{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T06:58:53Z","timestamp":1764831533063,"version":"3.46.0"},"reference-count":12,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Laboratory of Reproductive Health of Shaoxing City, Shaoxing Maternity and Child Health Care Hospital","award":["2023SSY007","2023SSY004"],"award-info":[{"award-number":["2023SSY007","2023SSY004"]}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2023YFC2705602","2023YFC2705600"],"award-info":[{"award-number":["2023YFC2705602","2023YFC2705600"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Health Commission of Shaoxing, China","award":["2024SKY052","2024SKY053","2024SKY003","2023SKY047","2022KY039","2022KY038","2022KY036","2022KY035"],"award-info":[{"award-number":["2024SKY052","2024SKY053","2024SKY003","2023SKY047","2022KY039","2022KY038","2022KY036","2022KY035"]}]},{"name":"Science Technology Department of Shaoxing, China","award":["2024A14004","2023A14034","2022A14006"],"award-info":[{"award-number":["2024A14004","2023A14034","2022A14006"]}]},{"name":"Health Commission of Zhejiang Province, China","award":["2023KY368","WKJ-ZJ-2449"],"award-info":[{"award-number":["2023KY368","WKJ-ZJ-2449"]}]},{"name":"Science Technology Department of Zhejiang Province, China","award":["LTGY24H040006","LTGY24H040005","LTGY23H040005","LTGY23H040004"],"award-info":[{"award-number":["LTGY24H040006","LTGY24H040005","LTGY23H040005","LTGY23H040004"]}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Fraser syndrome (FS) is an autosomal recessive inherited malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tracts. Variants in the FRAS1-related extracellular matrix 2 (FREM2) gene are the major genetic cause. However, clinical diagnosis remains challenging due to phenotypic heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A 24-week pregnant woman came to our hospital for genetic diagnosis. Ultrasound examination showed bilateral renal agenesis or dysplasia, absence of the bladder, and almost oligohydramnios. Trio whole-exome sequencing (Trio-WES) identified two novel compound heterozygous variants in the fetal FREM2 gene: a maternal, frameshift variant, c.5908_5909del, p.Leu1970ValfsTer33, and a paternal, nonsense variant, c.7881C&amp;gt;G,p.Tyr2627Ter.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We report a rare case of Fraser syndrome 2 caused by compound heterozygous mutations in the FREM2 gene. Our findings expanded the\n                      <jats:italic>FREM2<\/jats:italic>\n                      genotypic spectrum and demonstrated the significance of Trio-WES in the prenatal diagnosis of recessive disorders.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2025.1705708","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T05:16:28Z","timestamp":1764825388000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: A case of Fraser syndrome 2 in a Chinese fetus caused by novel compound heterozygous variants in the FREM2 gene"],"prefix":"10.3389","volume":"12","author":[{"given":"Weidong","family":"Wei","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinan","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yedan","family":"Lou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jieyuan","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sinan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1136\/jmg.39.9.623","article-title":"Fraser 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review of the literature","volume":"18","author":"Berg","year":"2001","journal-title":"Ultrasound Obstet Gynecol"},{"key":"ref5","first-page":"80","article-title":"Fraser syndrome\u2014a case report and review of literature","volume":"11","author":"Dumitru","year":"2016","journal-title":"Maedica"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/nrg.2017.75","article-title":"Human gene essentiality","volume":"19","author":"Bartha","year":"2018","journal-title":"Nat Rev Genet"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"839617","DOI":"10.3389\/fmolb.2022.839617","article-title":"Identification and comprehensive analysis of FREM2 mutation as a potential prognostic biomarker in colorectal cancer","volume":"9","author":"Du","year":"2022","journal-title":"Front Mol Biosci"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/j.exer.2019.02.013","article-title":"Loss-of-function mutations in FREM2 disrupt eye morphogenesis","volume":"181","author":"Zhang","year":"2019","journal-title":"Exp Eye Res"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41439-020-00119-5","article-title":"Prenatal diagnosis of Fraser syndrome caused by novel variants of FREM2","volume":"7","author":"Ikeda","year":"2020","journal-title":"Hum Genome Var"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"24786","DOI":"10.18632\/aging.203715","article-title":"Excluding embryos with two novel mutations in FREM2 gene by the next-generation sequencing-based single nucleotide polymorphism haplotyping","volume":"13","author":"Zhou","year":"2021","journal-title":"Aging"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/s10038-021-00972-4","article-title":"Cryptophthalmos, dental anomalies, oral vestibule defect, and a novel FREM2 mutation","volume":"67","author":"Kantaputra","year":"2022","journal-title":"J Hum Genet"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"2357","DOI":"10.1093\/hmg\/ddy144","article-title":"A homozygous mutation p.Arg2167Trp in FREM2 causes isolated cryptophthalmos","volume":"27","author":"Yu","year":"2018","journal-title":"Hum Mol Genet"}],"container-title":["Frontiers in 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