Abstracts from the 53rd European Society of Human Genetics (ESHG) Conference: Oral Presentations

2020 European Journal of Human Genetics  
Alternative RNA splicing, the process whereby a single gene can give rise to many different proteins, has long been known to be dysregulated in many cancers. Recent studies have provided concrete genetic evidence that splicing dysregulation directly promotes cancer initiation and progression. For example, genes encoding RNA splicing factors are recurrently mutated in both hematologic malignancies and solid tumors. However, uncovering the specific mechanisms by which these mutations promote
more » ... igenesis has proven challenging. Here, I will discuss recent progress in establishing functional links between somatic mutations affecting RNA splicing factors and tumorigenesis, the promise of correct mis-splicing for cancer therapy, and the recent creation of CRISPR/Cas-based technologies for conducting mRNA isoform-level genetic screens. Introduction: Large-scale exome sequencing studies have identified hundreds of genes with significant excess of de novo mutations (DNMs) in neurodevelopmental disorders (NDDs). In this collaborative study, we assessed 125 candidate and high-confidence genes in a large cohort of NDD cases. Materials and Methods: We targeted 63 candidate genes for resequencing among 16,321 NDD cases and an additional 62 high-confidence genes in 6,211 NDD cases. In order to test for significance at the level of case-control mutation burden and integrating with previously published data, we assessed these genes among NDD cases and compared the mutation burden to nonpsychiatric controls from ExAC. These genes were assessed also in a combined set of 17,426 NDD parent-child trios. Furthermore, Abstracts from the 53rd European Society of Human Genetics (ESHG) Conference: Oral Presentations thorough phenotype studies for seven of the genes with evidence of mutational burden were performed in a subset of the patients. Results: We identified 48 genes (25 newly reported) with a significant burden of ultra-rare (MAF < 0.01%) severe mutations. Among the 125 targeted genes, we show that 90 genes are also enriched for DNMs in parent-child trios. We here focus on seven genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN and LEO1) for detailed clinical descriptions to delineate the associated phenotypes and clinical presentation of these specific and newly described neurodevelopmental disorders.
doi:10.1038/s41431-020-00740-6 pmid:33262484 fatcat:6bfe5kviofdd7fw5tcdr6y3cgu