Evidence map›Paper›PMID 40963120›Full record

ArticleGenome medicine2025

Evaluating genome sequencing strategies: trio, singleton, and standard testing in rare disease diagnosis.

Daniel Kaschta, Christina Post, Franziska Gaass, Milad Al-Tawil, Vincent Arriens, Saranya Balachandran, Tobias Bäumer, Valerie Berge, Friederike Birgel, Andreas Dalski and 57 more

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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 9 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed, 1 pooled it
–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

9 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Trial
  3. Article
  4. Review
  5. Article
  6. Mainstreaming genomic testing for mitochondrial disease in Australia.European journal of human genetics : EJHG · 2026
    Article
  7. Article
  8. Review
  9. 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

67 authors.

Daniel KaschtaInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Christina PostInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Franziska GaassInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Milad Al-TawilDepartment of Neonatology and Pediatric Intensive Care Medicine, Westphalian Children's Center Dortmund, University of Witten-Herdecke, Witten, Germany.
Vincent ArriensInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Saranya BalachandranInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Tobias BäumerInstitute of Systems Motor Science, University Medical Center Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
Valerie BergeInstitute of Medical Genetics, University of Zürich, Zurich, Switzerland.
Friederike BirgelInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Andreas DalskiInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Maike DittmarInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Andre FrankeInstitute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Sören FranzenburgInstitute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Janina FußInstitute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Bettina GehringNeurology Center, Itzehoe, Germany.
Rebecca GembickiInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Bianca GreitenInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Kristin GrohteInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Britta HankerInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Kristian HändlerInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Lana HarderInstitute of Tumorgenetic Nord, Kiel, Germany.
Yorck HellenbroichInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Theresia HergetInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Gloria HerrmannDivision of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
Olaf HiortDivision of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, University of Lübeck, Lübeck, Germany.
Kirstin HoffInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Birga HoffmannPractice for Neuropaediatrics, Lüneburg, Germany.
Nadine HornigInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Irina HüningInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Monika Kautza-LuchtInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Juliane KöhlerInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Anna-Sophie LiegmannInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Jasmin LisfeldInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Britt-Sabina LöscherInstitute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Nils G MargrafEpilepsy Center Kiel, Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.
Michelle MeyenborgInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Anna MöllringInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hiltrud MuhleDepartment of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.
Eva Maria Murga PenasInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Henning NommelsGroup Practice for Pediatrics and Adolescent Medicine, Husum, Germany.
Dzhoy PapingiInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Imke PoggenburgPractice for Neuropaediatrics, Lüneburg, Germany.
Jelena PozojevicInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Philip RosenstielInstitute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Andreas ReckeDepartment of Dermatology, Allergology and Venereology, University Medical Center Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
Kimberly RobertsDepartment of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.
Laelia RöslerInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Franka RustInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Maj-Britt SalewskiInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Katharina Schau-RömerInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Christian SchleinInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Varun K A SreenivasanInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Louiza ToutounaInstitute of Human Genetics, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Caroline Utermann-ThüsingInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Amelie T van der VenInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Alexander E VolkInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Janne WehnertInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Sandra WilsonInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Rixa WoitschachInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Veronica YumicebaInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Christine ZühlkeInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Alexander MünchauInstitute of Systems Motor Science, University Medical Center Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
Norbert BrüggemannSection for Movement Disorder, Department of Neurology, University Medical Center Schleswig-Holstein, University of Lübeck, Lübeck, Germany.
Inga VaterInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Almuth CaliebeInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany.
Inga NagelInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany. Inga.nagel@uksh.de.
Malte SpielmannInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University, Lübeck, Germany. malte.spielmann@uksh.de.

Funding

M.S. is a DZHK principal investigator and is supported by grants from the Deutsche Forschungsgemeinschaft (DFG; SP1532/13-1, SP1532/3-2 and SP1532/5-1)
6 · The paper itself

Abstract

backgroundShort-read genome sequencing (GS) is among the most comprehensive genetic testing methods available, capable of detecting single-nucleotide variants, copy-number variants, mitochondrial variants, repeat expansions, and structural variants in a single assay. Despite its technical advantages, the full clinical utility of GS in real-world diagnostic settings remains to be fully established.

methodsThis study systematically compared singleton GS (sGS), trio GS (tGS), and exome sequencing-based standard-of-care (SoC) genetic testing in 416 patients with rare diseases in a blinded, prospective study. Three independent teams with divergent baseline expertise evaluated the diagnostic yield of GS as a unifying first-tier test and directly compared its variant detection capabilities, learning curve, and clinical feasibility. The SoC team had extensive prior experience in exome-based diagnostics, while the sGS and tGS teams were newly trained in GS interpretation. Diagnostic yield was assessed through both prospective and retrospective analyses.

resultsIn our prospective analysis, tGS achieved the highest diagnostic yield for likely pathogenic/pathogenic variants at 36.1% in the newly trained team, surpassing the experienced SoC team at 35.1% and the newly trained sGS team at 28.8%. To evaluate which variants could technically be identified and account for differences in team experience, we conducted a retrospective analysis, achieving diagnostic yields of 36.7% for SoC, 39.1% for sGS, and 40.0% for tGS. The superior yield of GS was attributed to its ability to detect deep intronic, non-coding, and small copy-number variants missed by SoC. Notably, tGS identified three de novo variants classified as likely pathogenic based on recent GeneMatcher collaborations and newly published gene-disease association studies.

conclusionsOur findings demonstrate that GS, particularly tGS, outperforms SoC in diagnosing rare diseases, with sGS providing a more cost-effective alternative. These results suggest that GS should be considered a first-tier genetic test, offering an efficient, single-step approach to reduce the diagnostic odyssey for patients with rare diseases. The trio approach proved especially valuable for less experienced teams, as inheritance data facilitated variant interpretation and maintained high diagnostic yield, while experienced teams achieved comparable results with singleton analysis alone.

Indexed as

Genetic TestingGenome, HumanRare DiseasesWhole Genome SequencingDNA Copy Number VariationsExome SequencingFemaleHumansMaleProspective StudiesSequence Analysis, DNADiagnostic yieldExome sequencingGenome sequencingRare diseaseStandard of care

Identifiers

PMID40963120
PMCPMC12445032

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