A Novel Heterozygous Intronic FBN1 Variant Contributes to Aberrant RNA Splicing in Marfan Syndrome.

IF 1.5 4区 医学 Q4 GENETICS & HEREDITY
Djouhayna Dougarem, Yi-Xiao Chen, Yi-Na Sun, He-Feng Huang, Qiong Luo
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引用次数: 0

Abstract

Background: Marfan syndrome (MFS) is a complex genetic systemic connective tissue disorder. It is well known that genetic factors play a critical role in the progression of MFS, with nearly all cases attributed to variants in the FBN1 gene.

Methods: We investigated a Chinese family with MFS spanning two generations. Whole exome sequencing, in silico analysis, minigene constructs, transfection, RT-PCR, and protein secondary structure analysis were used to analyze the genotype of the proband and his father.

Results: The main clinical manifestations of the proband and his father were subluxation of the left lens and high myopia with pectus deformity. Whole exome sequencing identified a novel single nucleotide variant (SNV) in the FBN1 gene at a non-canonical splice site, c.443-3C>G. This variant resulted in two abnormal mRNA transcripts, leading to a frameshift and an in-frame insertion. Further in vitro experiments indicated that the c.443-3C>G variant in FBN1 was pathogenic and functionally harmful.

Conclusion: This research identified a novel intronic pathogenic FBN1: c.443-3C>G gene variant, which led to two different aberrant splicing effects. Further functional analysis expands the variant spectrum and provides a strong indication and sufficient basis for preimplantation genetic testing for monogenic disease (PGT-M).

一种新型杂合子非线性 FBN1 变体导致马凡氏综合征的 RNA 剪接异常。
背景:马凡综合征(MFS)是一种复杂的遗传性系统性结缔组织疾病:马凡综合征(MFS)是一种复杂的遗传性系统性结缔组织疾病。众所周知,遗传因素在马凡氏综合征的发展过程中起着至关重要的作用,几乎所有病例都与 FBN1 基因变异有关:方法:我们调查了一个两代同堂的中国 MFS 家族。方法:我们对一个两代同堂的中国 MFS 家族进行了调查,采用全外显子测序、硅分析、迷你基因构建、转染、RT-PCR 和蛋白质二级结构分析等方法分析了原告及其父亲的基因型:结果:该患者及其父亲的主要临床表现为左眼晶状体半脱位和高度近视伴眼球畸形。全外显子组测序发现,FBN1 基因的一个非典型剪接位点上存在一个新的单核苷酸变异(SNV),即 c.443-3C>G,该变异导致两个异常的 mRNA 转录本,导致一个框架转换和一个框架内插入。进一步的体外实验表明,FBN1中的c.443-3C>G变异具有致病性和功能危害性:该研究发现了一种新型内含子致病性 FBN1:c.443-3C>G 基因变异,它导致了两种不同的异常剪接效应。进一步的功能分析扩展了变异谱,为单基因遗传病(PGT-M)的植入前基因检测提供了强有力的指征和充分的依据。
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来源期刊
Molecular Genetics & Genomic Medicine
Molecular Genetics & Genomic Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
4.20
自引率
0.00%
发文量
241
审稿时长
14 weeks
期刊介绍: Molecular Genetics & Genomic Medicine is a peer-reviewed journal for rapid dissemination of quality research related to the dynamically developing areas of human, molecular and medical genetics. The journal publishes original research articles covering findings in phenotypic, molecular, biological, and genomic aspects of genomic variation, inherited disorders and birth defects. The broad publishing spectrum of Molecular Genetics & Genomic Medicine includes rare and common disorders from diagnosis to treatment. Examples of appropriate articles include reports of novel disease genes, functional studies of genetic variants, in-depth genotype-phenotype studies, genomic analysis of inherited disorders, molecular diagnostic methods, medical bioinformatics, ethical, legal, and social implications (ELSI), and approaches to clinical diagnosis. Molecular Genetics & Genomic Medicine provides a scientific home for next generation sequencing studies of rare and common disorders, which will make research in this fascinating area easily and rapidly accessible to the scientific community. This will serve as the basis for translating next generation sequencing studies into individualized diagnostics and therapeutics, for day-to-day medical care. Molecular Genetics & Genomic Medicine publishes original research articles, reviews, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented.
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