{
    "abstract": "This 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.\nExome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and Drosophila knockdown models were utilized to characterize GTF3C3 variants.\nTwelve 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.\nThese findings confirm that GTF3C3 variants result in an autosomal recessive form of syndromic intellectual disability.",
    "authors": [
        {
            "affiliation": "School of Health, University of the Sunshine Coast, Maroochydore, QLD, Australia; National PTSD Research Centre, Thompson Institute, Birtinya, QLD, Australia.",
            "firstname": "Lachlan",
            "initials": "L",
            "lastname": "De Hayr"
        },
        {
            "affiliation": "Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.",
            "firstname": "Laura E R",
            "initials": "LER",
            "lastname": "Blok"
        },
        {
            "affiliation": "Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.",
            "firstname": "Kerith-Rae",
            "initials": "KR",
            "lastname": "Dias"
        },
        {
            "affiliation": "Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.",
            "firstname": "Jingyi",
            "initials": "J",
            "lastname": "Long"
        },
        {
            "affiliation": "Institute of Medical Genetics, University of Z\u00fcrich, Schlieren-Z\u00fcrich, Switzerland.",
            "firstname": "Ana\u00efs",
            "initials": "A",
            "lastname": "Begemann"
        },
        {
            "affiliation": "Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY.",
            "firstname": "Robyn D",
            "initials": "RD",
            "lastname": "Moir"
        },
        {
            "affiliation": "Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY.",
            "firstname": "Ian M",
            "initials": "IM",
            "lastname": "Willis"
        },
        {
            "affiliation": "Institute of Medical Genetics, University of Z\u00fcrich, Schlieren-Z\u00fcrich, Switzerland.",
            "firstname": "Martina",
            "initials": "M",
            "lastname": "Mocera"
        },
        {
            "affiliation": "Institute of Medical Genetics, University of Z\u00fcrich, Schlieren-Z\u00fcrich, Switzerland.",
            "firstname": "Gabriele",
            "initials": "G",
            "lastname": "Siegel"
        },
        {
            "affiliation": "Institute of Medical Genetics, University of Z\u00fcrich, Schlieren-Z\u00fcrich, Switzerland.",
            "firstname": "Katharina",
            "initials": "K",
            "lastname": "Steindl"
        },
        {
            "affiliation": "Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.",
            "firstname": "Carey-Anne",
            "initials": "CA",
            "lastname": "Evans"
        },
        {
            "affiliation": "New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.",
            "firstname": "Ying",
            "initials": "Y",
            "lastname": "Zhu"
        },
        {
            "affiliation": "New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.",
            "firstname": "Futao",
            "initials": "F",
            "lastname": "Zhang"
        },
        {
            "affiliation": "Genetics of Learning Disability Service, John Hunter Hospital, Waratah, NSW, Australia.",
            "firstname": "Michael",
            "initials": "M",
            "lastname": "Field"
        },
        {
            "affiliation": "Department 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.",
            "firstname": "Alan",
            "initials": "A",
            "lastname": "Ma"
        },
        {
            "affiliation": "Department 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.",
            "firstname": "Lesley",
            "initials": "L",
            "lastname": "Ad\u00e8s"
        },
        {
            "affiliation": "Department 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.",
            "firstname": "Sarah",
            "initials": "S",
            "lastname": "Josephi-Taylor"
        },
        {
            "affiliation": "Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.",
            "firstname": "Rolph",
            "initials": "R",
            "lastname": "Pfundt"
        },
        {
            "affiliation": "National Research Centre, Clinical Genetics Department, Human Genetics and Genome Research Institute, Cairo, Egypt.",
            "firstname": "Maha S",
            "initials": "MS",
            "lastname": "Zaki"
        },
        {
            "affiliation": "Ain Shams University, Department of Pediatrics, Cairo, Egypt.",
            "firstname": "Hoda",
            "initials": "H",
            "lastname": "Tomoum"
        },
        {
            "affiliation": "Inselspital, Bern University Hospital, University of Bern, Department of Human Genetics, Bern, Switzerland; Institute of Human Genetics, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Erlangen, Germany.",
            "firstname": "Anne",
            "initials": "A",
            "lastname": "Gregor"
        },
        {
            "affiliation": "Institute of Medical Genetics, University of Z\u00fcrich, Schlieren-Z\u00fcrich, Switzerland.",
            "firstname": "Julia",
            "initials": "J",
            "lastname": "Laube"
        },
        {
            "affiliation": "Institute of Human Genetics, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Erlangen, Germany.",
            "firstname": "Andr\u00e9",
            "initials": "A",
            "lastname": "Reis"
        },
        {
            "affiliation": "Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.",
            "firstname": "Sateesh",
            "initials": "S",
            "lastname": "Maddirevula"
        },
        {
            "affiliation": "Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.",
            "firstname": "Mais O",
            "initials": "MO",
            "lastname": "Hashem"
        },
        {
            "affiliation": "Institute of Medical Genetics, University of Z\u00fcrich, Schlieren-Z\u00fcrich, Switzerland.",
            "firstname": "Markus",
            "initials": "M",
            "lastname": "Zweier"
        },
        {
            "affiliation": "Department 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.",
            "firstname": "Fowzan S",
            "initials": "FS",
            "lastname": "Alkuraya"
        },
        {
            "affiliation": "Department of Neuromuscular Disorders, Institute of Neurology, University College London, London, United Kingdom.",
            "firstname": "Reza",
            "initials": "R",
            "lastname": "Maroofian"
        },
        {
            "affiliation": "New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.",
            "firstname": "Michael F",
            "initials": "MF",
            "lastname": "Buckley"
        },
        {
            "affiliation": "University of California, Department of Neurosciences, San Diego, CA; Rady Children's Institute for Genomic Medicine, San Diego, CA.",
            "firstname": "Joseph G",
            "initials": "JG",
            "lastname": "Gleeson"
        },
        {
            "affiliation": "Inselspital, Bern University Hospital, University of Bern, Department of Human Genetics, Bern, Switzerland; Institute of Human Genetics, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Erlangen, Germany.",
            "firstname": "Christiane",
            "initials": "C",
            "lastname": "Zweier"
        },
        {
            "affiliation": "Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.",
            "firstname": "Mireia",
            "initials": "M",
            "lastname": "Coll-Tan\u00e9"
        },
        {
            "affiliation": "Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.",
            "firstname": "David A",
            "initials": "DA",
            "lastname": "Koolen"
        },
        {
            "affiliation": "Institute of Medical Genetics, University of Z\u00fcrich, Schlieren-Z\u00fcrich, Switzerland; ITINERARE - University of Z\u00fcrich Research Priority Program, Z\u00fcrich, Switzerland; University of Z\u00fcrich and ETH Z\u00fcrich, Neuroscience Center Z\u00fcrich, Z\u00fcrich, Switzerland.",
            "firstname": "Anita",
            "initials": "A",
            "lastname": "Rauch"
        },
        {
            "affiliation": "Neuroscience 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.",
            "firstname": "Tony",
            "initials": "T",
            "lastname": "Roscioli"
        },
        {
            "affiliation": "Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.",
            "firstname": "Annette",
            "initials": "A",
            "lastname": "Schenck"
        },
        {
            "affiliation": "School 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.",
            "firstname": "Robert J",
            "initials": "RJ",
            "lastname": "Harvey"
        }
    ],
    "conclusions": "These findings confirm that GTF3C3 variants result in an autosomal recessive form of syndromic intellectual disability.",
    "copyrights": "Copyright \u00a9 2024 The Authors. Published by Elsevier Inc. All rights reserved.",
    "doi": "10.1016/j.gim.2024.101253",
    "journal": "Genetics in medicine : official journal of the American College of Medical Genetics",
    "keywords": [
        "GTF3C3",
        "Intellectual disability",
        "Minigene analysis",
        "RNA polymerase III",
        "Tfc4"
    ],
    "methods": null,
    "publication_date": "2024-12-05",
    "pubmed_id": "39636576",
    "results": "Twelve 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.",
    "title": "Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability.",
    "xml": "<Element 'PubmedArticle' at 0x788504e43470>"
}