resulted in a high yield. This approach not only enabled early confirmation of specific IMD, but also detected conditions not included in the current NBS.

Keyword

Newborn screening; inherited metabolic disease; dried blood spot; targeted gene panel sequencing; next-generation sequencing

MeSH Terms

Alleles
Diagnosis
Diagnosis, Differential*
Humans
Infant, Newborn*
Mass Screening*
Metabolic Diseases*
Molecular Biology
Pilot Projects
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