Evidence map›Paper›PMID 42090037›Full record

ArticleHuman genetics2026

A novel splice site variant in DEGS1 leads to aberrant splicing and loss of DEGS1 enzyme activity, a VUS resolved.

Holly C Beale, Victor Tse, Joanna Y Lee, Jon Akutagawa, Yusuph Mavura, Brandon Saint-John, Allison Cheney, Dennis R Mulligan, Guillermo Chacaltana, Martin Gutierrez and 15 more

Abstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Human genetics, 2026. 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. Neurology. Genetics · 2026
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

25 authors.

Holly C Beale *Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Victor Tse *Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA. vitse@ucsc.edu.
Joanna Y LeeDepartment of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
Jon AkutagawaGenomics Institute, University of California Santa Cruz, Santa Cruz, CA, 95060, USA.
Yusuph MavuraInstitute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
Brandon Saint-JohnDepartment of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Allison CheneyDepartment of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Dennis R MulliganDepartment of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Guillermo ChacaltanaCenter for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Martin GutierrezDepartment of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Jessica TenneyDepartment of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
Joseph T ShiehDepartment of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
Pierre-Marie MartinInstitute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
Tiffany YipDepartment of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
Ugur HodoglugilInstitute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
Alex J FayDepartment of Neurology, University of California San Francisco, San Francisco, CA, 94143, USA.
Angela N BrooksGenomics Institute, University of California Santa Cruz, Santa Cruz, CA, 95060, USA.
Jessica Van ZiffleInstitute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
Michael D StoneCenter for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Neil RischInstitute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
Jeremy R SanfordDepartment of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Patrick DevineInstitute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
Julie D Saba *Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
Olena M Vaske *Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Anne Slavotinek *Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.

Funding

Structure and dynamics of the Tetrahymena telomerase ribonucleoproteinR01GM095850 · NIGMS · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI STONE, MICHAEL D · 2011 to 2023
$4.4M
Regulation of mRNA FateR35GM130361 · NIGMS · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI Jeremy Robert Sanford · 2019 to 2026
$3.1M
Novel approaches to improve comprehensive profiling of the epigenome and epitranscriptomeR35GM138122 · NIGMS · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI Angela Norie Brooks · 2020 to 2026
$2.8M
Validating absolute lymphocyte count and plasma sphingosine-1-phosphate as disease biomarkers of sphingosine phosphate lyase insufficiency syndrome in anticipation of a pyridoxine clinical trialR21TR004262 · NCATS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SABA, JULIE D · 2022 to 2023
$444k
NHGRI/NIMHD/NCI U01HG009599NIH HHS R01GM095850NIH HHS R35GM130361NIH/NCATS R21TR004262NIH/NIGMS R35GM138122UC Foundation Colligan Presidential Chair for Pediatric Genomics
6 · The paper itself

Abstract

Pathogenic DEGS1 variants have been reported in individuals with autosomal recessive hypomyelinating leukodystrophy 18 (HLD18; MIM# 618404). Here we describe three participants with HLD features and a previously unreported homozygous DEGS1 5' splice site variant, c.825+4_825 + 5delAGinsTT (NM_003676.4). We used next-generation DNA and transcriptome sequencing, cell-based splicing assays, and tandem mass spectrometry to detect and characterize the variant's impact on DEGS1 expression. We then performed RNA structure probing and conventional antisense oligonucleotide screening to investigate molecular mechanisms for potential therapeutic intervention. We show that the splice site variant: (1) was sufficient to induce exon two skipping in most detected transcripts; (2) resulted in structural changes to the 5' and 3' splice site regions using RNA structure probing; and (3) corresponds to plasma sphingolipid profiles consistent with loss of sphingolipid delta(4)-desaturase activity. Our RNA and lipidomic evidence proved that the DEGS1 variant c.825+4_825 + 5delAGinsTT is pathogenic and suggested a mechanistic model that explains how exon two skipping is induced.

Indexed as

Alternative SplicingFatty Acid DesaturasesRNA Splice SitesRNA SplicingExonsFemaleHumansSphingolipidsDEGS1 protein, humanFatty Acid DesaturasesRNA Splice SitesSphingolipids

Identifiers

PMID42090037
PMCPMC13149559

What OpenQuestion holds

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LicenceCC BY
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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.