De Hayr, L., Blok, L.E.R., Dias, K.R., Long, J., Begemann, A., Moir, R.D., Willis, I.M., Mocera, M., Siegel, G., Steindl, K., Evans, C.A., Zhu, Y., Zhang, F., Field, M., Ma, A., Adès, L., Josephi-Taylor, S., Pfundt, R., Zaki, M.S., Tomoum, H., Gregor, A., Laube, J., Reis, A., Maddirevula, S., Hashem, M.O., Zweier, M., Alkuraya, F.S., Maroofian, R., Buckley, M.F., Gleeson, J.G., Zweier, C., Coll-Tané, M., Koolen, D.A., Rauch, A., Roscioli, T., Schenck, A., Harvey, R.J. (2025). Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability.  Genet Med 27(1): 101253.

FBrf0261380

Research paper

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.