Evidence map›Paper›PMID 39636576›Full record

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

Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability.

Lachlan De Hayr, Laura E R Blok, Kerith-Rae Dias, Jingyi Long, Anaïs Begemann, Robyn D Moir, Ian M Willis, Martina Mocera, Gabriele Siegel, Katharina Steindl and 27 more

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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.

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2citing papers in PubMed
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1 · What the graph read from it

What it found

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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

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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. Article
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4 · The record

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5 · Who and what money

Authors and funding

37 authors.

Lachlan De HayrSchool of Health, University of the Sunshine Coast, Maroochydore, QLD, Australia; National PTSD Research Centre, Thompson Institute, Birtinya, QLD, Australia.
Laura E R BlokDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Kerith-Rae DiasNeuroscience Research Australia (NeuRA), Sydney, NSW, Australia; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
Jingyi LongDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Anaïs BegemannInstitute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
Robyn D MoirDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, NY.
Ian M WillisDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, NY.
Martina MoceraInstitute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
Gabriele SiegelInstitute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
Katharina SteindlInstitute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
Carey-Anne EvansNeuroscience Research Australia (NeuRA), Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
Ying ZhuNew South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
Futao ZhangNew South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
Michael FieldGenetics of Learning Disability Service, John Hunter Hospital, Waratah, NSW, Australia.
Alan MaDepartment of Clinical Genetics, Children's Hospital Westmead, Sydney Children's Hospitals Network, Sydney, NSW, Australia; Specialty of Genomic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Lesley AdèsDepartment of Clinical Genetics, Children's Hospital Westmead, Sydney Children's Hospitals Network, Sydney, NSW, Australia; Specialty of Genomic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Sarah Josephi-TaylorDepartment of Clinical Genetics, Children's Hospital Westmead, Sydney Children's Hospitals Network, Sydney, NSW, Australia; Specialty of Genomic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Rolph PfundtDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Maha S ZakiNational Research Centre, Clinical Genetics Department, Human Genetics and Genome Research Institute, Cairo, Egypt.
Hoda TomoumAin Shams University, Department of Pediatrics, Cairo, Egypt.
Anne GregorInselspital, Bern University Hospital, University of Bern, Department of Human Genetics, Bern, Switzerland; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Julia LaubeInstitute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
André ReisInstitute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Sateesh MaddirevulaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Mais O HashemDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Markus ZweierInstitute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Prince Sultan Military Medical City, Department of Pediatrics, Riyadh, Saudi Arabia.
Reza MaroofianDepartment of Neuromuscular Disorders, Institute of Neurology, University College London, London, United Kingdom.
Michael F BuckleyNew South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
Joseph G GleesonUniversity of California, Department of Neurosciences, San Diego, CA; Rady Children's Institute for Genomic Medicine, San Diego, CA.
Christiane ZweierInselspital, Bern University Hospital, University of Bern, Department of Human Genetics, Bern, Switzerland; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Mireia Coll-TanéDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
David A KoolenDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Anita RauchInstitute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland; ITINERARE - University of Zürich Research Priority Program, Zürich, Switzerland; University of Zürich and ETH Zürich, Neuroscience Center Zürich, Zürich, Switzerland.
Tony RoscioliNeuroscience Research Australia (NeuRA), Sydney, NSW, Australia; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
Annette SchenckDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Robert J HarveySchool of Health, University of the Sunshine Coast, Maroochydore, QLD, Australia; National PTSD Research Centre, Thompson Institute, Birtinya, QLD, Australia. Electronic address: rharvey2@usc.edu.au.

Funding

SUPPORT FOR THE ROSE F KENNEDY IDDRC P50P50HD105352 · NICHD · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI SOPHIE MOLHOLM, Steven Upshaw Walkley · 2021 to 2026
$7.0M
Molecular Characterization of Pontocerebellar HypoplasiaR01NS098004 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JOSEPH G GLEESON · 2016 to 2026
$4.6M
NICHD NIH HHS P50 HD105352NINDS NIH HHS R01 NS098004
6 · The paper itself

Abstract

purposeThis study details a novel syndromic form of autosomal recessive intellectual disability resulting from recessive variants in GTF3C3, encoding a key component of the DNA-binding transcription factor IIIC, which has a conserved role in RNA polymerase III-mediated transcription.

methodsExome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and Drosophila knockdown models were utilized to characterize GTF3C3 variants.

resultsTwelve affected individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in GTF3C3 including c.503C>T p.(Ala168Val), c.1268T>C p.(Leu423Pro), c.1436A>G p.(Tyr479Cys), c.2419C>T p.(Arg807Cys), and c.2420G>A p.(Arg807His). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations. Consistent with disruptions in intra- and intermolecular interactions observed in molecular modeling, RNA polymerase III reporter assays confirmed that the majority of missense variants resulted in a loss of function. Minigene analysis of the recurrent c.503C>T p.(Ala168Val) variant confirmed the introduction of a cryptic donor site into exon 4, resulting in mRNA missplicing. Consistent with the clinical features of this cohort, neuronal loss of Gtf3c3 in Drosophila induced seizure-like behavior, motor impairment, and learning deficits.

conclusionThese findings confirm that GTF3C3 variants result in an autosomal recessive form of syndromic intellectual disability.

Indexed as

Genes, RecessiveIntellectual DisabilityMutation, MissenseAdolescentAdultAllelesAnimalsChildChild, PreschoolDrosophilaExome SequencingFemaleHumansMalePedigreePhenotypeRNA Polymerase IIITranscription FactorsGTF3C3Intellectual disabilityMinigene analysisRNA polymerase IIITfc4

Identifiers

PMID39636576
PMCPMC13108454

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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.