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Open AccessGenetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery
One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observ...
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Open AccessInvestigating the role of common cis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders
Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contrib...
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Article
Inferring compound heterozygosity from large-scale exome sequencing data
Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that th...
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Open AccessGenetic risk factors have a substantial impact on healthy life years
The impact of genetic variation on overall disease burden has not been comprehensively evaluated. We introduce an approach to estimate the effect of genetic risk factors on disability-adjusted life years (DALY...
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Article
Reduced reproductive success is associated with selective constraint on human genes
Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants1. Although genes under the strongest selectiv...
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Open AccessAddendum: The mutational constraint spectrum quantified from variation in 141,456 humans
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Open AccessAuthor Correction: The mutational constraint spectrum quantified from variation in 141,456 humans
A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03174-8.
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Open AccessThe contribution of X-linked coding variation to severe developmental disorders
Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate th...
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Article
Evidence for 28 genetic disorders discovered by combining healthcare and research data
De novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed e...
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Open AccessThe mutational constraint spectrum quantified from variation in 141,456 humans
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be d...
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Open AccessGene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders
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 ge...
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Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations
Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas schizophrenia (SCZ) risk associated with DNMs has thus far been shown to be modest. We analyze...
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Open AccessContribution of retrotransposition to developmental disorders
Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to R...
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Reply to ‘Selective effects of heterozygous protein-truncating variants’
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Correction: Corrigendum: High-throughput discovery of novel developmental phenotypes
Nature 537, 508–514 (2016); doi:10.1038/nature19356 In this Article, the author Wolfgang Wurst was erroneously omitted from the author list. They are associated with the affiliations: HelmholtzZentrum Munich, ...
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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
Elise Robinson and colleagues present the polygenic transmission disequilibrium test (pTDT) for evaluating transmission of polygenic risk in family-based study designs. The authors apply pTDT to a cohort of au...
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Estimating the selective effects of heterozygous protein-truncating variants from human exome data
Shamil Sunyaev, David Beier and colleagues report an analysis of the fitness effects of heterozygous protein-truncating variants from the Exome Aggregation Consortium. They find that high heterozygous selectio...
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Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity
By sequencing the exomes of 10,503 individuals living in Pakistan, the authors identify rare predicted loss-of-function mutations that are estimated to knock out genes and correlate these mutations with a broa...
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Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples
Mark Daly and colleagues use population reference samples to refine the role of de novo protein-truncating variants in neurodevelopmental disorders. They show that variants independently observed in population re...
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Patterns of genic intolerance of rare copy number variation in 59,898 human exomes
Douglas Ruderfer, Shaun Purcell and colleagues characterized the rates and properties of rare genic copy number variants in exome sequencing data from nearly 60,000 individuals in the Exome Aggregation Consort...
