Evidence map›Paper›PMID 40571398›Full record

ArticleJournal of medical genetics2025

Long-read DNA and RNA sequencing for inherited polyposis and colorectal cancer: cryptic intronic variants and multiple mutational mechanisms.

Angela L Jacobson, Amal AbuRayyan, Suleyman Gulsuner, Haley Slater, Yagiz Anasiz, Sirajummuneer M Ahmad, Ming K Lee, Jessica Mandell, Emily J Rettner, Eric Q Konnick and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of medical genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. 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.

Angela L JacobsonDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0000-0002-6565-1459
Amal AbuRayyanDepartments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0000-0002-8061-5173
Suleyman GulsunerDepartments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0000-0002-3897-1238
Haley SlaterDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0009-0000-3717-8724
Yagiz AnasizDepartments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0000-0001-6055-7167
Sirajummuneer M AhmadDepartments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0009-0005-1222-6570
Ming K LeeDepartments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0000-0002-2568-351X
Jessica MandellDepartments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0009-0002-7229-299X
Emily J RettnerOakland Medical Center, Kaiser Foundation Hospitals, Oakland, California, USA.ORCID http://orcid.org/0009-0007-6930-5004
Eric Q KonnickDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0000-0001-5904-1788
Colin PritchardDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0000-0002-2461-1557
Mary-Claire KingDepartments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA mcking@uw.edu.ORCID http://orcid.org/0000-0001-9426-1743
Tom WalshDepartments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington, USA.ORCID http://orcid.org/0000-0002-8875-0310
Brian H ShirtsDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.ORCID http://orcid.org/0000-0002-7188-6764

Funding

Medical Genetics Training GrantT32GM007454 · NIGMS · UNIVERSITY OF WASHINGTON · PI Gail Pairitz Jarvik, Andrew Ben Stergachis · 1985 to 2026
$6.9M
Genomic Analysis of Inherited Breast and Ovarian CancerR01CA292733 · NCI · UNIVERSITY OF WASHINGTON · PI MARY-CLAIRE KING, Tom Walsh · 2024 to 2026
$3.2M
NCI NIH HHS R01 CA292733NIGMS NIH HHS T32 GM007454
6 · The paper itself

Abstract

backgroundMolecular genetic diagnoses are critical to prevention and treatment of inherited polyposis and colorectal cancer. 19 genes responsible for these conditions are known, but many severely affected patients and families remain unsolved. Cryptic intronic variants that alter splicing of these genes and incomplete characterisation of recessive predisposition contribute to these diagnostic gaps.

methodsAdaptive sampling long-read DNA sequencing targeted to 19 colon cancer genes, paired with direct long-read RNA whole-transcriptome sequencing, was undertaken for four patients referred for deficiency of mismatch repair proteins and/or familial polyposis, for whom multigene panel testing yielded negative or uncertain germline results.

resultsGenetic diagnoses were obtained for all four patients. Each patient carried a cryptic intronic germline variant in a different colon cancer gene. The variants abrogated splicing by various mechanisms, all leading to loss of gene function. Patient 1 was heterozygous for intronic insertion into

conclusionPaired long-read DNA and RNA sequencing can enhance diagnostic yield through detection of cryptic intronic variants that impact cancer predisposition.

Indexed as

Adenomatous Polyposis ColiColorectal NeoplasmsAdultFemaleGenetic Predisposition to DiseaseGerm-Line MutationHumansIntronsMaleMiddle AgedMutationPedigreeRNA SplicingSequence Analysis, RNAGeneticsGenomicsMutationNanopore SequencingSequence Deletion

Identifiers

PMID40571398
PMCPMC12318545

What OpenQuestion holds

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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.