Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
- Klíčová slova
- Development, Genetic diseases, Genetics, Neurodevelopment, iPS cells,
- MeSH
- enzymy opravy DNA genetika MeSH
- genové regulační sítě MeSH
- jaderné proteiny genetika MeSH
- lidé MeSH
- missense mutace MeSH
- neurovývojové poruchy * genetika MeSH
- sestřih RNA MeSH
- sestřihové faktory genetika MeSH
- spliceozomy * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- enzymy opravy DNA MeSH
- jaderné proteiny MeSH
- PRPF19 protein, human MeSH Prohlížeč
- sestřihové faktory MeSH
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Publikační typ
- tisková chyba MeSH
Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
- MeSH
- CCCTC-vazebný faktor genetika MeSH
- DNA vazebné proteiny genetika MeSH
- draslíkový kanál KCNQ3 genetika MeSH
- genetická predispozice k nemoci * MeSH
- genetické asociační studie MeSH
- heterogenní jaderný ribonukleoprotein U genetika MeSH
- kohortové studie MeSH
- lidé MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- neurovývojové poruchy genetika MeSH
- proteiny vázající RNA genetika MeSH
- represorové proteiny genetika MeSH
- studie případů a kontrol MeSH
- transkripční faktory bHLH genetika MeSH
- transkripční faktory genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- CCCTC-vazebný faktor MeSH
- CTCF protein, human MeSH Prohlížeč
- DNA vazebné proteiny MeSH
- draslíkový kanál KCNQ3 MeSH
- heterogenní jaderný ribonukleoprotein U MeSH
- HNRNPU protein, human MeSH Prohlížeč
- KCNQ3 protein, human MeSH Prohlížeč
- LEO1 protein, human MeSH Prohlížeč
- proteiny vázající RNA MeSH
- represorové proteiny MeSH
- SPEN protein, human MeSH Prohlížeč
- TCF12 protein, human MeSH Prohlížeč
- transkripční faktory bHLH MeSH
- transkripční faktory MeSH
- ZBTB18 protein, human MeSH Prohlížeč
