HiFi Long-Reads Uncover Elusive Variants in Rare Diseases

High-fidelity (HiFi) long-read whole-genome sequencing is proving transformative for detecting variants that short-read methods often miss. In this study, researchers sequenced 100 samples containing 145 known pathogenic variants and successfully identified 93% of them, including structural variants, complex insertions/deletions, and repeat expansions. Many of these variants are difficult or impossible to detect with short-read sequencing, highlighting the unique power of long reads. Even at lower coverage, most variants remained detectable, demonstrating the method’s efficiency and robustness.

These results showcase the power of long-read sequencing to provide comprehensive, single-test detection of challenging variants, offering a promising path for rare disease diagnostics and reducing the need for multiple complementary assays. By capturing complex genomic features missed by short reads, HiFi long reads open new possibilities for understanding disease mechanisms and improving patient care.

(A) Pie chart depicting the cohort composition by variant type for all 145 variants. The number of samples is indicated within parentheses. (B) Different test modalities (y axis) that were used in a diagnostic laboratory to identify all 145 clinically relevant variants in the 100 selected samples (x axis). The number of assays required per patient is shown in an inlay pie chart. (C) Sensitivity of LRS by automated variant detection and visual inspection for all 145 variants from 100 analyzed samples (x axis), stratified by a priori known disease-associated variant types (y axis). LRS-based detection rates are indicated in green (detected by a variant caller, 83% [n = 120]), orange (detection by visual read inspection, 10% [n = 14]), and red (undetected variant, 7% [n = 11]).

Read more: https://www.cell.com/ajhg/fulltext/S0002-9297%2824%2900455-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0002929724004555%3Fshowall%3Dtrue