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<p>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 <i>AUTS2</i> inversion, a <i>DLX5/6</i> locus inversion, and an <i>FN1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Prasun Dutta,
  • Alistair T. Pagnamenta,
  • Christelle Robert,
  • Anthony E. F. McGuigan,
  • Alison Ross,
  • Edward S. Tobias,
  • Ruth McGowan,
  • Morad Ansari,
  • David Baty,
  • Jonathan Berg,
  • Therese Bradley,
  • Vera Cerqueira,
  • Austin Diamond,
  • Mihail Halachev,
  • Anne Lampe,
  • Alison Meynert,
  • Caitlin Newman,
  • Marian Thomson,
  • Urmi Trivedi,
  • Nicola Williams,
  • Jing Yu,
  • Javier Santoyo-Lopez,
  • Zosia Miedzybrodzka,
  • Jenny C. Taylor,
  • Timothy J. Aitman

摘要

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.