Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project.

Dutta P., Pagnamenta AT., Robert C., McGuigan AEF., Ross A., Tobias ES., McGowan R., Ansari M., Baty D., Berg J., Bradley T., Cerqueira V., Diamond A., Halachev M., Lampe A., Meynert A., Newman C., Thomson M., Trivedi U., Williams N., Yu J., Santoyo-Lopez J., Miedzybrodzka Z., Taylor JC., Aitman TJ.

Whole-genome sequencing (WGS) projects for rare disease diagnosis typically yield a diagnostic rate of 25-41%, depending on the methods for patient selection and the extent of prior genetic testing. The Scottish Genomes Partnership (SGP) is a collaborative programme using genome sequencing to diagnose rare disease patients with presumed monogenic aetiology in the Scottish NHS. Within SGP, short-read sequencing (SRS) had previously achieved a diagnostic rate of 23% in affected families. To increase diagnostic yield, we applied Oxford Nanopore Technologies (ONT) long-read sequencing (LRS) to a cohort of 24 SGP families (74 individuals) that remained undiagnosed after SRS-based SNV/indel analysis. We also retrospectively reviewed SRS-derived structural variant (SV) calls to assess whether LRS results could have been detected in SRS data. After quality, rarity, panel-based and inheritance-based filtering, 392 candidate SVs were retained across de novo, homozygous recessive, compound heterozygous and X-linked inheritance models, of which 8 overlapped PanelApp diagnostic-grade "green" genes. Pathogenic or likely pathogenic de novo SVs were identified in 3 of 24 families: an AUTS2 inversion, a DLX5/6 locus inversion, and an FN1 deletion. All three SVs were independently confirmed by retrospective SRS re-analysis using SVRare. These findings demonstrate that LRS-based SV analysis, supported by orthogonal SRS re-analysis, can resolve clinically significant SVs in families who remain unsolved after standard rare disease testing.

DOI

10.1038/s41431-026-02210-x

Type

Journal article

Publication Date

2026-08-01T00:00:00+00:00

Addresses

Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

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