Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders
Year: 2020
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. METHODS: Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. RESULTS: We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. CONCLUSION: This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.
Source: Genome Medicine
Authors: Dennis Lal, Patrick May, Kaitlin E. Samocha, Jack A. Kosmicki, Elise B. Robinson, Rikke S. Møller, Roland Krause, Peter Nüernberg, Sarah Weckhuysen, Peter De Jonghe, Renzo Guerrini, Lisa M. Neupert, Juliana Du, Eduardo Perez-Palma, Carla Marini, James S. Ware, Mitja Kurki, Padhraig Gormley, Sha Tang, Sitao Wu, Saskia Biskup, Annapura Poduri, Bernd A. Neubauer, Bobby P. Koeleman, Katherine L. Helbig, Yvonne G. Weber, Ingo Helbig, Amit R. Majithia, Aarno Palotie, Mark J. Daly
Institutions: Broad Institute, Cleveland Clinic, University of Cologne, Massachusetts General Hospital, Stanley Center for Psychiatric Research, University of Luxembourg, Luxembourg Centre for Systems Biomedicine, Cleveland Clinic Research, Harvard University, University of Southern Denmark, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University of Antwerp, Antwerp University Hospital, VIB-UAntwerp Center for Molecular Neurology, Institute Born-Bunge, Meyer Children's Hospital, University of Florence, MRC London Institute of Medical Sciences, Imperial College London, Ambry Genetics (United States), Hertie Institute for Clinical Brain Research, University of Tübingen, Boston Children's Hospital, Justus-Liebig-Universität Gießen, Universitätsklinikum Gießen und Marburg, University Medical Center Utrecht, RWTH Aachen University, Children's Hospital of Philadelphia, Christian-Albrechts-Universität zu Kiel, University Hospital Schleswig-Holstein, University of California San Diego, University of Helsinki, Institute for Molecular Medicine Finland
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,290
Funders: Université du Luxembourg, University of Dundee, Wellcome Trust, EU Joint Programme – Neurodegenerative Disease Research, European Commission, Deutscher Akademischer Austauschdienst, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Fonds Wetenschappelijk Onderzoek, Universiteit Antwerpen, Universität zu Köln, Medical Research Council, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Allele-specific silencing of mutant KCNQ2 as a targeted treatment for KCNQ2 encephalopathy: an in vitro proof of concept study, G1402406509, G195220990, G3070122537, MRC Centre for Neurodevelopmental Disorders, G3525344002, G4465499052, G4482688224, Development and Epilepsy - Strategies for Innovative Research to improve diagnosis, prevention and treatment in children with difficult to treat Epilepsy, Boston Intellectual and Developmental Disabilities Research Center, G8085446012, G8316927773, G8718829242, Genomic dissection of inherited cardiomyopathies: identifying alleles, genes and mechanisms, for patient stratification., Training in Bioinformatics and Integrative Genomics
OpenAlex ID: W3010981627