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A novel intron mutation in FBN-1 gene identified in a pregnant woman with Marfan syndrome.

ABSTRACT: Marfan syndrome (MFS) is one of the most common hereditary connective tissue diseases, with great individual heterogeneity. We reported a Chinese pregnancy with Clinical diagnosis of MFS, performed whole-exome sequencing, and screened for the genetic abnormality. We also conducted an in vitro mini-gene splicing assay to demonstrate the predicted harmful effects of an intronic variant of FBN-1. Exome sequencing identified a novel intronic variant (c.6497-13?T>A) in intron 53 of the FBN-1 gene (NM_000138.4). It's predicted to insert 11?bp of intron 53 into the mature mRNA. The mini-gene splicing experiment demonstrated that c.6497-13?T>A could result in 11?bp retention in intron 53 to exon 54 (c.6496_6497ins gtttcttgcag) and the use of an alternative donor causing the frameshift p.Asp2166Glyfs*23. According to the results, the pregnant woman chose to continue the pregnancy and gave birth to a healthy baby. This study expands the genetic mutation spectrum of MFS patients and indicates the importance of intron sequencing.

SUBMITTER: Wu Y

PROVIDER: S-EPMC7788922 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A novel intron mutation in FBN-1 gene identified in a pregnant woman with Marfan syndrome.

Wu Yuduo Y Sun Hairui H He Yihua Y Zhang Hongjia H

Hereditas 20210106 1

Marfan syndrome (MFS) is one of the most common hereditary connective tissue diseases, with great individual heterogeneity. We reported a Chinese pregnancy with Clinical diagnosis of MFS, performed whole-exome sequencing, and screened for the genetic abnormality. We also conducted an in vitro mini-gene splicing assay to demonstrate the predicted harmful effects of an intronic variant of FBN-1. Exome sequencing identified a novel intronic variant (c.6497-13 T>A) in intron 53 of the FBN-1 gene (NM ...[more]

PMID: 33407909

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Project description:BackgroundMarfan syndrome (MFS) is a heritable disorder of connective tissue resulting from pathogenic variants of the fibrillin-1 gene (FBN1). Neonatal Marfan syndrome (nMFS) is rare and the most severe form of MFS, involving rapidly progressive cardiovascular dysfunction leading to death during early childhood. The constant enrichment of the nMFS mutation spectrum is helpful to improve our understanding of genotype-phenotype correlations in the disease. Herein, we report a novel dominant mutation in exon 26 of FBN1 (c.3331 T > C) in a sporadic case with nMFS.Case presentationAn 8-month-old Han Chinese girl presented with the classic nMFS phenotype, including prominent manifestations of bone overgrowth, aortic root dilatation, and multiple cardiac valve dysfunctions. Genetic analysis revealed that she was heterozygous for a de novo FBN1 missense mutation (c.3331 T > C). The mutation leads to the substitution of a highly conserved FBN1 cysteine residue (p.Cys1111Arg), which is likely to severely perturb the FBN1 structure because of an alteration of the disulfide bond pattern in the calcium-binding epidermal growth factor-like (cbEGF) 12 domain. This variant was absent in 208 ethnically matched controls, providing further evidence that it may be causative of nMFS. An analysis of nMFS-associated mutations from the UMD-FBN1 database indicates that those de novo mutations altering disulfide bonds or Ca(2+) binding sites of the cbEGF domains encoded by exons 25-33, and a lack of phenotypic heterogeneity may be associated with an increased risk for nMFS.ConclusionWe diagnosed an infant with rare nMFS showing rapidly progressive cardiovascular dysfunction and widely systemic features. As the only causal FBN1 mutation identified in the patient, the missense mutation c.3331 T > C (p.Cys1111Arg) was associated with the severe phenotype of MFS. However, the pathogenicity of the novel mutation needs further confirmation in other patients with nMFS. Our review of the prominent characteristics of nMFS mutations relative to classic or incomplete MFS-related mutations will be helpful for the recognition of novel nMFS-associated variants.

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A novel intron mutation in FBN-1 gene identified in a pregnant woman with Marfan syndrome.

Publications

A novel intron mutation in FBN-1 gene identified in a pregnant woman with Marfan syndrome.

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