Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders
Open Access
- 17 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Genome Medicine
- Vol. 12 (1), 1-12
- https://doi.org/10.1186/s13073-020-00725-6
Abstract
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. 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. 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. 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.Keywords
This publication has 37 references indexed in Scilit:
- De novo mutations in epileptic encephalopathiesNature, 2013
- Ensembl BioMarts: a hub for data retrieval across taxonomic spaceDatabase: The Journal of Biological Databases and Curation, 2011
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Evolutionary constraint facilitates interpretation of genetic variation in resequenced human genomesGenome Research, 2010
- Evolutionary constraints on structural similarity in orthologs and paralogsProtein Science, 2009
- Jalview Version 2—a multiple sequence alignment editor and analysis workbenchBioinformatics, 2009
- EnsemblCompara GeneTrees: Complete, duplication-aware phylogenetic trees in vertebratesGenome Research, 2008
- Tree pattern matching in phylogenetic trees: automatic search for orthologs or paralogs in homologous gene sequence databasesBioinformatics, 2005
- MUSCLE: multiple sequence alignment with high accuracy and high throughputNucleic Acids Research, 2004
- Objective Criteria for the Evaluation of Clustering MethodsJournal of the American Statistical Association, 1971