{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:59:27Z","timestamp":1790290767720,"version":"4.1.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"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. Genet."],"abstract":"\n Background<\/jats:title>\n \n The heterozygous\n RPL15<\/jats:italic>\n gene (OMIM*604174) variants are associated with autosomal dominant Diamond-Blackfan anemia 12 (DBA12, OMIM#615550). Fewer than ten\n RPL15<\/jats:italic>\n variants have been reported to date, and they are commonly associated with hydrops fetalis, intrauterine growth restriction (IUGR) and neonatal anemia. Fetal demise attributable to the\n RPL15<\/jats:italic>\n variant identified in our patient was the first documented case of perinatal death associated with\n RPL15<\/jats:italic>\n -related DBA.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Trio-based whole-exome sequencing (trio-WES) was performed on genomic DNA (gDNA) of fetal muscular tissues and parental peripheral blood samples. Mutant\n RPL15<\/jats:italic>\n expression vectors pcDNA3.1 (+)-FLAG-\n RPL15<\/jats:italic>\n -mut and control pcDNA3.1 (+)-FLAG-\n RPL15<\/jats:italic>\n -wt mammalian expression vectors were constructed. Both vectors were subsequently transformed into HEK293\u00a0T cells. Assays measuring the relative expression of\n RPL15<\/jats:italic>\n gene mRNA and RPL15 protein were performed. Actinomycin D was used to detect the degradation of\n RPL15<\/jats:italic>\n mRNA. Meanwhile, we reviewed previously reported\n RPL15<\/jats:italic>\n -related cases with available clinical data, including relevant genetic testing results and prenatal\/postnatal manifestations.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Trio-WES identified a novel heterozygous frameshift\n RPL15<\/jats:italic>\n gene variant (NM_002948.5) c.227del (p.Pro76Leufs*17) in this fetus. The relative expression of\n RPL15<\/jats:italic>\n gene mRNA analysis showed that the mRNA expression of mutant RPL15 cell lines was significantly decreased, and the relative expression level of RPL15 protein in the\n RPL15<\/jats:italic>\n -mut cell lines was significantly lower than that in the\n RPL15<\/jats:italic>\n -wt cell lines (\n P<\/jats:italic>\n &lt; 0.0001). After actinomycin D treatment, mRNA transcription was inhibited in both the\n RPL15<\/jats:italic>\n -wt and\n RPL15<\/jats:italic>\n -mut cell lines; the\n RPL15<\/jats:italic>\n -mut cell lines exhibited a significantly accelerated mRNA decay rate and lower mRNA expression relative to the\n RPL15<\/jats:italic>\n -wt cell lines. All these results revealed that this variant resulted in a dramatic reduction in the formation of RPL15 protein due to the decay of mutant\n RPL15<\/jats:italic>\n mRNA. After reviewing the current literature, we found that fetuses with\n RPL15<\/jats:italic>\n gene variants commonly presented with hydrops fetalis, intrauterine growth restriction, and heart defect. The penetrance of loss-of-function variants in the\n RPL15<\/jats:italic>\n gene was high, but appears to be incomplete.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Fetuses with\n RPL15<\/jats:italic>\n gene variants can present with hydrops fetalis, IUGR, heart defects, decreased fetal movements, and extremity abnormalities. Our functional studies have provided preliminary evidence confirming the haploinsufficiency of the\n RPL15<\/jats:italic>\n gene as the underlying pathogenic mechanism of DBA12. This study also expands the mutational spectrum of the\n RPL15<\/jats:italic>\n gene and broadens the associated clinical spectrum of DBA12.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fgene.2026.1924019","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:10:16Z","timestamp":1790287816000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel frameshift RPL15 gene variant associated with hydrops fetalis and perinatal death"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoling","family":"Chen","sequence":"first","affiliation":[{"name":"Obstetrical Department, Quzhou Maternal and Child Healthcare Hospital","place":["Quzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Wu","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis Center, Quzhou Maternal and Child Healthcare Hospital","place":["Quzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhu","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Quzhou Maternal and Child Healthcare Hospital","place":["Quzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1111\/cge.14309","article-title":"Diagnostic yield from prenatal exome sequencing for non-immune hydrops fetalis: a systematic review and meta-analysis","volume":"103","author":"Al-Kouatly","year":"2023","journal-title":"Clin. 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