ArticleHuman genetics2023
Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project.
Article in Human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 17 citations in OpenAlex.
- Article
- Phenotypic Expansion ofGenes · 2026Article
- Integrating 730,947 exome sequences with clinical literature improves gene discovery.medRxiv : the preprint server for health sciences · 2026Article
- Individuals with intellectual disability have an increased burden ofmedRxiv : the preprint server for health sciences · 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
- Approaches to Evaluate Whole Exome Sequencing Data That Incorporate Genetic Intolerance Scores for Congenital Anomalies, Including Intronic Regions Adjacent to Exons.Molecular genetics & genomic medicine · 2025Article
- ZNFX1: a multifunctional modulator of the innate immune response.Frontiers in immunology · 2025Review
- Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project.BMC genomics · 2024Article
- A gene pathogenicity tool "GenePy" identifies missed biallelic diagnoses in the 100,000 Genomes Project.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- The evolutionary impact of childhood cancer on the human gene pool.Nature communications · 2024Article
- Identification of novel candidate genes associated with non-syndromic tooth agenesis in Mongolian families.Clinical oral investigations · 2023Article
- A Study and Analysis of Disease Identification using Genomic Sequence Processing Models: An Empirical Review.Current genomics · 2023Review
Corrections and comments
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Authors and funding
10 authors at 7 institutions in 2 countries.
Funding
Abstract
backgroundGenome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP). Analysis was restricted to predefined gene panels associated with the patient's phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnoses outside of the panel(s) applied. We propose a complementary method to rapidly identify pathogenic variants, including those missed by 100KGP methods.
methodsThe Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, loss-of-function variants in disease genes with a LOEUF score < 0.2. We compared our findings with the corresponding patient's diagnostic reports.
results324/332 (98%) of the variants identified using DeNovoLOEUF were diagnostic or partially diagnostic (whereby the variant was responsible for some of the phenotype). We identified 39 diagnoses that were "missed" by 100KGP standard analyses, which are now being returned to patients.
conclusionWe have demonstrated a highly specific and rapid method with a 98% positive predictive value that has good concordance with standard analysis, low false-positive rate, and can identify additional diagnoses. Globally, as more patients are being offered genome sequencing, we anticipate that DeNovoLOEUF will rapidly identify new diagnoses and facilitate iterative analyses when new disease genes are discovered.
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