{"doi":"10.1016/j.gimo.2023.100821","title":"First-tier next-generation sequencing for newborn screening: An important role for biochemical second-tier testing","abstract":"There is discussion of expanding newborn screening (NBS) through the use of genomic sequence data; yet, challenges remain in the interpretation of DNA variants. Population-level DNA variant databases are available, and it is possible to estimate the number of newborns who would be flagged as having a risk for a genetic disease (including rare variants of unknown significance, VUS) via next-generation sequencing (NGS) positive. Estimates of the number of newborns screened as NGS positive for monogenic recessive diseases were obtained by analysis of the Genome Aggregation Database (gnomAD). For a collection of diseases for which there is interest in NBS, we provided 2 estimates for the expected number of newborns screened as NGS positive. For a set of lysosomal storage diseases, we estimated that 100 to approximately 600 NGS screen positives would be found per disease per year in a large NBS laboratory (California), and this figure may be expected to rise to a limit of about 1000 if we account for the fact that gnomAD does not contain all worldwide variants. The number of positives would drop 2.5- to 10-fold if the 10 VUS with highest allele frequency were biochemically annotated as benign. It is proposed that a second-tier biochemical assay using the same dried blood spot could be carried out as a filter and as part of NBS to reduce the number of high-risk NGS positive newborns to a manageable number.","journal":"Genetics in Medicine Open","year":2023,"id":351248,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9366,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1058578,"name":"Madelynn Campagna","orcid":"0000-0003-2864-3182","position":1,"is_corresponding":false},{"id":27305,"name":"Anthony Philippakis","orcid":"0000-0001-6953-3794","position":2,"is_corresponding":false},{"id":995,"name":"Anne H. O’Donnell-Luria","orcid":"0000-0001-6418-9592","position":3,"is_corresponding":false},{"id":310980,"name":"Michael H. Gelb","orcid":"0000-0001-7000-5219","position":4,"is_corresponding":false},{"id":804482,"name":"Sarah L. Stenton","orcid":"0000-0003-4071-449X","position":0,"is_corresponding":true}],"reference_count":20,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:12:41.740237Z","pmid":"39238532","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":[]}