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oai:figshare.com:article/33991045 2026-09-24T22:03:20Z category_13 portal_316 item_type_3 month_year_09_2026

Supplementary file 1_A novel frameshift RPL15 gene variant associated with hydrops fetalis and perinatal death.docx Xiaoling Chen (679181) Ke Wu (320733) Bo Zhu (118038) Genetics diamond-blackfan anemia 12 hydrops fetalis intrauterine growth restriction perinatal death RPL15 gene Background<p>The heterozygous RPL15 gene (OMIM*604174) variants are associated with autosomal dominant Diamond-Blackfan anemia 12 (DBA12, OMIM#615550). Fewer than ten RPL15 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 RPL15 variant identified in our patient was the first documented case of perinatal death associated with RPL15-related DBA.</p>Methods<p>Trio-based whole-exome sequencing (trio-WES) was performed on genomic DNA (gDNA) of fetal muscular tissues and parental peripheral blood samples. Mutant RPL15 expression vectors pcDNA3.1 (+)-FLAG-RPL15-mut and control pcDNA3.1 (+)-FLAG-RPL15-wt mammalian expression vectors were constructed. Both vectors were subsequently transformed into HEK293 T cells. Assays measuring the relative expression of RPL15 gene mRNA and RPL15 protein were performed. Actinomycin D was used to detect the degradation of RPL15 mRNA. Meanwhile, we reviewed previously reported RPL15-related cases with available clinical data, including relevant genetic testing results and prenatal/postnatal manifestations.</p>Results<p>Trio-WES identified a novel heterozygous frameshift RPL15 gene variant (NM_002948.5) c.227del (p.Pro76Leufs*17) in this fetus. The relative expression of RPL15 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 RPL15-mut cell lines was significantly lower than that in the RPL15-wt cell lines (P < 0.0001). After actinomycin D treatment, mRNA transcription was inhibited in both the RPL15-wt and RPL15-mut cell lines; the RPL15-mut cell lines exhibited a significantly accelerated mRNA decay rate and lower mRNA expression relative to the RPL15-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 RPL15 mRNA. After reviewing the current literature, we found that fetuses with RPL15 gene variants commonly presented with hydrops fetalis, intrauterine growth restriction, and heart defect. The penetrance of loss-of-function variants in the RPL15 gene was high, but appears to be incomplete.</p>Conclusion<p>Fetuses with RPL15 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 RPL15 gene as the underlying pathogenic mechanism of DBA12. This study also expands the mutational spectrum of the RPL15 gene and broadens the associated clinical spectrum of DBA12.</p> 2026-09-24T22:03:20Z Dataset Dataset 10.3389/fgene.2026.1924019.s001 https://figshare.com/articles/dataset/Supplementary_file_1_A_novel_frameshift_RPL15_gene_variant_associated_with_hydrops_fetalis_and_perinatal_death_docx/33991045 CC BY 4.0