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

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.

SUBMITTER: Lal D

PROVIDER: S-EPMC7079346 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Lal Dennis D May Patrick P Perez-Palma Eduardo E Samocha Kaitlin E KE Kosmicki Jack A JA Robinson Elise B EB Møller Rikke S RS Krause Roland R Nürnberg Peter P Weckhuysen Sarah S De Jonghe Peter P Guerrini Renzo R Niestroj Lisa M LM Du Juliana J Marini Carla C Ware James S JS Kurki Mitja M Gormley Padhraig P Tang Sha S Wu Sitao S Biskup Saskia S Poduri Annapurna A Neubauer Bernd A BA Koeleman Bobby P C BPC Helbig Katherine L KL Weber Yvonne G YG Helbig Ingo I Majithia Amit R AR Palotie Aarno A Daly Mark J MJ

Genome medicine 20200317 1

<h4>Background</h4>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 ...[more]

PMID: 32183904

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Project description:Introduction De novo mutations contribute to a large proportion of sporadic psychiatric and developmental disorders, yet the potential role of environmental carcinogens as drivers of causal de novo mutations in neurodevelopmental disorders is poorly studied. Methods To explore environmental mutation vulnerability of disease-associated gene sets, we analyzed publicly available whole genome sequencing datasets of mutations in human induced pluripotent stem cell clonal lines exposed to 12 classes of environmental carcinogens, and human lung cancers from individuals living in highly polluted regions. We compared observed rates of exposure-induced mutations in disease-related gene sets with the expected rates of mutations based on control genes randomly sampled from the genome using exact binomial tests. To explore the role of sequence characteristics in mutation vulnerability, we modeled the effects of sequence length, gene expression, and percent GC content on mutation rates of entire genes and gene coding sequences using multivariate Quasi-Poisson regressions. Results We demonstrate that several mutagens, including radiation and polycyclic aromatic hydrocarbons, disproportionately mutate genes related to neurodevelopmental disorders including autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder. Other disease genes including amyotrophic lateral sclerosis, Alzheimer’s disease, congenital heart disease, orofacial clefts, and coronary artery disease were generally not mutated more than expected. Longer sequence length was more strongly associated with elevated mutations in entire genes compared with mutations in coding sequences. Increased expression was associated with decreased coding sequence mutation rate, but not with the mutability of entire genes. Increased GC content was associated with increased coding sequence mutation rates but decreased mutation rates in entire genes. Discussion Our findings support the possibility that neurodevelopmental disorder genetic etiology is partially driven by a contribution of environment-induced germ line and somatic mutations.

Dataset Information

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

Publications

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

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