An intronic variant disrupts mRNA splicing and causes FGFR3-related skeletal dysplasia
An intronic variant disrupts mRNA splicing and causes FGFR3-related skeletal dysplasia
复制标题
内含子变异破坏 mRNA 剪接并导致 FGFR3 相关骨骼发育不良
DOI：
10.1515/jpem-2020-0679
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发表时间：
2021-06
影响因子：
1.4
通讯作者：
Yanjie Fan
中科院分区：
文献类型：
--
作者：
Ting Xu;Liang Shi;Weiqian Dai;Xuefan Gu;Yongguo Yu;Yanjie Fan
摘要目的软骨发育不良和软骨发育不良是不成比例矮小的最常见形式，绝大多数病例可归因于FGFR3基因的热点错义突变。在这里，我们提出了一种新的FGFR3基因的隐蔽剪接变体的病例，目的是询问该变体的致病性。1例在两例软骨发育不良样特征患者的外显子全序列中，发现了一个新的内含子变异体C.1075+95C>；G，预测会改变mRNA的剪接。微基因分析表明，该内含子变异导致了mRNA中内含子8的90个核苷酸片段的保留，导致在蛋白质的胞外区插入了30个氨基酸。这是在FGFR3基因中发现的第一个可能的致病剪接变异，并在26名遗传未解决的患者中另外一名患者中检测到。结论C.1075+95C>；G是一种复发性突变，应纳入FGFR3基因检测，尤其是临床表现不明确且未发现外显子突变的患者。
Abstract Objectives Achondroplasia and hypochondroplasia are the most common forms of disproportionate short stature, of which the vast majority of cases can be attributed to the hotspot missense mutations in the gene FGFR3. Here we presented cases with a novel cryptic splicing variant of FGFR3 gene and aimed to interrogate the variant pathogenicity. Case presentaiton In whole exome sequencing of two patients with hypochondroplasia-like features, a de novo intronic variant c.1075 + 95C>G was identified, predicted to alter mRNA splicing. Minigene assay showed that this intronic variant caused retention of a 90-nucleotide segment of intron 8 in mRNA, resulting in a 30-amino acid insertion at the extracellular domain of the protein. This is the first likely pathogenic splicing variant identified in the FGFR3 gene and was detected in one additional patient among 26 genetically unresolved patients. Conclustions Our results strongly suggest that c.1075 + 95C>G is a recurrent mutation and should be included in genetic testing of FGFR3 especially for those patients with equivocal clinical findings and no exonic mutations identified.