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Journal article
Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability
Genetics in Medicine, Vol.27(1), pp.1-17
2025
PMID: 39636576
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Purpose
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.
Methods
Exome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and Drosophila knockdown models were utilized to characterize GTF3C3 variants.
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.
Conclusion
These findings confirm that GTF3C3 variants result in an autosomal recessive form of syndromic intellectual disability.
Details
- Title
- Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability
- Authors
- Lachlan De Hayr - University of the Sunshine Coast, Queensland, School of Health - BiomedicineLaura E R Blok - Radboud University Medical CenterKerith-Rae Dias - Neuroscience Research AustraliaJingyi Long - Radboud University Medical CenterAnais Begemann - University of ZurichRobyn D Moir - Albert Einstein College of MedicineIan M Willis - Albert Einstein College of MedicineMartina Morcera - University of ZurichGabriele Siegel - University of ZurichKatharina Steindl - University of ZurichCarey-Anne Evans - Neuroscience Research AustraliaYing Zhu - Prince of Wales HospitalFutao Zhang - Prince of Wales HospitalMichael Field - John Hunter HospitalAlan Ma - The University of SydneyLesley Adès - The University of SydneySarah Josephi-Taylor - The University of SydneyRolph Pfundt - Radboud University Medical CenterMaha S Zaki - National Research CentreHoda Tomoum - Ain Shams UniversityAnne Gregor - University of BernJulia Laube - University of ZurichAndré Reis - Friedrich-Alexander-Universität Erlangen-NürnbergSateesh Maddirevula - King Faisal Specialist Hospital & Research CentreMais O Hashem - King Faisal Specialist Hospital & Research CentreMarkus Zweier - University of ZurichFowzan S Alkuraya - King Faisal Specialist Hospital & Research CentreReza Maroofian - University College LondonMichael F Buckley - Prince of Wales HospitalJoseph G Gleeson - University of California, San DiegoChristiane Zweier - University of BernMireia Coll-Tané - Radboud University Medical CenterDavid A Koolen - Radboud University Medical CenterAnita Rauch - University of ZurichTony Roscioli - Prince of Wales HospitalAnnette Schenck - Radboud University Medical CenterRobert Harvey (Corresponding Author) - University of the Sunshine Coast, Queensland, School of Health
- Publication details
- Genetics in Medicine, Vol.27(1), pp.1-17
- Publisher
- Elsevier Inc.
- Date published
- 2025
- DOI
- 10.1016/j.gim.2024.101253
- ISSN
- 1530-0366; 1098-3600
- PMID
- 39636576
- Copyright note
- © 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- Data Availability
- This study did not generate data sets or code. All methods are provided in the manuscript or in supplemental files. For data or resource enquiries, please contact Prof Robert J. Harvey, School of Health, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia. Email: rharvey2@usc.edu.au
- Organisation Unit
- School of Health - Biomedicine; School of Health
- Language
- English
- Record Identifier
- 991087798502621
- Output Type
- Journal article
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