Evidence map›Paper›PMID 40927908›Full record

ArticleGenetics in medicine : official journal of the American College of Medical Genetics2025

Genome sequencing reveals the impact of pseudoexons in rare genetic disease.

Georgia Pitsava, Megan Hawley, Light Auriga, Ivan de Dios, Arthur Ko, Sofia Marmolejos, Miguel Almalvez, Ingrid Chen, Kaylee Scozzaro, Jianhua Zhao and 16 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing 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

2 citing papers in PubMed.

  1. Review
  2. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

26 authors.

Georgia PitsavaInstitute for Clinical and Translational Science, University of California, Irvine, CA.
Megan HawleyLabcorp Genetics Inc, Burlington, NC.
Light AurigaInstitute for Clinical and Translational Science, University of California, Irvine, CA.
Ivan de DiosInstitute for Clinical and Translational Science, University of California, Irvine, CA.
Arthur KoCenter for Genetic Medicine Research, Children's National Research Institute, Washington, DC.
Sofia MarmolejosCenter for Genetic Medicine Research, Children's National Research Institute, Washington, DC.
Miguel AlmalvezInstitute for Clinical and Translational Science, University of California, Irvine, CA.
Ingrid ChenLabcorp Genetics Inc, Burlington, NC.
Kaylee ScozzaroLabcorp Genetics Inc, Burlington, NC.
Jianhua ZhaoLabcorp Genetics Inc, Burlington, NC.
Rebekah BarrickDivision of Metabolic Disorders, Children's Hospital of Orange County (CHOC), Orange, CA.
Nicholas Ah MewCenter for Genetic Medicine Research, Children's National Research Institute, Washington, DC; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC.
Vincent A FusaroInstitute for Clinical and Translational Science, University of California, Irvine, CA.
Jonathan LoTempioInstitute for Clinical and Translational Science, University of California, Irvine, CA.
Matthew TaylorCardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO.
Luisa MestroniCardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO.
Sharon GrawCardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO.
Dianna MilewiczDivision of Medical Genetics, University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Houston, TX.
Dongchuan GuoDivision of Medical Genetics, University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Houston, TX.
David R MurdockDivision of Medical Genetics, University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School, Houston, TX.
Kinga M BujakowskaOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA.
UCI-GREGoR Consortium
Changrui XiaoDepartment of Neurology, University of California, Irvine, CA.
Emmanuèle C DélotInstitute for Clinical and Translational Science, University of California, Irvine, CA.
Seth I BergerCenter for Genetic Medicine Research, Children's National Research Institute, Washington, DC; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC. Electronic address: sberger@childrensnational.org.
Eric VilainInstitute for Clinical and Translational Science, University of California, Irvine, CA.

Funding

P30 Core Grant for Vision ResearchP30EY014104 · NEI · MASSACHUSETTS EYE AND EAR INFIRMARY · PI Janey L Wiggs · 2002 to 2026
$15.1M
University of Washington (UW) Mendelian Genomics Data Coordinating CenterU24HG011746 · NHGRI · UNIVERSITY OF WASHINGTON · PI Susanne May, ALI SHOJAIE · 2021 to 2026
$14.8M
Pediatric Mendelian Genomics Research CenterU01HG011745 · NHGRI · UNIVERSITY OF CALIFORNIA-IRVINE · PI Eric J. Vilain · 2021 to 2026
$13.3M
Finding Missing Genetic Causality of Inherited Retinal DegenerationsR01EY035717 · NEI · MASSACHUSETTS EYE AND EAR INFIRMARY · PI Kinga Bujakowska · 2024 to 2026
$2.1M
NEI NIH HHS P30 EY014104NEI NIH HHS R01 EY035717NHGRI NIH HHS U01 HG011745NHGRI NIH HHS U24 HG011746
6 · The paper itself

Abstract

purposeAdvancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap.

methodsWe tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing.

resultsWe sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not originally interrogated. In 5 cases, they were deep intronic variants, all of which led to abnormal splicing and pseudoexons, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis.

conclusionGenome sequencing can overcome limitations of clinical genetic testing, such as the inability to call intronic variants. Our findings highlight pseudoexons as a common mechanism via which deep intronic variants cause Mendelian disease.

Indexed as

Genetic Diseases, InbornRare DiseasesAortic DiseasesCardiomyopathy, DilatedExome SequencingExonsFemaleGenetic Predisposition to DiseaseGenetic TestingGenome, HumanHigh-Throughput Nucleotide SequencingHumansIntronsMaleSequence Analysis, DNAWhole Genome SequencingGenome sequencingIntronic variantsPseudoexonRare diseaseRNA sequencing

Identifiers

PMID40927908
PMCPMC12501780

What OpenQuestion holds

Textmetadata
LicenceTDM
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.