Evidence map›Paper›PMID 36965478›Full record

ArticleAmerican journal of human genetics2023

Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.

F Graeme Frost, Marie Morimoto, Prashant Sharma, Lyse Ruaud, Newell Belnap, Daniel G Calame, Yuri Uchiyama, Naomichi Matsumoto, Machteld M Oud, Elise A Ferreira and 29 more

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
1.7field-weighted citation impact, top 16% of its field
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.

NCT02450851 recruitingnot on this map

Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network

TypeobservationalSponsorNational Human Genome Research Institute (NHGRI)Ran2015 to 2028Enrolled20,000ConditionsGenetic Disease
3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 11 citations in OpenAlex.

  1. Neurodevelopmental Disorder with Dystonia and Chorea Linked to De Novo Variants in the Splicing Regulator SRRM4.Movement disorders : official journal of the Movement Disorder Society · 2026
    Article
  2. Article
  3. Article
  4. Article
  5. Article
  6. Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024
    Review
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

39 authors at 15 institutions in 5 countries.

F Graeme FrostNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
Marie MorimotoNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
Prashant SharmaNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
Lyse RuaudAPHP.Nord, Robert Debré University Hospital, Department of Genetics, Paris, France; Université Paris Cité, Inserm UMR 1141, NeuroDiderot, 75019 Paris, France.
Newell BelnapCenter for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, AZ, USA.
Daniel G CalameSection of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
Yuri UchiyamaDepartment of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Naomichi MatsumotoDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Machteld M OudDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
Elise A FerreiraDepartment of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands; United for Metabolic Diseases, Amsterdam, the Netherlands.
Vinodh NarayananCenter for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, AZ, USA.
Sampath RangasamyCenter for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, AZ, USA.
Matt HuentelmanCenter for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, AZ, USA.
Lisa T EmrickSection of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
Ikuko Sato-ShiraiDepartment of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; Department of Pediatrics, Shimada Ryoiku Medical Center Hachioji for Challenged Children, Tokyo, Japan.
Satoko KumadaDepartment of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
Nicole I WolfAmsterdam Leukodystrophy Center, Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Vrije Universiteit, Amsterdam, the Netherlands.
Peter J SteinbachBioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Yan HuangNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
Undiagnosed Diseases Network
Barbara N PuseyNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
Sandrine PassemardUniversité Paris Cité, Inserm UMR 1141, NeuroDiderot, 75019 Paris, France; Service de Neurologie Pédiatrique, DMU INOV-RDB, APHP, Hôpital Robert Debré, Paris, France.
Jonathan LevyDepartment of Genetics, APHP-Robert Debré University Hospital, Paris, France; Laboratoire de biologie médicale multisites Seqoia - FMG2025, Paris, France.
Séverine DrunatDepartment of Genetics, APHP-Robert Debré University Hospital, Paris, France; Laboratoire de biologie médicale multisites Seqoia - FMG2025, Paris, France; INSERM UMR1141, Neurodiderot, University of Paris, Paris, France.
Marie VincentService de Génétique Médicale, CHU Nantes, Nantes, France; Inserm, CNRS, University Nantes, l'institut du thorax, Nantes, France.
Agnès GuetAPHP.Nord, Louis Mourier Hospital, Pediatrics Department, Paris, France.
Emanuele AgoliniLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Antonio NovelliLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Maria Cristina DigilioMedical Genetics Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Jennifer L MurphyNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
James R LupskiSection of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Gilbert VezinaDepartment of Diagnostic Radiology and Imaging, Children's National Hospital, Washington, DC, USA.
Ellen F MacnamaraNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
David R AdamsNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Maria T AcostaNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
Cynthia J TifftNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
William A GahlNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
May Christine V MalicdanNational Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: maychristine.malicdan@nih.gov.
National Institutes of Health · USBaylor College of Medicine · USTranslational Genomics Research Institute · USBambino Gesù Children's Hospital · ITEmma Kinderziekenhuis · NLInserm · FRTokyo Metropolitan Neurological Hospital · JPAssistance Publique – Hôpitaux de Paris · FRCentre National de la Recherche Scientifique · FRChildren's National · USDélégation Paris 5 · FRHôpital Louis-Mourier · FRRadboud University Nijmegen · NLYokohama City University · JPYokohama City University Hospital · JP

Funding

Human Biochemical GeneticsZIAHG000215 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI GAHL, WILLIAM · 2009 to 2025
$72.6M
Baylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5M
Frequency of variants of unknown significance by ancestry groups in the All of Us Research Program cohortU01HG011758 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI RICHARD A GIBBS, JAMES R. LUPSKI · 2021 to 2026
$13.8M
STRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0M
Mutidisciplinary Training;Brain Disorders &DevelopmentT32NS043124 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI SWANN, JOHN WILLIAM · 2002 to 2021
$4.6M
Undiagnosed Diseases ProgramZIAHG200421 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI GAHL, WILLIAM · 2023 to 2025
$825k
NHGRI NIH HHS U01 HG011758NHGRI NIH HHS UM1 HG006542NINDS NIH HHS R35 NS105078NINDS NIH HHS T32 NS043124
6 · The paper itself

Abstract

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.

Indexed as

Alternative SplicingDNA-Binding ProteinsParaparesis, SpasticTranscription FactorsAdolescentAllelesChildChild, PreschoolFemaleHeLa CellsHumansInfantMalePedigreeProtein IsoformsProtein Structure, SecondaryDNA-Binding ProteinsProtein IsoformsRNA, Small NuclearSNAPC4 protein, humanTranscription Factorsalternative splicinggene discoveryMendelian disordermonogenic diseasesprogressive spasticityrare diseasesspliceosome

Identifiers

PMID36965478
PMCPMC10119142
OpenAlexW4360877685

What OpenQuestion holds

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Registered trials

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.