Balanced translocation (BT) carriers have a high risk of recurrent miscarriage and abnormal offspring due to unbalanced gamete production. Clinical genetic testing often fails to detect BTs that fall below microscopic resolution or occur in repetitive genomic regions. Long-read sequencing technologies can overcome these limitations by spanning large genomic segments, but whole-genome long-read sequencing remains costly and data-intensive. Nanopore adaptive sampling sequencing, a computational enrichment technique, enables selective sequencing of target regions, offering a cost-effective and flexible alternative. We aimed to assess the efficacy of adaptive sampling for detecting BTs.
Fourteen participants from eight families with suspected BTs were recruited. Peripheral blood samples from parents were subjected to nanopore adaptive sampling sequencing. Karyotyping and Sanger sequencing were performed to confirm the detected breakpoints.
Adaptive sampling accurately identified all BT breakpoints in eight families, with translocated fragment sizes ranging from 0.8 to 18 Mb. Our data suggested that a 500 kb flanking region at 20X depth was sufficient for detection, while a 5 Mb region at 15X depth provided enough efficiency. The method achieved comparable sequencing depth to whole-genome long-read sequencing but with reduced data output and lower cost.
Nanopore adaptive sampling sequencing enables high-resolution, cost-effective detection of submicroscopic BTs, offering a practical alternative to whole-genome long-read sequencing. This clinical workflow is suitable for cases in which candidate BT regions have been indicated by prior genetic testing.