Language
English
Publication Date
9-4-2026
Journal
Nature Communications
DOI
10.1038/s41467-026-77535-8
PMID
42838976
PMCID
PMC13642241
PubMedCentral® Posted Date
9-4-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Rare diseases often remain unsolved because causal genetic changes can be complex and thus missed by standard sequencing or difficult to prioritize. Long-read sequencing can reveal structural variants, repeat expansions, DNA methylation and inherited haplotypes, but trio sequencing of an affected child and both parents remains costly. Here we show that phenotype-driven Trio-barcoded Oxford Nanopore Adaptive Sequencing (TBAS) enables cost-efficient long-read analysis of rare-disease trios on one flow cell. TBAS workflow uses clinical features to select broad disease-gene panels, barcodes all three family members and enriches these regions during sequencing rather than targeting a known causal locus. In benchmark regions, TBAS increased coverage and accurately detected small variants, structural variants, tandem repeat expansions, methylation and read-backed phasing, while reducing estimated sequencing consumable costs to 32.2% of conventional three-flow-cell trio long-read sequencing. Across 13 trios, TBAS recovered all five known diagnoses and prioritized candidates in five of eight unresolved cases.
Keywords
Humans, Rare Diseases, Cost-Benefit Analysis, Sequence Analysis, DNA, High-Throughput Nucleotide Sequencing, Nanopore Sequencing, DNA Methylation, Haplotypes, Genome informatics, Biotechnology, Genetics
Published Open-Access
yes
Recommended Citation
Fu, Yilei; English, Adam C; Paulin, Luis F; et al., "Cost-Efficient Long-Read Trio-Barcoded Adaptive Sequencing Improves Rare Disease Diagnosis" (2026). Faculty, Staff and Students Publications. 8658.
https://digitalcommons.library.tmc.edu/baylor_docs/8658