ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 2 of them syntheses that pooled it.
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Who cites it
25 citing papers in PubMed, 2 syntheses or guidelines pooled it, 28 citations in OpenAlex.
- BCL11B-related disease: a single phenotypic entity?European journal of human genetics : EJHG · 2025Pooled it
- Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.Genes · 2023Pooled it
- Reanalysis of genomic data doubles the diagnostic yield for Welsh patients recruited to the UK 100,000 Genomes Project.European journal of human genetics : EJHG · 2026Article
- Automated reanalysis of genomic data for rare disease diagnostics at scale.Nature medicine · 2026Article
- A case report: camptodactyly-arthropathy-coxa vara-pericarditis syndrome: confirmation of a previously undescribed PRG4 splicing variant using synovial tissue RNA studies.EULAR rheumatology open · 2026Article
- Analysis of familial exudative vitreoretinopathy (FEVR) cases in the UK 100 000 genomes project increases diagnostic rate and implicates heterozygousJournal of medical genetics · 2026Article
- Exploring the size limits of Bionano optical genome mapping to resolve alternative structures of linked interspersed chromosomal duplications.Genome medicine · 2025Article
- The power of mouse models in the diagnostic odyssey of patients with rare congenital anomalies.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Review
- Using a Disentangled Neural Network to Objectively Assess the Outcomes of Midfacial Surgery in Syndromic Craniosynostosis.Plastic and reconstructive surgery · 2025Article
- Identification and characterization of short-chain dehydrogenase/reductase 3 (DHRS3) deficiency, a retinoic acid embryopathy of humans.Genetics in medicine open · 2025Article
- Cardiomyopathies in 100,000 genomes project: interval evaluation improves diagnostic yield and informs strategies for ongoing gene discovery.Genome medicine · 2024Article
- Article
- The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.European journal of human genetics : EJHG · 2024Article
- The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.American journal of human genetics · 2024Article
- Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project.BMC genomics · 2024Article
- Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.Genome medicine · 2023Article
- Craniosynostosis, inner ear, and renal anomalies in a child with complete loss ofJournal of medical genetics · 2023Article
- Conclusion of diagnostic odysseys due to inversions disruptingJournal of medical genetics · 2023Article
- The value of genome-wide analysis in craniosynostosis.Frontiers in genetics · 2023Article
- A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations andHuman mutation · 2023Article
Corrections and comments
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Authors and funding
24 authors at 13 institutions in 1 country.
Funding
Abstract
purposeGenome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease.
methodsGS data from 114 probands with craniosynostosis and their relatives (314 samples), negative on routine genetic testing, were scrutinized by a specialized research team, and diagnoses compared with those made by 100kGP.
resultsSixteen likely pathogenic/pathogenic variants were identified by 100kGP. Eighteen additional likely pathogenic/pathogenic variants were identified by the research team, indicating that for craniosynostosis, 100kGP panels had a diagnostic sensitivity of only 47%. Measures that could have augmented diagnoses were improved calling of existing panel genes (+18% sensitivity), review of updated panels (+12%), comprehensive analysis of de novo small variants (+29%), and copy-number/structural variants (+9%). Recent NHS England recommendations that partially incorporate these measures should achieve 85% overall sensitivity (+38%).
conclusionGS identified likely pathogenic/pathogenic variants in 29.8% of previously undiagnosed patients with craniosynostosis. This demonstrates the value of research analysis and the importance of continually improving algorithms to maximize the potential of clinical GS.
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