Evidence map›Paper›PMID 41935954›Full record

ArticleHGG advances2026

Exome sequencing early in outpatient evaluation in NCGENES 2: Changing the course of the diagnostic odyssey?

Tamara S Roman, Shannon M Gray, Tam P Sneddon, Ann Katherine M Foreman, Kristy Lee, Cynthia M Powell, Karen E Weck, Jonathan S Berg, Bradford C Powell

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in HGG advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

9 authors.

Tamara S RomanDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Shannon M GrayDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Tam P SneddonDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ann Katherine M ForemanDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kristy LeeDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Cynthia M PowellDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Karen E WeckDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jonathan S BergDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Bradford C PowellDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: bpow@unc.edu.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The impact of clinical exome and genome sequencing (ES/GS) depends on the clinical setting. In the sequencing arm of a multifactor randomized clinical trial to evaluate broadening access, we assessed the diagnostic and inconclusive findings of ES as a "first-tier" test in 101 pediatric participants in whom suspicion of a genetic condition by primary care providers had prompted initial outpatient consultation in a pediatric genetics or neurology clinic. This implementation focused on the early stages of the diagnostic odyssey, capturing a clinically less-selected population with lower pre-test probability than traditional specialist cohorts. Variants were prioritized using phenotype-driven gene lists. After returning the results to participants, the clinical teams performed familial variant testing or additional phenotyping at their discretion, based on potential diagnostic benefit. We then implemented a multidisciplinary case conference in which the laboratory and clinical teams assessed additional clinical information. Initially, 57% of participants had non-negative reports: 5% had one or more variant findings considered explanatory for the presenting phenotype, with 52% having results initially classified as inconclusive. After family testing and/or phenotypic characterization, a total of 9% were considered positive/diagnostic, 10% were reclassified from inconclusive to negative, and 38% remained inconclusive. While ES, as a first-tier genetic test, can expedite some diagnoses, these results demonstrate challenges in early implementation. In this population, initial testing can leave substantial residual uncertainty, shifting the diagnostic odyssey rather than concluding it and necessitating factors such as parental testing, ongoing phenotyping, and reassessment of variants over time to resolve inconclusive results.

Indexed as

ExomeExome SequencingGenetic TestingOutpatientsChildChild, PreschoolFemaleHumansMalePhenotypediagnostic odysseygenomic sequencingreverse phenotyping

Identifiers

PMID41935954
PMCPMC13137186

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Registered trials

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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.