ArticleAmerican journal of human genetics2025
HiFi long-read genomes for difficult-to-detect, clinically relevant variants.
Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Diagnostic discovery of structural variants causing foveal hypoplasia using SVRare and long-read nanopore sequencing.European journal of human genetics : EJHG · 2026Article
- Toward the clinical application of long-read sequencing in repeat-expansion disorders.Nature genetics · 2026Review
- Rare disease genomics in an era of human pangenomics and telomere-to-telomere genome references.European journal of human genetics : EJHG · 2026Review
- Artificial Intelligence and Genomic Data Analysis: New Frontiers in Precision Medicine.International journal of molecular sciences · 2026Review
- Best practice recommendations for bioinformatics approaches applied to high-throughput sequencing for rare disease and cancer diagnosis within the UK National Health Service.Journal of medical genetics · 2026Article
- Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials.Genes · 2026Review
- Near-perfect genome sequencing in medical genetics.Nature genetics · 2026Review
- Sensitivity of HiFi long-read genome sequencing for difficult-to-detect pathogenic variants when applied to real-world clinical laboratory samples.American journal of human genetics · 2026Article
- A clinical protocol for the detection of comorbidities associated with monogenic causes of male infertility.Human reproduction (Oxford, England) · 2026Article
- Optical Genome Mapping for the Identification of Complex Structural Variants in Hereditary Angioedema.Journal of clinical immunology · 2026Article
- Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.Brain : a journal of neurology · 2026Article
- Integrative analysis of in silico predictions and clinical evidence to delineate the capability of HiFi long-read sequencing in paralogous genes.NPJ genomic medicine · 2026Article
- Juvenile-Onset Cerebrotendinous Xanthomatosis with Novel Compound Heterozygous CYP27A1 Mutations: Case Series and Literature Review.Cerebellum (London, England) · 2026Review
- Long-read genome sequencing enhances diagnostics of pediatric neurological disorders.Genome medicine · 2026Article
- Untargeted Metabolomics for Diagnosis, Monitoring, and Understanding the Pathophysiology of Inherited Metabolic Disorders.Journal of inherited metabolic disease · 2026Review
- Blended Length Genome Sequencing (blend-seq): Combining Short Reads with Low-Coverage Long Reads to Maximize Variant Discovery.bioRxiv : the preprint server for biology · 2025Article
- Article
- Toward clinical long-read genome sequencing for rare diseases.Nature genetics · 2025Review
- A Hitchhiker's Guide to long-read genomic analysis.Genome research · 2025Review
- Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing.Genome research · 2025Article
Corrections and comments
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Authors and funding
17 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Clinical short-read exome and genome sequencing approaches have positively impacted diagnostic testing for rare diseases. Yet, technical limitations associated with short reads challenge their use for the detection of disease-associated variation in complex regions of the genome. Long-read sequencing (LRS) technologies may overcome these challenges, potentially qualifying as a first-tier test for all rare diseases. To test this hypothesis, we performed LRS (30× high-fidelity [HiFi] genomes) for 100 samples with 145 known clinically relevant germline variants that are challenging to detect using short-read sequencing and necessitate a broad range of complementary test modalities in diagnostic laboratories. We show that relevant variant callers readily re-identified the majority of variants (120/145, 83%), including ∼90% of structural variants, SNVs/insertions or deletions (indels) in homologous sequences, and expansions of short tandem repeats. Another 10% (n = 14) was visually apparent in the data but not automatically detected. Our analyses also identified systematic challenges for the remaining 7% (n = 11) of variants, such as the detection of AG-rich repeat expansions. Titration analysis showed that 90% of all automatically called variants could also be identified using 15-fold coverage. Long-read genomes thus identified 93% of challenging pathogenic variants from our dataset. Even with reduced coverage, the vast majority of variants remained detectable, possibly enhancing cost-effective diagnostic implementation. Most importantly, we show the potential to use a single technology to accurately identify all types of clinically relevant variants.
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