{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:02:02Z","timestamp":1759881722066,"version":"build-2065373602"},"reference-count":75,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["R.11012\/02\/2018\u2010HR"],"award-info":[{"award-number":["R.11012\/02\/2018\u2010HR"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["obgyn.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Prenatal Diagnosis"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To evaluate the diagnostic utility of exome sequencing (ES) in structurally abnormal fetuses and infants with suspected severe Mendelian developmental defects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This retrospective study included fetuses (\u2265\u00a012\u00a0weeks) and infants (\u2264\u00a06\u00a0months old) with suspected severe Mendelian disorders, clinically categorized as multiple malformations (MM), non\u2010immune hydrops (NIH), and skeletal dysplasia (SKD). All subjects underwent detailed evaluation by a clinical geneticist, which included a clinical examination or fetal autopsy, as applicable, with parental consent. Based on the type of anomaly, investigations such as karyotype, chromosomal microarray (CMA), and\/or proband exome sequencing (ES) were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Ninety\u2010seven unrelated subjects were enrolled, including 25 (25.8%) multiplex and 17 (17.5%) consanguineous families. They were categorized as multiple malformations (MM) (60\/97), skeletal dysplasia (SKD) (19\/97), and non\u2010immune hydrops (NIH) (18\/97), respectively. The CMA performed in 23 subjects was normal. The overall diagnostic yield of ES for pathogenic\/likely pathogenic variants was 40.2% (39\/97) and was higher in SKD (57.9%, 11\/19), followed by NIH (44.4%, 8\/18) and MM (33.3%, 20\/60). Eighteen novel variants were identified in 16 genes in various categories. Additional findings on fetal autopsy helped in making a precise diagnosis in 8\/21 (38%) subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study elucidates the molecular basis of severe Mendelian developmental defects in early life. Proband\u2010only ES helps in reaching a precise diagnosis in combination with deep phenotyping using fetal autopsy and has a good diagnostic yield. It could be used as a first\u2010tier test, especially in resource\u2010poor settings.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pd.6872","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T01:20:27Z","timestamp":1757640027000},"page":"1220-1233","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genomic Exploration of Severe Mendelian Developmental Anomalies: Insights From Exome Sequencing Analyses in a Large Indian Cohort"],"prefix":"10.1002","volume":"45","author":[{"given":"Neerja","family":"Gupta","sequence":"first","affiliation":[{"name":"Division of Genetics Department of Pediatrics All India Institute of Medical Sciences  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mounika","family":"Endrakanti","sequence":"additional","affiliation":[{"name":"Division of Genetics Department of Pediatrics All India Institute of Medical Sciences  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3299-3794","authenticated-orcid":false,"given":"Rohit","family":"Sadanand","sequence":"additional","affiliation":[{"name":"Division of Genetics Department of Pediatrics All India Institute of Medical Sciences  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamal","family":"Naini","sequence":"additional","affiliation":[{"name":"Division of Genetics Department of Pediatrics All India Institute of Medical Sciences  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vatsla","family":"Dadhwal","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology All India Institute of Medical Sciences  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manisha","family":"Jana","sequence":"additional","affiliation":[{"name":"Department of Radiodiagnosis All India Institute of Medical Sciences  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aparna","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology All India Institute of Medical Sciences  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3315-9782","authenticated-orcid":false,"given":"Madhulika","family":"Kabra","sequence":"additional","affiliation":[{"name":"Division of Genetics Department of Pediatrics All India Institute of Medical Sciences  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.24862"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j2249"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-021-04213-w"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJGM.S483290"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2017.3438"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32042-7"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-018-0582-x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-0750-4"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/aogs.14053"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2013.129"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi1110s43"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3036"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw971"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","unstructured":"K. J.Karczewski L. C.Francioli G.Tiao et\u00a0al. \u201cVariation Across 141 456 Human Exomes and Genomes Reveals the Spectrum of Loss\u2010of\u2010Function Intolerance Across Human Protein\u2010Coding Genes \u201d bioRxiv (2019) https:\/\/doi.org\/10.1101\/531210.","DOI":"10.1101\/531210"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_21_1","unstructured":"C. E.\u2010J.Durkie I.Berry M.Owens et\u00a0al. ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024 (n.d.)."},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.18-26275"},{"key":"e_1_2_10_23_1","unstructured":"National Center for Biotechnology Information ClinVar; [VCV001064604.12] (n.d.) accessed August 22 2025 https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/VCV001064604.12."},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2012.254"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv242"},{"key":"e_1_2_10_26_1","unstructured":"National Center for Biotechnology Information ClinVar; [VCV002181970.2] (n.d.) accessed August 22 2025 https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/VCV002181970.2."},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2016-0173"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43141-021-00204-4"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.40.5.333"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2018.50"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq377"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.59"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI20641"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.594"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2012.06.002"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.18999\/nagjms.84.4.871"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.038695"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.25920"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/neup.12036"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32880"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr037"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-016-3709-1"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20799"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.1124"},{"key":"e_1_2_10_45_1","unstructured":"LOVD Variant #0000000093 (Record #00000180) [Internet]. Leiden Open Variation Database (2025) https:\/\/databases.lovd.nl\/shared\/variants\/0000000093#00000180."},{"key":"e_1_2_10_46_1","unstructured":"National Center for Biotechnology Information ClinVar; [VCV002894806.3] (n.d.) accessed August 22 2025 https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/VCV002894806.3."},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.10.003"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-97149-y"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/ahg.12417"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2018-105390"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.6022"},{"key":"e_1_2_10_52_1","unstructured":"National Center for Biotechnology Information ClinVar; [VCV000653322.43] (n.d.) accessed August 22 2025 https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/VCV000653322.43."},{"key":"e_1_2_10_53_1","unstructured":"National Center for Biotechnology Information ClinVar; [VCV000451330.17] (n.d.) accessed August 22 2025 https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/VCV000451330.17."},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.4081\/ejtm.2017.6832"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2015.01.010"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0298-8"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.27647"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.6115"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02142-1"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.1710"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jp.7211482"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.6172"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.24885"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1159\/000504818"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.03.009"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1159\/000521331"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14309"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2023643"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP275718"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-75738-x"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes14061203"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30531"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx239"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.31"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1159\/000519701"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2023.06.009"}],"container-title":["Prenatal Diagnosis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/obgyn.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pd.6872","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T23:40:15Z","timestamp":1759794015000},"score":1,"resource":{"primary":{"URL":"https:\/\/obgyn.onlinelibrary.wiley.com\/doi\/10.1002\/pd.6872"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":75,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1002\/pd.6872"],"URL":"https:\/\/doi.org\/10.1002\/pd.6872","archive":["Portico"],"relation":{},"ISSN":["0197-3851","1097-0223"],"issn-type":[{"type":"print","value":"0197-3851"},{"type":"electronic","value":"1097-0223"}],"subject":[],"published":{"date-parts":[[2025,9]]},"assertion":[{"value":"2024-12-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}