{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T12:04:51Z","timestamp":1790337891353,"version":"4.1.0"},"reference-count":26,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T00:00:00Z","timestamp":1685404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University Grants Committee-Collaborative Research Fund","award":["C4062-21GF"],"award-info":[{"award-number":["C4062-21GF"]}]},{"name":"University Grants Committee-Collaborative Research Fund","award":["14115322"],"award-info":[{"award-number":["14115322"]}]},{"name":"General Research Fund","award":["C4062-21GF"],"award-info":[{"award-number":["C4062-21GF"]}]},{"name":"General Research Fund","award":["14115322"],"award-info":[{"award-number":["14115322"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Skeletal dysplasias are a group of diseases characterized by bone and joint abnormalities, which can be detected during prenatal ultrasound. Next-generation sequencing has rapidly revolutionized molecular diagnostic approaches in fetuses with structural anomalies. This review studies the additional diagnostic yield of prenatal exome sequencing in fetuses with prenatal sonographic features of skeletal dysplasias. This was a systematic review by searching PubMed for studies published between 2013 and July 2022 that identified the diagnostic yield of exome sequencing after normal karyotype or chromosomal microarray analysis (CMA) for cases with suspected fetal skeletal dysplasias based on prenatal ultrasound. We identified 10 out of 85 studies representing 226 fetuses. The pooled additional diagnostic yield was 69.0%. The majority of the molecular diagnoses involved de novo variants (72%), while 8.7% of cases were due to inherited variants. The incremental diagnostic yield of exome sequencing over CMA was 67.4% for isolated short long bones and 77.2% for non-isolated cases. Among phenotypic subgroup analyses, features with the highest additional diagnostic yield were an abnormal skull (83.3%) and a small chest (82.5%). Prenatal exome sequencing should be considered for cases with suspected fetal skeletal dysplasias with or without a negative karyotype or CMA results. Certain sonographic features, including an abnormal skull and small chest, may indicate a potentially higher diagnostic yield.<\/jats:p>","DOI":"10.3390\/genes14061203","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T02:01:15Z","timestamp":1685498475000},"page":"1203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Diagnostic Yield of Exome Sequencing in Fetuses with Sonographic Features of Skeletal Dysplasias but Normal Karyotype or Chromosomal Microarray Analysis: A Systematic Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8919-0848","authenticated-orcid":false,"given":"Kai Yeung","family":"Tse","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Queen Elizabeth Hospital, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilham Utama","family":"Surya","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6260-6273","authenticated-orcid":false,"given":"Rima","family":"Irwinda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9289-6857","authenticated-orcid":false,"given":"Kwok Yin","family":"Leung","sequence":"additional","affiliation":[{"name":"Gleneagles Hospital Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuen Ha","family":"Ting","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3616-6200","authenticated-orcid":false,"given":"Kwong Wai","family":"Choy","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China"},{"name":"Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"key":"ref_1","unstructured":"The Fetal Medicine Foundation (2023, April 15). Skeletal Dysplasia. Available online: https:\/\/fetalmedicine.org\/education\/fetal-abnormalities\/skeleton\/skeletal-dysplasia."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/(SICI)1096-8628(19960102)61:1<49::AID-AJMG10>3.0.CO;2-W","article-title":"Epidemiology of osteochondrodysplasias: Changing trends due to advances in prenatal diagnosis","volume":"61","author":"Rasmusen","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"ref_3","first-page":"441","article-title":"Birth prevalence of skeletal dysplasias in the Italian multicentric monitoring system for birth defects","volume":"104","author":"Camera","year":"1982","journal-title":"Prog. Clin. Biol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1002\/ajmg.a.61366","article-title":"Nosology and classification of genetic skeletal disorders: 2019 revision","volume":"179","author":"Mortier","year":"2019","journal-title":"Am. J. Med. Genet. Part. A"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1056\/NEJMoa1203382","article-title":"Chromosomal microarray versus karyotyping for prenatal diagnosis","volume":"367","author":"Wapner","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/uog.17533","article-title":"Frequency of submicroscopic chromosomal aberrations in pregnancies without increased risk for structural chromosomal aberrations: Systematic review and meta-analysis","volume":"51","author":"Srebniak","year":"2018","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1002\/pd.3945","article-title":"Experience with microarray-based comparative genomic hybridization for prenatal diagnosis in over 5000 pregnancies","volume":"10","author":"Shaffer","year":"2012","journal-title":"Prenat. Diagn."},{"key":"ref_8","first-page":"1","article-title":"Exome sequencing in genetic disease: Recent advances and considerations","volume":"9","author":"Rouleau","year":"2020","journal-title":"F1000Research"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S0140-6736(18)31940-8","article-title":"Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): A cohort study","volume":"393","author":"Lord","year":"2019","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/S0140-6736(18)32042-7","article-title":"Whole-exome sequencing in the evaluation of fetal structural anomalies: A prospective cohort study","volume":"393","author":"Petrovski","year":"2019","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1002\/pd.6157","article-title":"International Society for Prenatal Diagnosis Updated Position Statement on the use of genome-wide sequencing for prenatal diagnosis","volume":"42","author":"Chandler","year":"2022","journal-title":"Prenat. Diagn."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/uog.12575","article-title":"Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: A systematic review of the literature","volume":"43","author":"Srebniak","year":"2014","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_13","first-page":"1430","article-title":"Rapid prenatal diagnosis using targeted exome sequencing: A cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management","volume":"20","author":"Chandler","year":"2018","journal-title":"Anesth. Analg."},{"key":"ref_14","first-page":"2492590","article-title":"Genetic Analysis in Fetal Skeletal Dysplasias by Trio Whole-Exome Sequencing","volume":"2019","author":"Yang","year":"2019","journal-title":"BioMed. Res. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13000-019-0853-x","article-title":"Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: An analysis of 30 cases","volume":"14","author":"Liu","year":"2019","journal-title":"Diagn. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.cca.2020.04.031","article-title":"Prenatal diagnosis of skeletal dysplasias using whole exome sequencing in China","volume":"507","author":"Tang","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1002\/pd.5653","article-title":"Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: Benefit for prenatal counseling and pregnancy management","volume":"40","author":"Han","year":"2020","journal-title":"Prenat. Diagn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"728544","DOI":"10.3389\/fgene.2021.728544","article-title":"Whole Exome Sequencing Analysis in Fetal Skeletal Dysplasia Detected by Ultrasonography: An Analysis of 38 Cases","volume":"12","author":"Peng","year":"2021","journal-title":"Front. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"599863","DOI":"10.3389\/fgene.2021.599863","article-title":"Whole Exome Sequencing Aids the Diagnosis of Fetal Skeletal Dysplasia","volume":"12","author":"Tang","year":"2021","journal-title":"Front. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1002\/pd.5974","article-title":"Combined exome sequencing and deep phenotyping in highly selected fetuses with skeletal dysplasia during the first and second trimesters improves diagnostic yield","volume":"41","author":"Zhang","year":"2021","journal-title":"Prenat. Diagn."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/cge.13976","article-title":"Molecular diagnosis for 55 fetuses with skeletal dysplasias by whole-exome sequencing: A retrospective cohort study","volume":"100","author":"Zhang","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1007\/s00438-022-01899-x","article-title":"Prenatal trio-based whole exome sequencing in fetuses with abnormalities of the skeletal system","volume":"297","author":"Yang","year":"2022","journal-title":"Mol. Genet. Genom."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/aogs.14003","article-title":"The role of chromosomal microarray analysis among fetuses with normal karyotype and single system anomaly or nonspecific sonographic findings","volume":"100","author":"Hui","year":"2021","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1186\/s13023-021-02025-7","article-title":"Diagnostic utility of next-generation sequencing-based panel testing in 543 patients with suspected skeletal dysplasia","volume":"16","author":"Scocchia","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/pd.6115","article-title":"Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta-analysis","volume":"42","author":"Mellis","year":"2022","journal-title":"Prenat. Diagn."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1032346","DOI":"10.3389\/fgene.2023.1032346","article-title":"Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study","volume":"14","author":"Huang","year":"2023","journal-title":"Front. 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