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

De Hayr, LachlanLachlanDe HayrBlok, Laura E RLaura E RBlokDias, Kerith-RaeKerith-RaeDiasLong, JingyiJingyiLongBegemann, AnaïsAnaïsBegemannMoir, Robyn DRobyn DMoirWillis, Ian MIan MWillisMocera, MartinaMartinaMoceraSiegel, GabrieleGabrieleSiegelSteindl, KatharinaKatharinaSteindlEvans, Carey-AnneCarey-AnneEvansZhu, YingYingZhuZhang, FutaoFutaoZhangField, MichaelMichaelFieldMa, AlanAlanMaAdès, LesleyLesleyAdèsJosephi-Taylor, SarahSarahJosephi-TaylorPfundt, RolphRolphPfundtZaki, Maha SMaha SZakiTomoum, HodaHodaTomoumGregor, AnneAnneGregorLaube, JuliaJuliaLaubeReis, AndréAndréReisMaddirevula, SateeshSateeshMaddirevulaHashem, Mais OMais OHashemZweier, MarkusMarkusZweierAlkuraya, Fowzan SFowzan SAlkurayaMaroofian, RezaRezaMaroofianBuckley, Michael FMichael FBuckleyGleeson, Joseph GJoseph GGleesonZweier, ChristianeChristianeZweierColl-Tané, MireiaMireiaColl-TanéKoolen, David ADavid AKoolenRauch, AnitaAnitaRauchRoscioli, TonyTonyRoscioliSchenck, AnnetteAnnetteSchenckHarvey, Robert JRobert JHarvey2025-01-072025-01-072025-01https://boris-portal.unibe.ch/handle/20.500.12422/194314Purpose 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.enGTF3C3Intellectual disabilityMinigene analysisRNA polymerase IIITfc4600 - Technology::610 - Medicine & healthBiallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability.article10.48620/788883963657610.1016/j.gim.2024.101253