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

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

doi:10.1038/s41431-026-02210-x

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

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 (Lead / Corresponding author)

Undergraduate Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Number of pages	11
Journal	European Journal of Human Genetics
DOIs	https://doi.org/10.1038/s41431-026-02210-x
Publication status	Published - 5 Aug 2026

Access to Document

10.1038/s41431-026-02210-xLicence: CC BY

Final published version
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Final published version, 3.17 MBLicence: CC BY

Cite this

Dutta, P., Pagnamenta, A. T., Robert, C., McGuigan, A. E. F., Ross, A., Tobias, E. S., 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., ... Aitman, T. J. (2026). Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project. European Journal of Human Genetics. https://doi.org/10.1038/s41431-026-02210-x

@article{e1d7efdadf294bde9fee1e6ba19f633a,

title = "Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project",

abstract = "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.",

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

note = "{\textcopyright} 2026. The Author(s).",

year = "2026",

month = aug,

day = "5",

doi = "10.1038/s41431-026-02210-x",

language = "English",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature",

}

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 2026, 'Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project', European Journal of Human Genetics. https://doi.org/10.1038/s41431-026-02210-x

TY - JOUR

T1 - Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project

AU - Dutta, Prasun

AU - Pagnamenta, Alistair T

AU - Robert, Christelle

AU - McGuigan, Anthony E F

AU - Ross, Alison

AU - Tobias, Edward S

AU - McGowan, Ruth

AU - Ansari, Morad

AU - Baty, David

AU - Berg, Jonathan

AU - Bradley, Therese

AU - Cerqueira, Vera

AU - Diamond, Austin

AU - Halachev, Mihail

AU - Lampe, Anne

AU - Meynert, Alison

AU - Newman, Caitlin

AU - Thomson, Marian

AU - Trivedi, Urmi

AU - Williams, Nicola

AU - Yu, Jing

AU - Santoyo-Lopez, Javier

AU - Miedzybrodzka, Zosia

AU - Taylor, Jenny C

AU - Aitman, Timothy J

PY - 2026/8/5

Y1 - 2026/8/5

N2 - 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.

AB - 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.

U2 - 10.1038/s41431-026-02210-x

DO - 10.1038/s41431-026-02210-x

M3 - Article

C2 - 42557338

SN - 1018-4813

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

ER -

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

Abstract

Access to Document

Fingerprint

Cite this