Combinatorial batching of DNA for ultralow-cost detection of pathogenic variants

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt


  • Fulltext

    Forlagets udgivne version, 2,16 MB, PDF-dokument

Background: Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but the costs associated with screening millions of humans remain prohibitive. New methods for population genetic testing that lower the costs of NGS without compromising diagnostic power are needed. Methods: We developed double batched sequencing where DNA samples are batch-sequenced twice — directly pinpointing individuals with rare variants. We sequenced batches of at-birth blood spot DNA using a commercial 113-gene panel in an explorative (n = 100) and a validation (n = 100) cohort of children who went on to develop pediatric cancers. All results were benchmarked against individual whole genome sequencing data. Results: We demonstrated fully replicable detection of cancer-causing germline variants, with positive and negative predictive values of 100% (95% CI, 0.91–1.00 and 95% CI, 0.98–1.00, respectively). Pathogenic and clinically actionable variants were detected in RB1, TP53, BRCA2, APC, and 19 other genes. Analyses of larger batches indicated that our approach is highly scalable, yielding more than 95% cost reduction or less than 3 cents per gene screened for rare disease-causing mutations. We also show that double batched sequencing could cost-effectively prevent childhood cancer deaths through broad genomic testing. Conclusions: Our ultracheap genetic diagnostic method, which uses existing sequencing hardware and standard newborn blood spots, should readily open up opportunities for population-wide risk stratification using genetic screening across many fields of clinical genetics and genomics.

TidsskriftGenome Medicine
Antal sider12
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
This study received financial support from the Danish Childhood Cancer Foundation, the Danish Childhood Brain Tumour Foundation, the Danish Cancer Society, and the European Union’s Interregional Oresund–Kattegat–Skagerrak grant. Funding bodies had no influence on the design of the study, the collection, analysis, and interpretation of data, or the writing of the manuscript. S.R. was personally supported by the Novo Nordisk Foundation (grant NNF14CC0001).

Publisher Copyright:
© 2023, The Author(s).

Antal downloads er baseret på statistik fra Google Scholar og

Ingen data tilgængelig

ID: 341019222