{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T16:15:51Z","timestamp":1770135351482,"version":"3.49.0"},"reference-count":27,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:00:00Z","timestamp":1769817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["BG16RFPR002-1.014-0007"],"award-info":[{"award-number":["BG16RFPR002-1.014-0007"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background: Prenatal detection of fetal structural anomalies often prompts chromosomal analysis; however, chromosomal microarray analysis (CMA) has limited diagnostic yield for monogenic disorders. Whole-exome sequencing (WES) has emerged as a powerful tool for identifying single-gene etiologies, particularly in cases with complex neurodevelopmental phenotypes. Case Presentation: We report a female infant presenting with prenatally detected ventriculomegaly and inconclusive chromosomal testing. Prenatal investigations, including karyotyping and genome-wide chromosomal sequencing, identified several copy number variants classified as variants of uncertain significance but failed to establish a definitive diagnosis. Postnatally, the patient developed progressive neurological abnormalities, including microcephaly, facial dysmorphism, dystonic movements, and severe global developmental delay. Trio-based whole-exome sequencing identified a heterozygous de novo pathogenic missense variant in the DDX3X gene (c.976C&gt;T; p.Arg326Cys), establishing the diagnosis of DDX3X-related neurodevelopmental disorder. Conclusions: This case highlights the diagnostic limitations of standard prenatal chromosomal testing in detecting monogenic neurodevelopmental disorders and underscores the critical role of timely genetic counseling and exome sequencing. Earlier selective implementation of WES during pregnancy could have enabled an earlier diagnosis, improved prognostic counseling, and optimized clinical decision-making.<\/jats:p>","DOI":"10.3390\/children13020202","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:00:47Z","timestamp":1770033647000},"page":"202","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exome Sequencing Resolving a Complex Pediatric Neurodevelopmental Disorder After Inconclusive Prenatal Testing: A Case Report"],"prefix":"10.3390","volume":"13","author":[{"given":"Margarita","family":"Panova","sequence":"first","affiliation":[{"name":"Department of Pediatrics \u201cProf. Dr. Ivan Andreev\u201d, Medical University Plovdiv, 4000 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7912-3673","authenticated-orcid":false,"given":"Hristo","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical University Plovdiv, 4000 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iglika","family":"Sotkova-Ivanova","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical University Plovdiv, 4000 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2025072219","DOI":"10.1542\/peds.2025-072219","article-title":"Genetic Evaluation of the Child with Intellectual Disability or Global Developmental Delay: Clinical Report","volume":"156","author":"Rodan","year":"2025","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1097\/GCO.0000000000000692","article-title":"The Role of Chromosomal Microarray and Exome Sequencing in Prenatal Diagnosis","volume":"33","author":"Chau","year":"2021","journal-title":"Curr. Opin. Obstet. Gynecol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.fertnstert.2018.01.005","article-title":"Prenatal Diagnosis by Chromosomal Microarray Analysis","volume":"109","author":"Levy","year":"2018","journal-title":"Fertil. Steril."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"B2","DOI":"10.1016\/j.ajog.2016.07.016","article-title":"The Use of Chromosomal Microarray for Prenatal Diagnosis","volume":"215","author":"Dugoff","year":"2016","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"15920","DOI":"10.1038\/s41598-024-67123-5","article-title":"Chromosomal Abnormalities Detected by Chromosomal Microarray Analysis and Pregnancy Outcomes of 4211 Fetuses with High-Risk Prenatal Indications","volume":"14","author":"Li","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"\u00d6zer, L., Aktuna, S., and \u00dcnsal, E. (2025). Diagnostic Performance of Chromosomal Microarray and Whole Exome Sequencing in Fetal Structural Anomalies: A Single-Center Retrospective Study. BMC Pregnancy Childbirth, 25.","DOI":"10.1186\/s12884-025-08167-x"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1001\/jamapediatrics.2023.0008","article-title":"Diagnostic Yield of Exome Sequencing in Cerebral Palsy and Implications for Genetic Testing Guidelines: A Systematic Review and Meta-Analysis","volume":"177","author":"Hu","year":"2023","journal-title":"JAMA Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"483.e1","DOI":"10.1016\/j.ajog.2025.05.003","article-title":"Evaluating the Clinical Utility and Strategy of Whole-Exome Sequencing Testing for Fetuses with Increased Nuchal Translucency","volume":"233","author":"Zhou","year":"2025","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s41431-024-01590-2","article-title":"Prenatal Genome-Wide Sequencing Analysis (Exome or Genome) in Detecting Pathogenic Single Nucleotide Variants in Fetal Central Nervous System Anomalies: A Systematic Review and Meta-Analysis","volume":"32","author":"Marchionni","year":"2024","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_10","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_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":"931","DOI":"10.1136\/jmedgenet-2021-107897","article-title":"Clinical Application of Fetal Genome-Wide Sequencing during Pregnancy: Position Statement of the Canadian College of Medical Geneticists","volume":"59","author":"Lazier","year":"2022","journal-title":"J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1111\/jnc.16174","article-title":"DDX3X syndrome: From clinical phenotypes to biological insights","volume":"168","year":"2024","journal-title":"J. Neurochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.neuron.2020.01.042","article-title":"Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development","volume":"106","author":"Lennox","year":"2020","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4512","DOI":"10.1038\/s41467-025-59680-8","article-title":"Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X","volume":"16","author":"Mossa","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.pediatrneurol.2022.10.009","article-title":"DDX3X Syndrome: Summary of Findings and Recommendations for Evaluation and Care","volume":"138","author":"Levy","year":"2023","journal-title":"Pediatr. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mosti, F., Hoye, M.L., Escobar-Tomlienovich, C.F., and Silver, D.L. (2025). Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations. PLoS Genet., 21.","DOI":"10.1371\/journal.pgen.1011555"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23622","DOI":"10.1038\/s41598-025-06714-2","article-title":"Genetic Etiology of Ventriculomegaly in 73 Fetuses Identified by High-Throughput Sequencing","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1111\/1471-0528.17710","article-title":"Diagnostic Yield of Prenatal Exome Sequencing in the Genetic Screening of Fetuses with Brain Anomalies Detected by MRI and Ultrasonography: A Systematic Review and Meta-Analysis","volume":"131","author":"Moradi","year":"2024","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1111\/1471-0528.18222","article-title":"Prenatal Diagnosis of Fetal Structural Anomalies Using Medium-Coverage Whole Genome Sequencing (CMA-Seq): A Large-Scale Comparative Study with CMA in 3973 Pregnancies","volume":"132","author":"Jiang","year":"2025","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1038\/s41431-019-0392-7","article-title":"Three De Novo DDX3X Variants Associated with Distinctive Brain Developmental Abnormalities and Brain Tumor in Intellectually Disabled Females","volume":"27","author":"Scala","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_22","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_23","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_24","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1002\/uog.24885","article-title":"Exome Sequencing as First-Tier Test for Fetuses with Severe Central Nervous System Structural Anomalies","volume":"60","author":"Yaron","year":"2022","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.1111\/1471-0528.16616","article-title":"Evidence to Support the Clinical Utility of Prenatal Exome Sequencing in Evaluation of the Fetus with Congenital Anomalies: Scientific Impact Paper No. 64","volume":"128","author":"Mone","year":"2021","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"265ra168","DOI":"10.1126\/scitranslmed.3010076","article-title":"Effectiveness of Exome and Genome Sequencing Guided by Acuity of Illness for Diagnosis of Neurodevelopmental Disorders","volume":"6","author":"Soden","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"a036533","DOI":"10.1101\/cshperspect.a036533","article-title":"Genetic Counseling in Neurodevelopmental Disorders","volume":"10","author":"Blesson","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/13\/2\/202\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T05:16:33Z","timestamp":1770095793000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/13\/2\/202"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,31]]},"references-count":27,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["children13020202"],"URL":"https:\/\/doi.org\/10.3390\/children13020202","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,31]]}}}