Abstract
BackgroundClassifying 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.MethodsGene 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.ResultsWe 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.ConclusionThis 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.
Highlights
Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs)
Paralog conservation of missense de novo mutations in NDD patients To investigate the degree to which de novo mutations (DNMs) in NDDs are enriched in paralog-conserved sites, we compared the variant distribution of De novo mutation (DNM) in 10,068 NDD patients to 2078 individuals without NDDs
We evaluated the contribution of paralogconserved and non-conserved missense variants to NDDs
Summary
Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Differentiating risk-conferring from benign missense variants represents a major challenge in clinical practice to diagnose rare and genetic heterogeneous neurodevelopmental disorders (NDDs). Two previous studies have highlighted the utility of systematic functional annotation of disease-causing residues across human paralogs for genes associated with long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia [5, 6] Both studies showed improved variant interpretation by comparing corresponding mutations in paralogs in patients with the same phenotype
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