Browsing by Author "Nothnagel, Michael"
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Publication CNV-ClinViewer: enhancing the clinical interpretation oflarge copy-number variants online(2023) Macnee, Marie; Pérez Palma, Eduardo; Brünger, Tobias; Klöckner, Chiara; Platzer, Konrad; Stefansk, Arthur; Montanucci, Ludovica; Bayat, Allan; Radtke, Maximilian; Collins, Ryan; Talkowski, Michael; Blankenberg, Daniel; Møller, Rikke; Lemke, Johannes; Nothnagel, Michael; May, Patrick; Lal, DennisMotivation: Pathogenic copy-number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts. Results: Here, we introduce the CNV-ClinViewer, an open-source web application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface and facilitates semi-automated clinical CNV interpretation following the ACMG guidelines by integrating the ClassifCNV tool. In combination with clinical judgment, the application enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators' patient care and for basic scientists' translational genomic research.Publication Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes(2025) Brünger, Tobias; Ivaniuk, Alina; Pérez Palma, Eduardo; Montanucci, Ludovica; Cohen, Stacey; Smith, Lacey; Parthasarathy, Shridhar; Helbig, Ingo; Nothnagel, Michael; May, Patrick; Lal, DennisBackground: The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Prior research shows that the deleterious effects and the subsequent molecular consequences of variants are often conserved among paralogous protein sequences within a gene family. Here, we systematically quantify on an exome-wide scale whether the existence of pathogenic variants in paralogous genes at a conserved position can serve as evidence for the pathogenicity of a new variant. For the gene family of voltage-gated sodium channels, where variants and expert-curated clinical phenotypes are available, we also assess whether phenotype patterns of multiple disorders for each gene are conserved across variant positions within the gene family. Results: Mapping 590,000 pathogenic and 1.9 million population variants onto 9928 genes grouped into 2054 paralogous families increases the number of residues with classifiable evidence 5.1-fold compared with gene-specific data alone. The presence of a pathogenic variant in a paralogous gene is associated with a positive likelihood ratio of 13.0 for variant pathogenicity. Across ten genes encoding voltage-gated sodium channels and 22 expert-curated disorders, we identify cross-paralog correlated phenotypes based on 3D structure spatial position. For example, multiple established loss-of-function related disorders across SCN1A, SCN2A, SCN5A, and SCN8A show overlapping spatial variant clusters. Finally, we show that phenotype integration in paralog variant selection improves variant classification. Conclusion: Conserved pathogenic missense variants in paralogous genes provide robust, quantifiable support for clinical variant interpretation, and phenotype-informed mapping further improves predictions.Publication Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes(2022) Brünger, Tobias; Pérez, Eduardo; Montanucci, Ludovica; Nothnagel, Michael; Møller, Rikke; Schorge, Stephanie; Zuberi, Sameer; Symonds, Joseph; Lemke, Johannes; Brunklaus, Andreas; Traynelis, Stephen; May, Patrick; Lal, DennisClinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion-channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated. We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion-channel families. We collected and curated 3049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12 546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures. We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis centre and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and functional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1422 neurodevelopmental disorder pathogenic patient variants and 679 electrophysiological experiments, we show that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain versus loss-of-channel function. In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional readouts and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.