Nearby genes are often expressed as a group. PL2.2 Local gene co-expression measurements in single-cells highlight inter-individual specificity Diogo Ribeiro 1,2, Olivier Delaneau 1,2 1University of Lausanne, Lausanne, Switzerland, 2Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland. Finally, we have gathered a reference dataset containing gene- and junction- level counts that can be integrated as controls for studies with small sample sizes.Ĭonclusion: Our study demonstrates the routine implementation of RNA-seq as a complementary tool to DNA sequencing for the diagnosis of rare diseases, paving the path towards more comprehensive OMICS-based diagnostics. We also assessed the importance of RNA source material and showed that the majority of OMIM disease genes are expressed in clinically accessible tissues, with the highest number in fibroblasts. By associating transcriptome aberrations with rare variants, we found a major role of nonsense-mediated decay in underexpression outliers and of coding and intronic variants in splicing outliers. Results: We provided a diagnosis for 16% (33 out of 205) of WES unsolved cases.
To detect the genetic cause, we prioritize genes harbouring aberrant expression (using OUTRIDER), aberrant splicing (using FRASER), or mono-allelic expression of a rare allele, compiled with our recently developed computational workflow DROP, which is further extended with an RNA-seq based variant calling module.
Materials and Methods: We performed RNA-seq on fibroblasts from 305 individuals affected with a mitochondrial disease who had previously undergone WES, which represents one of the largest RNA-seq compendium for rare disease diagnostics. RNA sequencing (RNA-seq), which directly probes gene expression defects, has emerged as a promising complementary tool increasing the diagnosis rate. Introduction: Whole exome (WES) and whole genome sequencing remain unsuccessful in providing a firm diagnosis for about half of the individuals with a suspected Mendelian disorder. PL2.1 Clinical implementation of RNA sequencing for Mendelian disease diagnostics Vicente Yepez 1, Mirjana Gusic 2, Julien Gagneur 1, Holger Prokisch 2 1Technical University of Munich, Munich, Germany, 2Helmholtz Zentrum, Munich, Germany. This working model of international collaboration a blue-print for future genetic discoveries in the event of pandemics or for any complex human disease. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was enabled by prioritization of shared resources and analytical frameworks. We further identified smoking and body mass index as causal risk factors for severe COVID-19. They also represent potentially actionable mechanisms in response to infection. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases. We reported 15 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. We describe the results of three genome-wide association meta-analyses comprising 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. The genetic makeup of an individual contributes to susceptibility and response to infectious viruses.
PL1.2 The COVID-19 host genetics initiative - an international, open science effort to identify genetic risk factors for COVID19 severity and susceptibility Andrea Ganna Finnish Institute for Molecular Medicine, Helsinki, Finland.