{"doi":"10.1093/clinchem/hvae025","title":"More Than a Decade of Rapid Genomic Sequencing: Where Are We Now?","abstract":"Since the first proof of concept paper describing rapid genome sequencing (rGS) in 2012, this testing has become a commonly used tool in the evaluation of patients in neonatal intensive care units (NICUs). It is estimated that 26% of neonates in this setting have rare genetic diseases. Given the heterogeneity of rare disease, broad testing is the fastest route to early definitive diagnosis. Genome sequencing (GS) allows for the most comprehensive analysis, identifying diagnostic variants in about 30% of cases. This includes those on a clinician's differential diagnosis as well as those not thought of, which may be for many reasons including human fallibility, incomplete or undifferentiated clinical presentation, or new gene-disease associations and phenotypic expansions. In the acute setting, the overall time to diagnosis is important, and rGS has been shown by multiple studies to result in a decreased time to diagnosis. Studies of rGS have also evaluated the impact of a rapid diagnosis by examining changes in medical management and length of NICU stay. Overwhelmingly, it has been demonstrated that running a faster test produces a faster answer, which is beneficial in some cases. Which patients are the most likely to benefit from rGS is ill-defined: for a small number it is undeniably lifesaving. The implementation of rGS requires a careful balance between the desire for rapid molecular diagnosis and limited laboratory and institutional/financial resources, with many scientific and ethical questions concerning the benefits, harms, and costs of this approach. Other testing modalities, such as lower-cost sequencing panels and exome sequencing, are also used for rapid diagnosis of critically ill infants, and other use cases have emerged, such as newborn screening. Though rGS is a great step forward, there are still technical shortcomings in the use of short-read sequencing, and much of the genome remains uninterpretable. Perspectives on the use of rGS were gathered from a virtual roundtable panel of experts regarding the eligibility, benefits, ethics, goals, and future directions of this testing, largely restricting the discussion to the use of rGS for the purpose of diagnosing infants in the NICU. The panel addressing this Q&A has expertise in clinical genetics, neonatology, ethics, genetic counseling, and genomic sequencing/laboratory operations. Please define what qualifies as rapid genome sequencing (rGS) and who should be eligible? Zornitza Stark: The answer to this question seems to vary depending on local context and is often measured in relation to the turnaround times of standard testing, so for example 2 to 3 weeks is often considered “rapid” where usual testing takes many months. However, we need to consider this from the perspective of our intensive care colleagues: “rapid” turnaround times in the ICU often mean results available in minutes from point-of-care tests. Striking a balance, for me rGS means results in <3 to 5 days, which places it in the realm of other commonly used but complex to perform and interpret pathology tests. In terms of eligibility, collectively we now have experience of rGS (and rapid exome sequencing) in thousands of critically ill pediatric patients worldwide, and eligibility should be based on the evidence of benefit in specific groups. This needs to be balanced against the relatively high costs associated with rGS, and as these costs decrease, it is likely that eligibility will widen. Particular groups of patients that we know are highly likely to benefit are, for example, those presenting with neonatal seizures (in the absence of trauma or infection) and those with features of underlying neurometabolic disorders. Luca Brunelli: rGS in the NICU has markedly shortened turnaround times, typically in the order of about 1 week. More recently, ultra-rapid GS (urGS) has become available with turnaround times of about 48 to 72 hours. There remains significant uncertainty about which newborns shoul","journal":"Clinical Chemistry","year":2024,"id":496158,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9425,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":901693,"name":"Luca Brunelli","orcid":"0000-0002-9542-2243","position":1,"is_corresponding":false},{"id":1342767,"name":"Michael J. Deem","orcid":"0000-0002-4379-8257","position":2,"is_corresponding":false},{"id":308534,"name":"Emily Farrow","orcid":"0000-0002-8864-7073","position":3,"is_corresponding":false},{"id":55849,"name":"Madhuri Hegde","orcid":"0000-0002-4500-0368","position":4,"is_corresponding":false},{"id":433620,"name":"Zornitza Stark","orcid":"0000-0001-8640-1371","position":5,"is_corresponding":false},{"id":33073,"name":"Carol Saunders","orcid":"0000-0002-7407-7735","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:09:23.333150Z","pmid":"38565214","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}