{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T03:06:26Z","timestamp":1773198386353,"version":"3.50.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Copy number variants of uncertain significance (VUS-CNVs) pose significant challenges in prenatal counseling for congenital heart malformations (CHMs). Their clinical relevance remains poorly defined, particularly in the absence of postnatal validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To characterize the phenotypic and molecular features of VUS-CNVs in CHM fetuses and evaluate their clinical implications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      From a cohort of 644 fetuses with CHMs undergoing chromosomal microarray analysis (CMA), we identified 9 VUS-CNV cases. All reportable CNVs (\u2265200\u2005kb or in known pathogenic regions such as 22q11.21) were validated by TaqMan qPCR. Detailed prenatal echocardiography, trio CMA (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097), and postnatal follow-up were integrated for comprehensive assessment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>VUS-CNVs were identified in 9 of 644 (1.40%) CMA-tested fetuses with CHMs. These included 3 in isolated CHM, 1 in complex CHM, 3 in CHM with extracardiac structural anomalies, and 2 in CHM with isolated soft markers. VUS-CNVs in non-isolated cases were larger (median: 2.5 Mb vs. 0.72 Mb in isolated CHM) and encompassed more OMIM-listed genes (mean: 3.8 vs. 1.5 in isolated CHM) than those in isolated CHM. Trio analysis reclassified 3 of 7 tested VUS-CNVs (2 as likely benign, 1 as likely pathogenic). Six pregnancies continued to term\u20143 with isolated and 3 with non-isolated CHM\u2014and all live-born infants showed no major postnatal abnormalities. The three terminations involved non-isolated phenotypes; decisions were primarily driven by structural anomaly severity, though the VUS amplified prognostic uncertainty.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Although VUS-CNVs are uncommon in fetuses with CHMs, they occur more frequently in non-isolated phenotypes and carry the potential for future reclassification\u2014posing significant challenges in prenatal genetic counseling. These two aspects underscore the necessity of trio-based genomic testing, cautious interpretation of results, and longitudinal follow-up. Given the limited sample size of this study, no causal relationship between VUS-CNVs and clinical phenotypes can be inferred; however, our findings support a risk-stratified management framework that integrates detailed fetal phenotyping, trio analysis, and postnatal follow-up to enable accurate variant interpretation and informed decision-making.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fped.2026.1696089","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T06:41:24Z","timestamp":1773124884000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic spectrum and molecular characteristics of variants of uncertain significance in copy number variations associated with fetal cardiac malformations: a case series of 9 patients"],"prefix":"10.3389","volume":"14","author":[{"given":"Jun","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Ultrasound, Pediatrics, Cardiology, Obstetrics and Gynecology, Anorectal Surgery, West China Hospital Sichuan University Jintang Hospital, Jintang First People\u2019s Hospital","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingsong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Pediatrics, Cardiology, Obstetrics and Gynecology, Anorectal Surgery, West China Hospital Sichuan University Jintang Hospital, Jintang First People\u2019s Hospital","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Pediatrics, Cardiology, Obstetrics and Gynecology, Anorectal Surgery, West China Hospital Sichuan University Jintang Hospital, Jintang First People\u2019s Hospital","place":["Chengdu, Sichuan, 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