Methods and feasibility study for exome sequencing as a universal second-tier test in newborn screening
| Autor: | Jordan Little, David W. Sant, Warunee Dansithong, Erin L Young, Krystal Y. Chung, Kim Hart, Andreas Rohrwasser, Bryce Asay, Stevie Norcross, Kelly F. Oakeson, Nicole Ruiz-Schultz, Karen Eilbeck |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Sanger sequencing Newborn screening Pipeline (computing) In silico Concordance Infant Newborn High-Throughput Nucleotide Sequencing Computational biology 030105 genetics & heredity Biology Database normalization 03 medical and health sciences symbols.namesake Neonatal Screening 030104 developmental biology Exome Sequencing symbols Feasibility Studies Humans Exome Genetics (clinical) Exome sequencing |
| Zdroj: | Genetics in Medicine. 23:767-776 |
| ISSN: | 1098-3600 |
| Popis: | Purpose Newborn screening disorders increasingly require genetic variant analysis as part of second-tier or confirmatory testing. Sanger sequencing and gene-specific next-generation sequencing (NGS)-based tests, the current methods of choice, are costly and lack scalability when expanding to new conditions. We describe a scalable, exome sequencing-based NGS pipeline with a priori analysis restriction that can be universally applied to any NBS disorder. Methods De-identified abnormal newborn screening specimens representing severe combined immune deficiency (SCID), cystic fibrosis (CF), VLCAD deficiency, metachromatic leukodystrophy (MLD), and in silico sequence read data sets were used to validate the pipeline. To support interpretation and clinical decision-making within the bioinformatics pipeline, variants from multiple databases were curated and validated. Results CFTR variant panel analysis correctly identified all variants. Concordance compared with diagnostic testing results for targeted gene analysis was between 78.6% and 100%. Validation of the bioinformatics pipeline with in silico data sets revealed a 100% detection rate. Varying degrees of overlap were observed between ClinVar and other databases ranging from 3% to 65%. Data normalization revealed that 11% of variants across the databases required manual curation. Conclusion This pipeline allows for restriction of analysis to variants within a single gene or multiple genes, and can be readily expanded to full exome analysis if clinically indicated and parental consent is granted. |
| Databáze: | OpenAIRE |
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