小基因
生物
RNA剪接
遗传学
剪接
毛囊素
外显子
参考文献
错义突变
生物信息学
计算生物学
基因
dbSNP公司
核糖核酸
突变
基因型
单核苷酸多态性
基因组
作者
Xinxin Zhang,Minghui Cai,Yuanchun Ma,Jie Chen,Shaoping Huang,Mengru Cai,Yibing Ding,Dehua Mao,Qian Gao,Xiaowen Hu,Chengchu Zhu,Long Yi
标识
DOI:10.1016/j.jmoldx.2022.10.005
摘要
Primary spontaneous pneumothorax (PSP) or pulmonary cyst is one of the manifestations of Birt-Hogg-Dubé syndrome, which is caused by pathogenic variants in FLCN gene. Genetic testing in patients with PSP identifies a certain number of missense or intronic variants. These variants are usually considered as variants of uncertain significance, whose functional interpretations pose a challenge in clinical genetics. To improve recognition of pathogenic splice-altering variants in FLCN gene, computational tools are used to prioritize potential splice-altering variants and then a hybrid minigene assay is performed to verify the RNA splicing pattern. Herein, variants in FLCN exon 11 and its flanking sequence are focused. Eight variants detected in 11 patients with PSP are evaluated, and six variants are prioritized by in silico tools as potential splice-altering variants of uncertain significance. Four variants (c.1177-5_1177-3delCTC, c.1292_1300+4del, c.1300+4C>T, and c.1300+5G>A) are demonstrated by minigene assay to alter RNA splicing of FLCN, and the last three of them are novel. RT-PCR of patient-derived RNA gives consistent results. Genotype-phenotype correlation analysis in patients with PSP with these variants demonstrates good concordance. Our results underline the importance of RNA analysis, which could provide molecular evidence for pathogenicity of a variant, and provide essential information for the clinical interpretation of variants. Combining the clinical information, a definitive diagnosis could be made.
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