A New Integrated Newborn Screening Workflow Can Provide a Shortcut to Differential Diagnosis and Confirmation of Inherited Metabolic Diseases
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Purpose: We developed a new workflow design which included results from both biochemical and targeted gene sequencinganalysis interpreted comprehensively. We then conducted a pilot study to evaluate the benefit of this new approach in newbornscreening (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 inGroup 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 classifiedas pathogenic and likely pathogenic, respectively. In Group 2, 11 and 6 of 17 alleles with identified causative variants werepathogenic and likely pathogenic, respectively. There were no variants of uncertain significance. For each individual, the NewbornDiscoveryand biochemical analysis results reached 100% concordance, since the single newborn testing negative for causativegenetic 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 ofspecific IMD, but also detected conditions not included in the current NBS.
Abstract
Purpose: We developed a new workflow design which included results from both biochemical and targeted gene sequencinganalysis interpreted comprehensively. We then conducted a pilot study to evaluate the benefit of this new approach in newbornscreening (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 inGroup 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 classifiedas pathogenic and likely pathogenic, respectively. In Group 2, 11 and 6 of 17 alleles with identified causative variants werepathogenic and likely pathogenic, respectively. There were no variants of uncertain significance. For each individual, the NewbornDiscoveryand biochemical analysis results reached 100% concordance, since the single newborn testing negative for causativegenetic 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 ofspecific IMD, but also detected conditions not included in the current NBS.
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