ArticleGenetics in medicine : official journal of the American College of Medical Genetics2022
A gene-to-patient approach uplifts novel disease gene discovery and identifies 18 putative novel disease genes.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed.
- Regional nonsense constraint offers biological and clinical insights into genetic disease.Nature communications · 2026Article
- Contribution of rare coding variants to microcephaly in individuals with neurodevelopmental disorders.Genome medicine · 2025Article
- Unique signatures of highly constrained genes across publicly available genomic databases.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder.Brain : a journal of neurology · 2025Article
- Automated Shared Phenotype Discovery in Undiagnosed Cohorts for Rare Disease Research.Proceedings of the ... International Conference on Machine Learning and Applications. International Conference on Machine Learning and Applications · 2024Article
- Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes.European journal of human genetics : EJHG · 2024Article
- Improving estimates of loss-of-function constraint for short genes.Nature genetics · 2024Article
- Modelling human genetic disorders in Xenopus tropicalis.Disease models & mechanisms · 2024Review
- A Panel-Agnostic Strategy 'HiPPo' Improves Diagnostic Efficiency in the UK Genomic Medicine Service.Healthcare (Basel, Switzerland) · 2023Article
- Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.Genome medicine · 2023Article
- Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project.Human genetics · 2023Article
- A panel-agnostic strategy 'HiPPo' improves diagnostic efficiency in the UK Genome Medicine Service.medRxiv : the preprint server for health sciences · 2023Article
- A retrospective analysis of phosphatase catalytic subunit gene variants in patients with rare disorders identifies novel candidate neurodevelopmental disease genes.Frontiers in cell and developmental biology · 2023Article
- De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder.Human mutation · 2022Article
- Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes.BMJ open ophthalmology · 2022Article
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10 authors.
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Abstract
purposeExome and genome sequencing have drastically accelerated novel disease gene discoveries. However, discovery is still hindered by myriad variants of uncertain significance found in genes of undetermined biological function. This necessitates intensive functional experiments on genes of equal predicted causality, leading to a major bottleneck.
methodsWe apply the loss-of-function observed/expected upper-bound fraction metric of intolerance to gene inactivation to curate a list of predicted haploinsufficient disease genes. Using data from the 100,000 Genomes Project, we adopt a gene-to-patient approach that matches de novo loss-of-function variants in constrained genes to patients with rare disease. Through large-scale aggregation of data, we reduce excess analytical noise currently hindering novel discoveries.
resultsResults from 13,949 trios revealed 643 rare, de novo predicted loss-of-function events filtered from 1044 loss-of-function observed/expected upper-bound fraction-constrained genes. A total of 168 variants occurred within 126 genes without a known disease-gene relationship. Of these, 27 genes had >1 kindred affected, and for 18 of these genes, multiple kindreds had overlapping phenotypes. Two years after initial analysis, 11 of 18 (61%) of these genes have been independently published as novel disease gene discoveries.
conclusionUsing large cohorts and adopting gene-based approaches can rapidly and objectively accelerate dominantly inherited novel gene discovery by targeting the most appropriate genes for functional validation.
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