Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation.
Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russian Federation.
Clin Genet. 2023 Jan;103(1):93-96. doi: 10.1111/cge.14221. Epub 2022 Sep 12.
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by erythroid aplasia. Pathogenic variants in ribosomal protein (RP) genes, GATA1, TSR2, and EPO, are considered to be the etiology of DBA. Variants in 5'-untranslated regions (UTRs) of these genes are poorly studied and can complicate the variant interpretation. We investigated the functional consequences NM_001011.4:c.-19 + 1G > T variant in the donor splice-site of the RPS7 5'-UTR. This variant was found in a family where two sons with DBA were carriers. Father, who also had this variant, developed myelodysplastic syndrome, which caused his death. Search for candidate causal variants and copy number variations in DBA-associated genes left RPS7 variant as the best candidate. Trio whole exome sequencing analysis revealed no pathogenic variants in other genes. Functional analysis using luciferase expression system revealed that this variant leads to disruption of splicing. Also, a decrease in the levels of mRNA and protein expression was detected. In conclusion, the established consequences of 5'-UTR splice-site variant c.-19 + 1G > T in the RPS7 gene provide evidence that it is likely pathogenic.
Diamond-Blackfan 贫血（DBA）是一种遗传性骨髓衰竭综合征，其特征是红系发育不全。核糖体蛋白（RP）基因、GATA1、TSR2 和 EPO 的致病性变异被认为是 DBA 的病因。这些基因 5'-非翻译区（UTR）中的变异研究较少，可能会使变异解释复杂化。我们研究了 RPS7 5'-UTR 供体位点 NM_001011.4:c.-19+1G>T 变异的功能后果。该变体在一个家族中被发现，该家族中有两个患有 DBA 的儿子是携带者。父亲也有这个变体，后来发展成骨髓增生异常综合征，导致他死亡。在 DBA 相关基因中寻找候选致病变异和拷贝数变异，结果 RPS7 变体成为最佳候选者。对三人全外显子组测序分析显示，其他基因没有致病性变异。使用荧光素酶表达系统进行的功能分析表明，该变体导致剪接中断。同时，还检测到 mRNA 和蛋白表达水平下降。总之，RPS7 基因 5'-UTR 剪接位点变异 c.-19+1G>T 的既定后果提供了证据，表明该变异很可能是致病的。
