{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:36:43Z","timestamp":1759451803186,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["C92F17003560001"],"award-info":[{"award-number":["C92F17003560001"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Trieste, Italy","award":["D70-RESRICGIROTTO"],"award-info":[{"award-number":["D70-RESRICGIROTTO"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Foetal structural abnormalities can be detected in approximately 3% of all pregnancies and frequently remain without a genetic diagnosis. This study aims to apply an integrated approach with the final goal of providing a molecular diagnosis in the challenging Italian setting of early termination of pregnancy. Methods: In a cohort of 86 foetuses, post-mortem dysmorphological examination, radiological assessments, and molecular autopsy through Whole-Exome Sequencing\u2014WES\u2014analysis were performed. Results: Forty-two foetuses were phenotypically classified as presenting a single major malformation (i.e., central nervous system, skeletal, urogenital, or cardiac anomalies, or fluid accumulation), while 44 foetuses presented multiple malformations and\/or dysmorphic features. Overall, WES provided a diagnostic yield of 26.7%; additionally, seven Variants of Uncertain Significance (VUS) potentially liked to the foetal phenotype were identified. The highest detection rate was achieved for foetuses presenting a single major urogenital (50%) or skeletal (42.9%) malformation, followed by foetuses presenting multiple malformations (27.3%). Peculiar results of particular interest were (1) the identification of two splicing variants (within the INPPL1 and RHOA genes), functionally characterised through minigene assay, which contributed to evaluate their pathogenicity, and (2) the identification of a novel de novo missense ZNF292 variant (NM_015021.3:c.6325A&gt;C p.(Ser2109Arg)) in a foetus affected by corpus callosum hypoplasia. The ZNF292 gene is associated with the Intellectual developmental disorder, autosomal dominant 64 and this finding represents the first report of prenatally detected anomalies of the central nervous system in a foetus carrying a ZNF292 variant. Conclusions: This study underlines the diagnostic utility of an integrated approach to achieve a precise genetic diagnosis for structural foetal abnormalities, thus providing families with precise recurrence risk estimations and detailed options about future pregnancies. Additionally, a systematic implementation of this strategy could be crucial to better characterise new variants and discover new genes involved in embryonic and foetal development.<\/jats:p>","DOI":"10.3390\/genes16101167","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T08:20:28Z","timestamp":1759393228000},"page":"1167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond the Curtains: Identification of the Genetic Cause of Foetal Developmental Abnormalities Through the Application of Molecular Autopsy"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7432-4708","authenticated-orcid":false,"given":"Beatrice","family":"Spedicati","sequence":"first","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"},{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0851-1473","authenticated-orcid":false,"given":"Giulia","family":"Pianigiani","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"},{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8940-5463","authenticated-orcid":false,"given":"Aurora","family":"Santin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"},{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa Rebecca","family":"Gasparini","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"},{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Falcomer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4187-6282","authenticated-orcid":false,"given":"Agnese","family":"Feresin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8024-0482","authenticated-orcid":false,"given":"Maria Teresa","family":"Bonati","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Mazz\u00e0","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1240-6513","authenticated-orcid":false,"given":"Elisa","family":"Paccagnella","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8220-3420","authenticated-orcid":false,"given":"Domizia","family":"Pasquetti","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6609-4220","authenticated-orcid":false,"given":"Elisa","family":"Rubinato","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Granata","sequence":"additional","affiliation":[{"name":"Radiology Department, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flora Maria","family":"Murru","sequence":"additional","affiliation":[{"name":"Radiology Department, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9277-9378","authenticated-orcid":false,"given":"Maurizio","family":"Pinamonti","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Trieste, 34149 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-9726","authenticated-orcid":false,"given":"Rossana","family":"Bussani","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Trieste, 34149 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Fantasia","sequence":"additional","affiliation":[{"name":"Unit of Fetal Medicine and Prenatal Diagnosis, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara","family":"Stampalija","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"},{"name":"Unit of Fetal Medicine and Prenatal Diagnosis, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Gasparini","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"},{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Zampieri","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4507-6589","authenticated-orcid":false,"given":"Giorgia","family":"Girotto","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy"},{"name":"Medical Genetics Unit, Institute for Maternal and Child Health\u2014I.R.C.C.S. \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Al-Dewik, N., Samara, M., Younes, S., Al-jurf, R., Nasrallah, G., Al-Obaidly, S., Salama, H., Olukade, T., Hammuda, S., and Marlow, N. 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