Navigation auf uzh.ch
Navigation auf uzh.ch
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.
Exome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and Drosophila knockdown models were utilized to characterize GTF3C3 variants.
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.
These findings confirm that GTF3C3 variants result in an autosomal recessive form of syndromic intellectual disability.
GTF3C3, Intellectual disability, Minigene analysis, RNA polymerase III, Tfc4
Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability.
PMID: 39636576, DOI: 10.1093/braincomms/fcae408, S2CID: 274526461. Genetics in Medicine, (101253):1-17. 2024, Dec. 05.
De Hayr, Lachlan; Blok, Laura E R; Dias, Kerith-Rae M; Long, Jingyi; Begemann, Anaïs; Moir, Robyn D; Willis, Ian M; Mocera, Martina; Siegel, Gabriele; Steindl, Katharina; Evans, Carey-Anne; Zhu, Yinghao; Zhang, Futao; Field, Michael; Ma, Alan; Adès, Lesley C; Josephi-Taylor, Sarah; Pfundt, Rolph; Zaki, Maha S; Tomoum, Hoda; Gregor, Anne; Laube, Julia; Reis, André; Maddirevula, Sateesh; Hashem, Mais O; Zweier, Markus; Alkuraya, Fowzan S; Maroofian, Reza; Buckley, Michael F; Gleeson, Joseph G; Zweier, Christiane; Coll-Tané, Mireia; Koolen, David A; Rauch, Anita; Roscioli, Tony; Schenck, Annette; Harvey, Robert J.
