Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

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http://hdl.handle.net/10138/314216

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EuroEPINOMICS- RES Consortium , Lal , D , May , P , Perez-Palma , E , Kurki , M , Palotie , A , Daly , M J & Lehesjoki , A-E 2020 , ' Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders ' , Genome medicine , vol. 12 , no. 1 , 28 . https://doi.org/10.1186/s13073-020-00725-6

Title: Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders
Author: EuroEPINOMICS- RES Consortium; Lal, Dennis; May, Patrick; Perez-Palma, Eduardo; Kurki, Mitja; Palotie, Aarno; Daly, Mark J.; Lehesjoki, Anna-Elina
Contributor: University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Department of Medical and Clinical Genetics
Date: 2020-03-17
Language: eng
Number of pages: 12
Belongs to series: Genome medicine
ISSN: 1756-994X
URI: http://hdl.handle.net/10138/314216
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.
Subject: Paralogs
Gene family
Conservation
Missense variants
Neurodevelopmental disorders
DE-NOVO MUTATIONS
MULTIPLE SEQUENCE ALIGNMENT
PHYLOGENETIC TREES
ORTHOLOGS
1184 Genetics, developmental biology, physiology
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