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; Carey-Anne Evans; Ying Zhu; Futao Zhang; Michael Field; Alan Ma; Lesley Adès; Sarah Josephi-Taylor; Rolph Pfundt; Maha S Zaki; Hoda Tomoum; Anne Gregor; Julia Laube; André Reis; Sateesh Maddirevula; Mais O Hashem; Markus Zweier; Fowzan S Alkuraya; Reza Maroofian; Michael F Buckley; Joseph G Gleeson; Christiane Zweier; Mireia Coll-Tané; David A Koolen; Anita Rauch; Tony Roscioli; Annette Schenck; Robert J Harvey

doi:10.1016/j.gim.2024.101253

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

Genet Med. 2024 Nov 7:101253. doi: 10.1016/j.gim.2024.101253. Online ahead of print.

Authors

Lachlan De Hayr¹, Laura E R Blok², Kerith-Rae Dias³, Jingyi Long², Anaïs Begemann⁴, Robyn D Moir⁵, Ian M Willis⁵, Martina Mocera⁴, Gabriele Siegel⁴, Katharina Steindl⁴, Carey-Anne Evans⁶, Ying Zhu⁷, Futao Zhang⁷, Michael Field⁸, Alan Ma⁹, Lesley Adès⁹, Sarah Josephi-Taylor⁹, Rolph Pfundt², Maha S Zaki¹⁰, Hoda Tomoum¹¹, Anne Gregor¹², Julia Laube⁴, André Reis¹³, Sateesh Maddirevula¹⁴, Mais O Hashem¹⁴, Markus Zweier⁴, Fowzan S Alkuraya¹⁵, Reza Maroofian¹⁶, Michael F Buckley⁷, Joseph G Gleeson¹⁷, Christiane Zweier¹², Mireia Coll-Tané², David A Koolen², Anita Rauch¹⁸, Tony Roscioli¹⁹, Annette Schenck², Robert J Harvey²⁰

Affiliations

¹ School of Health, University of the Sunshine Coast, Maroochydore, QLD, Australia; National PTSD Research Centre, Thompson Institute, Birtinya, QLD, Australia.
² Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
⁴ Institute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
⁵ Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY.
⁶ Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
⁷ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
⁸ Genetics of Learning Disability Service, John Hunter Hospital, Waratah, NSW, Australia.
⁹ 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.
¹⁰ National Research Centre, Clinical Genetics Department, Human Genetics and Genome Research Institute, Cairo, Egypt.
¹¹ Ain Shams University, Department of Pediatrics, Cairo, Egypt.
¹² Inselspital, 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.
¹³ Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
¹⁴ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
¹⁵ 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.
¹⁶ Department of Neuromuscular Disorders, Institute of Neurology, University College London, London, United Kingdom.
¹⁷ University of California, Department of Neurosciences, San Diego, CA; Rady Children's Institute for Genomic Medicine, San Diego, CA.
¹⁸ Institute 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.
¹⁹ 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.
²⁰ School of Health, University of the Sunshine Coast, Maroochydore, QLD, Australia; National PTSD Research Centre, Thompson Institute, Birtinya, QLD, Australia. Electronic address: [email protected].

PMID: 39636576
DOI: 10.1016/j.gim.2024.101253

Abstract

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.

Keywords: GTF3C3; Intellectual disability; Minigene analysis; RNA polymerase III; Tfc4.