{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:15:29Z","timestamp":1792048529555,"version":"4.4.0"},"reference-count":37,"publisher":"American Academy of Pediatrics (AAP)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,10,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Rapid diagnostic whole-genome sequencing has been explored in critically ill newborns, hoping to improve their clinical care and replace time-consuming and\/or invasive diagnostic testing. A previous retrospective study in a research setting showed promising results with diagnoses in 57%, but patients were highly selected for known and likely Mendelian disorders. The aim of our prospective study was to assess the speed and yield of rapid targeted genomic diagnostics for clinical application.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We included 23 critically ill children younger than 12 months in ICUs over a period of 2 years. A quick diagnosis could not be made after routine clinical evaluation and diagnostics. Targeted analysis of 3426 known disease genes was performed by using whole-genome sequencing data. We measured diagnostic yield, turnaround times, and clinical consequences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>A genetic diagnosis was obtained in 7 patients (30%), with a median turnaround time of 12 days (ranging from 5 to 23 days). We identified compound heterozygous mutations in the EPG5 gene (Vici syndrome), the RMND1 gene (combined oxidative phosphorylation deficiency-11), and the EIF2B5 gene (vanishing white matter), and homozygous mutations in the KLHL41 gene (nemaline myopathy), the GFER gene (progressive mitochondrial myopathy), and the GLB1 gene (GM1-gangliosidosis). In addition, a 1p36.33p36.32 microdeletion was detected in a child with cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Rapid targeted genomics combined with copy number variant detection adds important value in the neonatal and pediatric intensive care setting. It led to a fast diagnosis in 30% of critically ill children for whom the routine clinical workup was unsuccessful.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1542\/peds.2016-2854","type":"journal-article","created":{"date-parts":[[2017,9,22]],"date-time":"2017-09-22T05:10:12Z","timestamp":1506057012000},"source":"Crossref","is-referenced-by-count":111,"title":["Rapid Targeted Genomics in Critically Ill Newborns"],"prefix":"10.1542","volume":"140","author":[{"given":"Cleo C.","family":"van Diemen","sequence":"first","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilhelmina S.","family":"Kerstjens-Frederikse","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klasien A.","family":"Bergman","sequence":"additional","affiliation":[{"name":"Beatrix Children\u2019s Hospital, University Medical Center Groningen, Groningen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom J.","family":"de Koning","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"},{"name":"Beatrix Children\u2019s Hospital, University Medical Center Groningen, Groningen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Sikkema-Raddatz","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joeri K.","family":"van der Velde","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin M.","family":"Abbott","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna C.","family":"Herkert","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"L\u00f6hner","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Rump","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine T.","family":"Meems-Veldhuis","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter B.T.","family":"Neerincx","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan D.H.","family":"Jongbloed","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conny M.","family":"van Ravenswaaij-Arts","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morris A.","family":"Swertz","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Sinke","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene M.","family":"van Langen","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cisca","family":"Wijmenga","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2017,10,1]]},"reference":[{"key":"2021121014422409000_B1","unstructured":"Online Mendelian Inheritance in Man (OMIM). OMIM Entry Statistics. Available at: www.omim.org\/statistics\/entry. Accessed July 22, 2016"},{"issue":"24","key":"2021121014422409000_B2","doi-asserted-by":"crossref","first-page":"9851","DOI":"10.1073\/pnas.1302575110","article-title":"Clinical genomic database.","volume":"110","author":"Solomon","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"issue":"154","key":"2021121014422409000_B3","doi-asserted-by":"crossref","first-page":"154ra135","DOI":"10.1126\/scitranslmed.3004041","article-title":"Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units.","volume":"4","author":"Saunders","year":"2012","journal-title":"Sci Transl Med"},{"issue":"5","key":"2021121014422409000_B4","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S2213-2600(15)00139-3","article-title":"Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings.","volume":"3","author":"Willig","year":"2015","journal-title":"Lancet Respir Med"},{"issue":"14","key":"2021121014422409000_B5","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform.","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"issue":"12","key":"2021121014422409000_B6","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1093\/bioinformatics\/btv098","article-title":"Sambamba: fast processing of NGS alignment formats.","volume":"31","author":"Tarasov","year":"2015","journal-title":"Bioinformatics"},{"issue":"9","key":"2021121014422409000_B7","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res"},{"key":"2021121014422409000_B8","doi-asserted-by":"crossref","first-page":"11.10.1","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline.","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Curr Protoc Bioinformatics"},{"key":"2021121014422409000_B9","unstructured":"National Human Genome Research Institute . Clinical genomic database. Available at: http:\/\/research.nhgri.nih.gov\/CGD\/. Accessed October 20, 2014"},{"key":"2021121014422409000_B10","unstructured":"ExAC Browser (Beta). Version 0.3. Cambridge, MA: Exome Aggregation Consortium; 2015."},{"key":"2021121014422409000_B11","unstructured":"NHLBI GO Exome Sequencing Project (ESP) . Exome Variant Server. Available at: http:\/\/evs.gs.washington.edu\/EVS\/"},{"issue":"7422","key":"2021121014422409000_B12","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes.","volume":"491","author":"Abecasis","year":"2012","journal-title":"Nature"},{"key":"2021121014422409000_B13","unstructured":"NCBI . dbSNP Short Genetic Variations. Available at: www.ncbi.nlm.nih.gov\/SNP\/"},{"issue":"8","key":"2021121014422409000_B14","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/ng.3021","article-title":"Whole-genome sequence variation, population structure and demographic history of the Dutch population.","volume":"46","author":"Genome of the Netherlands Consortium","year":"2014","journal-title":"Nat Genet"},{"issue":"3","key":"2021121014422409000_B15","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants.","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat Genet"},{"key":"2021121014422409000_B16","doi-asserted-by":"crossref","first-page":"S12","DOI":"10.1186\/1471-2105-11-S12-S12","article-title":"The MOLGENIS toolkit: rapid prototyping of biosoftware at the push of a button.","volume":"11","author":"Swertz","year":"2010","journal-title":"BMC Bioinformatics"},{"key":"2021121014422409000_B17","unstructured":"MOLGENIS. Version 1.4.0. Groningen, Netherlands: University Medical Center Groningen; 2015."},{"key":"2021121014422409000_B18","unstructured":"Hudson-Alpha Institute for Biotechnology . Combined Annotation Dependent Depletion (CADD) scores. Version 1.0. Available at: http:\/\/cadd.gs.washington.edu\/download. Accessed April 1, 2014"},{"key":"2021121014422409000_B19","author":"Online Mendelian Inheritance in Man (OMIM)","year":"2014"},{"issue":"5","key":"2021121014422409000_B20","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"issue":"Database issue","key":"2021121014422409000_B21","doi-asserted-by":"crossref","first-page":"D966","DOI":"10.1093\/nar\/gkt1026","article-title":"The human phenotype ontology project: linking molecular biology and disease through phenotype data.","volume":"42","author":"K\u00f6hler","year":"2014","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"2021121014422409000_B22","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/ng.2497","article-title":"Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.","volume":"45","author":"Cullup","year":"2013","journal-title":"Nat Genet"},{"issue":"6","key":"2021121014422409000_B23","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/j.ajhg.2013.10.020","article-title":"Identification of KLHL41 mutations implicates BTB-kelch-mediated ubiquitination as an alternate pathway to myofibrillar disruption in nemaline myopathy.","volume":"93","author":"Gupta","year":"2013","journal-title":"Am J Hum Genet"},{"issue":"4","key":"2021121014422409000_B24","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.ajhg.2012.08.020","article-title":"An RMND1 Mutation causes encephalopathy associated with multiple oxidative phosphorylation complex deficiencies and a mitochondrial translation defect.","volume":"91","author":"Janer","year":"2012","journal-title":"Am J Hum Genet"},{"issue":"1","key":"2021121014422409000_B25","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1001\/jama.2014.7184","article-title":"Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.","volume":"312","author":"Taylor","year":"2014","journal-title":"JAMA"},{"issue":"5","key":"2021121014422409000_B26","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.ajhg.2009.04.004","article-title":"The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency.","volume":"84","author":"Di Fonzo","year":"2009","journal-title":"Am J Hum Genet"},{"issue":"4","key":"2021121014422409000_B27","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/ng764","article-title":"Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.","volume":"29","author":"Leegwater","year":"2001","journal-title":"Nat Genet"},{"issue":"9","key":"2021121014422409000_B28","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1002\/humu.21535","article-title":"Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes.","volume":"32","author":"Liu","year":"2011","journal-title":"Hum Mutat"},{"issue":"10","key":"2021121014422409000_B29","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1194\/jlr.M700308-JLR200","article-title":"Expression and characterization of 14 GLB1 mutant alleles found in GM1-gangliosidosis and Morquio B patients.","volume":"48","author":"Santamaria","year":"2007","journal-title":"J Lipid Res"},{"issue":"5","key":"2021121014422409000_B30","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/humu.22969","article-title":"CoNVaDING: single exon variation detection in targeted NGS data.","volume":"37","author":"Johansson","year":"2016","journal-title":"Hum Mutat"},{"issue":"2","key":"2021121014422409000_B31","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1542\/peds.2007-0929","article-title":"Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation [published correction appears in Pediatrics. 2008;121(5):1081].","volume":"121","author":"Battaglia","year":"2008","journal-title":"Pediatrics"},{"key":"2021121014422409000_B32","unstructured":"UMCG . Preconception screening trial in general population. Available at: www.rug.nl\/research\/genetics\/research\/pcs-pilot-study. Accessed July 22, 2016"},{"issue":"3","key":"2021121014422409000_B33","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1111\/cge.12654","article-title":"Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.","volume":"89","author":"Sawyer","year":"2016","journal-title":"Clin Genet"},{"issue":"9","key":"2021121014422409000_B34","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/gim.2015.200","article-title":"Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability.","volume":"18","author":"Monroe","year":"2016","journal-title":"Genet Med"},{"key":"2021121014422409000_B35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3389\/fped.2015.00067","article-title":"Clinical impact and cost-effectiveness of whole exome sequencing as a diagnostic tool: a pediatric center\u2019s experience.","volume":"3","author":"Valencia","year":"2015","journal-title":"Front Pediatr"},{"issue":"11","key":"2021121014422409000_B36","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1038\/gim.2016.1","article-title":"A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.","volume":"18","author":"Stark","year":"2016","journal-title":"Genet Med"},{"issue":"3","key":"2021121014422409000_B37","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.mayocp.2015.12.018","article-title":"Outcome of whole exome sequencing for diagnostic Odyssey cases of an individualized medicine clinic: the Mayo Clinic experience.","volume":"91","author":"Lazaridis","year":"2016","journal-title":"Mayo Clin Proc"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/doi\/10.1542\/peds.2016-2854\/1096916\/peds_20162854.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/doi\/10.1542\/peds.2016-2854\/1096916\/peds_20162854.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,26]],"date-time":"2023-08-26T03:18:41Z","timestamp":1693019921000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/140\/4\/e20162854\/38075\/Rapid-Targeted-Genomics-in-Critically-Ill-Newborns"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,1]]},"references-count":37,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,10,1]]},"published-print":{"date-parts":[[2017,10,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2016-2854","relation":{},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"value":"0031-4005","type":"print"},{"value":"1098-4275","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,1]]},"article-number":"e20162854"}}