小基因
外显子
RNA剪接
内含子
生物
遗传学
外显子跳跃
选择性拼接
突变
外显子剪接增强剂
基因
核糖核酸
作者
Yasuyo Suzuki,Noriko Nomura,Kenichiro Yamada,Yasukazu Yamada,Atsushi Fukuda,Kyoko Hoshino,Shinpei Abe,Kenji Kurosawa,Masafumi Inaba,Seiji Mizuno,Nobuaki Wakamatsu,Shin Ichi Hayashi
标识
DOI:10.1016/j.ejmg.2023.104882
摘要
High-throughput sequencing has identified vast numbers of variants in genetic disorders. However, the significance of variants at the exon-intron junction remains controversial. Even though most cases of Mowat-Wilson syndrome (MOWS) are caused by heterozygous loss-of-function variants in ZEB2, the pathogenicity of variants at exon-intron junction is often indeterminable. We identified four intronic variants in 5/173 patients with clinical suspicion for MOWS, and evaluated their pathogenicity by in vitro analyses. The minigene analysis showed that c.73+2T>G caused most of the transcripts skipping exon 2, while c.916+6T>G led to partial skipping of exon 7. No splicing abnormalities were detected in both c.917-21T>C and c.3067+6A>T. The minigene analysis reproduced the splicing observed in the blood cells of the patient with c.73+2T>G. The degree of the exon skipping was concordant with the severity of MOWS; while the patient with c.73+2T>G was typical MOWS, the patient with c.916+6T>G showed milder phenotype which has been seldom reported. Our results demonstrate that mRNA splicing assays using the minigenes are valuable for determining the clinical significance of intronic variants in patients with not only MOWS but also other genetic diseases with splicing aberrations and may explain atypical or milder cases, such as the current patient.
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