Evidence map›Paper›PMID 41233895›Full record

ArticleGenome medicine2025

Exploring the size limits of Bionano optical genome mapping to resolve alternative structures of linked interspersed chromosomal duplications.

Yang Pei, Eduardo Calpena, Jill M Brown, Ron Schwessinger, Lucy Platts, Simon J McGowan, Tazeen Ashraf, Francesca Forzano, Jane A Hurst, Wendy D Jones and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Yang PeiClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.ORCID 0000-0002-0115-5851
Eduardo CalpenaClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Jill M BrownMRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Ron SchwessingerMRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Lucy PlattsRare and Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, WC1N 3JH, UK.
Simon J McGowanCentre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Tazeen AshrafNorth East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, WC1N 3JH, UK.
Francesca ForzanoClinical Genetics Department, Thomas' NHS Foundation Trust, Guy's Hospital, Guy's & St, London, SE1 9RT, UK.
Jane A HurstNorth East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, WC1N 3JH, UK.
Wendy D JonesNorth East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, WC1N 3JH, UK.
Ajoy SarkarClinical Genetics Service, Nottingham University Hospitals NHS Foundation Trust, City Hospital, Nottingham, NG5 1PB, UK.
Richard J GibbonsMRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Stephen R F Twigg *Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.ORCID 0000-0001-5024-049X
Andrew O M Wilkie *Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK. andrew.wilkie@imm.ox.ac.uk.ORCID 0000-0002-2972-5481

Funding

UKRI Medical Research Council MR/T031670/1
6 · The paper itself

Abstract

backgroundDetermining the correct structure of large, interspersed duplications and related complex genomic rearrangements in genetic disease is critical when establishing causal roles and requires a technology able to span the entire duplicated segment(s) on single molecules. We assessed the use of Bionano optical genome mapping (OGM) for this purpose.

methodsWe combined OGM, Illumina short-read sequencing and fluorescence in situ hybridisation (FISH) to characterise three large interspersed duplications/triplications, and used the deepC algorithm to predict impact on local topologically-associating domains (TADs), assisting functional interpretation.

resultsCase 1 harboured paired interspersed duplications (244/323 kb) on chromosome 13. By analysing multiple molecules > 300 kb completely spanning the smaller duplication, we unambiguously determined the correct structure, which potentially alters the TAD containing FGF9, a candidate gene. In Case 2, involving a child with hypertrichosis and gingival hyperplasia (HTC), duplications on chromosomes 16 (2.01 Mb) and 17 (564 kb) were linked on short-read sequencing. By obtaining three OGM molecules spanning the 564 kb segment, we deduced that a t(16;17) translocation was present, which we confirmed by FISH. This interpretation has important implications for clinical risk and highlights KCNJ2 as a potential driver of the HTC3 locus at 17q24.3. Case 3 involved a complex chromoanasynthesis event on chromosome 20. OGM readily resolved all but two of 12 alternative structures; however full resolution required reads to span a 627 kb duplication, which we could not achieve consistently.

conclusionsOGM represents a powerful tool for disambiguating complex structural variants, but requires multiple individual reads to completely span the duplicated segment. In our hands the upper size of duplications that could be resolved was ~ 550 kb. Deducing the correct configuration is critical both for mechanistic understanding of pathogenesis and accurate recurrence risk counselling.

Indexed as

Chromosome DuplicationChromosome MappingHumansIn Situ Hybridization, FluorescenceChromoanasynthesisChromosomal duplicationCraniosynostosisGingival hyperplasiaHTC3HypertrichosisKCNJ2Optical genome mappingTopologically-associating domainTranslocationTriplication

Identifiers

PMID41233895
PMCPMC12616954

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.