ArticleNature communications2025
Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Genome-wide tandem repeat expansions modify schizophrenia risk in the presence of a 22q11.2 deletion.Molecular psychiatry · 2026Article
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.Nature communications · 2026Article
- Gene dosage differences and non-linear impacts on complex traits.Cell genomics · 2026Article
- Uncovering apparent incomplete penetrance of TSC1/TSC2 variants: Insights from multiple population cohorts and implications for newborn screening.European journal of human genetics : EJHG · 2026Article
- Exploring the pathogenesis of a compound heterozygous variant in ATP7B associated with Wilson disease in an Iranian family.Molecular biology reports · 2026Article
- Genetic background shapes AI-predicted variant effects.bioRxiv : the preprint server for biology · 2026Article
- Genotype-based prevalence of Birt-Hogg-Dubé syndrome in the healthcare and genomic registry populations - breaking the 'rare disease' status?NPJ genomic medicine · 2026Article
- Revisiting low penetrance retinoblastoma: an integrated clinical, genetic, and bioinformatic analysis.Human molecular genetics · 2026Article
- Clinical Profiles, Genetic Variants, and Neurodevelopmental Outcomes Following Liver Transplantation in Maple Syrup Urine Disease: A Study From Palestine.JIMD reports · 2026Article
- A scalable approach to resolving variants of uncertain significance.bioRxiv : the preprint server for biology · 2026Article
- Genetic spectrum analysis of high-carrier-frequency monogenic disorders based on whole-exome sequencing in the Chinese general population.Human genomics · 2026Article
- Compound heterozygous splicing and missense variants inFrontiers in medicine · 2026Article
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.bioRxiv : the preprint server for biology · 2025Article
- Residual allelic activity likely underlies the low rates of disease expression for predicted loss-of-function variants in population-scale biobanks.American journal of human genetics · 2025Article
- GREGoR: accelerating genomics for rare diseases.Nature · 2025Article
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- Frequency and Spectrum of Actionable Secondary Findings in the Maltese Population.Molecular genetics & genomic medicine · 2025Article
- Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype.American journal of human genetics · 2025Article
- ABCA4 Deep Intronic Variants Contributed to Nearly Half of Unsolved Stargardt Cases With a Milder Phenotype.Investigative ophthalmology & visual science · 2025Article
- GREGoR: Accelerating Genomics for Rare Diseases.ArXiv · 2024Article
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12 authors.
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Abstract
Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. Here, we identify explanations for the presumed lack of disease manifestation in 701 of 734 variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders are rare, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.