Abstract：
BACKGROUND: Wilms tumor 1 (WT1; NM_024426) causes Denys-Drash syndrome, Frasier syndrome, or isolated focal segmental glomerulosclerosis. Several WT1 intron variants are pathogenic; however, the pathogenicity of some variants remains undefined. Whether a candidate variant detected in a patient is pathogenic is very important for determining the therapeutic options for the patient.
METHODS: In this study, we evaluated the pathogenicity of WT1 gene intron variants with undetermined pathogenicity by comparing their splicing patterns with those of the wild-type using an in vitro splicing assay using minigenes. The three variants registered as likely disease-causing genes: Mut1 (c.1017-9 T > C(IVS5)), Mut2 (c.1355-28C > T(IVS8)), Mut3 (c.1447 + 1G > C(IVS9)), were included as subjects along the 34 splicing variants registered in the Human Gene Mutation Database (HGMD)®.
RESULTS: The results showed no significant differences in splicing patterns between Mut1 or Mut2 and the wild-type; however, significant differences were observed in Mut3.
CONCLUSIONS: We concluded that Mut1 and Mut2 do not possess pathogenicity although they were registered as likely pathogenic, whereas Mut3 exhibits pathogenicity. Our results suggest that the pathogenicity of intronic variants detected in patients should be carefully evaluated.
METHODS: In this study, we evaluated the pathogenicity of WT1 gene intron variants with undetermined pathogenicity by comparing their splicing patterns with those of the wild-type using an in vitro splicing assay using minigenes. The three variants registered as likely disease-causing genes: Mut1 (c.1017-9 T > C(IVS5)), Mut2 (c.1355-28C > T(IVS8)), Mut3 (c.1447 + 1G > C(IVS9)), were included as subjects along the 34 splicing variants registered in the Human Gene Mutation Database (HGMD)®.
RESULTS: The results showed no significant differences in splicing patterns between Mut1 or Mut2 and the wild-type; however, significant differences were observed in Mut3.
CONCLUSIONS: We concluded that Mut1 and Mut2 do not possess pathogenicity although they were registered as likely pathogenic, whereas Mut3 exhibits pathogenicity. Our results suggest that the pathogenicity of intronic variants detected in patients should be carefully evaluated.
摘要：
背景：Wilms肿瘤1（WT1;NM_024426）导致Denys-Drash综合征，Frasier综合征,或孤立的局灶节段性肾小球硬化。几种WT1内含子变体是致病性的；然而，某些变异的致病性仍未定义.在患者中检测到的候选变体是否是致病性的对于确定患者的治疗选择非常重要。
方法：在本研究中，我们使用小基因体外剪接试验,通过比较其剪接模式与野生型的剪接模式,评估了致病性未定的WT1基因内含子变异体的致病性.登记为可能的致病基因的三个变异：Mut1（c.1017-9T>C（IVS5）），Mut2（c.1355-28C>T（IVS8）），Mut3（c.1447+1G>C（IVS9）），在人基因突变数据库(HGMD)®中登记的34个剪接变体中作为受试者包括在内。
结果：结果显示Mut1或Mut2与野生型之间的剪接模式没有显着差异；但是，在Mut3中观察到显著差异。
结论：我们得出结论，Mut1和Mut2不具有致病性，尽管它们被登记为可能的致病性，而Mut3表现出致病性。我们的结果表明，应仔细评估患者中检测到的内含子变异的致病性。
方法：在本研究中，我们使用小基因体外剪接试验,通过比较其剪接模式与野生型的剪接模式,评估了致病性未定的WT1基因内含子变异体的致病性.登记为可能的致病基因的三个变异：Mut1（c.1017-9T>C（IVS5）），Mut2（c.1355-28C>T（IVS8）），Mut3（c.1447+1G>C（IVS9）），在人基因突变数据库(HGMD)®中登记的34个剪接变体中作为受试者包括在内。
结果：结果显示Mut1或Mut2与野生型之间的剪接模式没有显着差异；但是，在Mut3中观察到显著差异。
结论：我们得出结论，Mut1和Mut2不具有致病性，尽管它们被登记为可能的致病性，而Mut3表现出致病性。我们的结果表明，应仔细评估患者中检测到的内含子变异的致病性。
