ESPE Yearbook of Paediatric Endocrinology

Nat Genet. Jun;57(6):1334-1343 2025. doi.org/10.1038/s41588-025-02160-y

Brief Summary: This “Perspective” outlines the roadmap for implementing long-read whole genome sequencing (LR-WGS) into clinical diagnostics for rare diseases. The authors highlight the advantages of long-read technologies in overcoming the limitations of short-read sequencing, particularly for detecting complex variants. The authors emphasize the value of generating haplotype-resolved genome assemblies and direct methylation profiling which are critical for the diagnosis of disorders caused by complex or non-coding variation. They also call for the development of standard protocols, quality metrics, and scalable analysis pipelines to enable the routine use of LR-WGS in healthcare settings at reasonable costs.

The paper underscores LR-WGS as a transformative technology that could unify genetic and epigenetic testing into a single, comprehensive diagnostic platform, potentially replacing multiple current methods. LR-WGS can detect previously inaccessible variant types (e.g., repeat expansions, balanced structural variants, methylation changes), thereby improving diagnostic yield for rare diseases. It enables more accurate variant interpretation through phasing and methylation profiling, especially in complex or mosaic cases. The authors suggest that national-scale implementation efforts could serve as models for global adoption.

Still, LR-WGS remains more expensive and labor-intensive than short-read sequencing, with lower throughput and greater computational demands. Its accuracy, particularly for detecting low-level mosaicism or somatic variants, still trails that of some short-read platforms. Moreover, bioinformatics tools and reference databases tailored to long-read data are still in early stages of development. Nevertheless, past advances in genetic technologies have shown that such challenges can be overcome.