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在一项对1500例携带FBN1致病变异的马凡综合征患者的队列研究中，基因型-表型相关性在血管事件之外的临床意义。

Clinical relevance of genotype-phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants.

作者信息

Arnaud Pauline, Milleron Olivier, Hanna Nadine, Ropers Jacques, Ould Ouali Nadia, Affoune Amel, Langeois Maud, Eliahou Ludivine, Arnoult Florence, Renard Philippe, Michelon-Jouneaux Marlène, Cotillon Marie, Gouya Laurent, Boileau Catherine, Jondeau Guillaume

机构信息

Université de Paris, LVTS, INSERM U1148, Hôpital Bichat-Claude-Bernard, Paris, France.

Centre National de Reference pour le Syndrome de Marfan et les Syndromes Apparentés, VASCERN HTAD European Reference Centre, AP-HP, Hôpital Bichat-Claude-Bernard, Paris, France.

出版信息

Genet Med. 2021 Jul;23(7):1296-1304. doi: 10.1038/s41436-021-01132-x. Epub 2021 Mar 17.

DOI:10.1038/s41436-021-01132-x
PMID:33731877
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8257477/
Abstract

PURPOSE: Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype-phenotype correlations have been found in proband studies only. METHODS: In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations. RESULTS: A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants. CONCLUSION: This study shows that FBN1 genotype-phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.

摘要

目的：马凡综合征（MFS）是一种结缔组织疾病，其中多个系统受到影响，表型变异很大。尽管已知与FBN1基因的致病变异有关，但仅在先证者研究中发现的基因型-表型相关性很少。 方法：在来自全球最全面数据库的1575例连续的MFS先证者及其亲属中，我们建立了生存曲线并寻找基因型-表型相关性。 结果：可以根据临床和遗传数据建立风险图。过早终止密码子变异不仅与预期寿命缩短和主动脉事件的终身高风险相关，还与严重脊柱侧凸的最高风险和晶状体异位（EL）手术的较低风险相关。框内变异可根据其对原纤蛋白-1半胱氨酸含量的影响进行细分，半胱氨酸缺失变异的总体严重程度更高，半胱氨酸添加变异的EL手术频率最高。 结论：本研究表明，FBN1基因型-表型相关性在主动脉和主动脉外特征中均存在。它可用于患者的最佳风险分层，对遗传咨询和个性化医疗非常重要。这也为全面了解原纤蛋白-1在各个器官中的作用提供了额外的数据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cfd/8257477/1aab2cd36db9/41436_2021_1132_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cfd/8257477/ca88738ac5c1/41436_2021_1132_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cfd/8257477/87ab23f39eb6/41436_2021_1132_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cfd/8257477/03ec62632df5/41436_2021_1132_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cfd/8257477/1aab2cd36db9/41436_2021_1132_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cfd/8257477/ca88738ac5c1/41436_2021_1132_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cfd/8257477/87ab23f39eb6/41436_2021_1132_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cfd/8257477/03ec62632df5/41436_2021_1132_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cfd/8257477/1aab2cd36db9/41436_2021_1132_Fig4_HTML.jpg

相似文献

[1]
Clinical relevance of genotype-phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants.

Genet Med. 2021-7

[2]
Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome.

Hum Mutat. 2005-12

[3]
Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome.

Arch Intern Med. 2001-11-12

[4]
Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.

Am J Hum Genet. 2007-9

[5]
Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies.

Hum Mutat. 2002-9

[6]
The roles of two novel FBN1 gene mutations in the genotype-phenotype correlations of Marfan syndrome and ectopia lentis patients with marfanoid habitus.

Genet Test. 2008-6

[7]
Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype-phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy.

Am J Med Genet A. 2009-2

[8]
Genotype and clinical phenotype of children with Marfan syndrome in Southeastern Anatolia.

Eur J Pediatr. 2024-8

[9]
Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort.

Genet Med. 2022-5

[10]
Correlation between FBN1 mutations and ocular features with ectopia lentis in the setting of Marfan syndrome and related fibrillinopathies.

Hum Mutat. 2021-12

引用本文的文献

[1]
Therapeutic Opportunities of Marfan Syndrome: Current Perspectives.

Drug Des Devel Ther. 2025-8-26

[2]
Indications and Outcomes of Select Vitreoretinal Surgery in Patients With Marfan Syndrome.

J Vitreoretin Dis. 2025-8-22

[3]
Phenotypic Diversity of Marfan Syndrome.

JACC Adv. 2025-8-8

[4]
Combined genome and transcriptome analysis identifies molecular signatures of aortic disease in patients with Marfan syndrome.

J Mol Cell Cardiol Plus. 2025-6-19

[5]
Determinants of fatigue in patients with Marfan syndrome: a study using PROMS.

Orphanet J Rare Dis. 2025-7-11

[6]
The Evidence Surrounding Type B Dissection in Marfan Syndrome: Miles to Go Before We Sleep.

JACC Adv. 2025-7

[7]
Aortopathy in pregnancy: Unanswered questions.

JRSM Cardiovasc Dis. 2025-6-17

[8]
Genome-First Approach to Rare and Common Variant Risk of Thoracic Aortic Aneurysm and Dissection.

medRxiv. 2025-5-19

[9]
Painful symptoms and spine-specific activity limitations associated with dural ectasia in individuals with Marfan syndrome: a cross-sectional comparative study (MARFANLOMB).

Eur Spine J. 2025-5-31

[10]
A Review on the Role of DNA Methylation in Aortic Disease Associated With Marfan Syndrome.

Cardiol Res. 2025-6

本文引用的文献

[1]
Impact of Pathogenic Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome.

Circ Genom Precis Med. 2018-6

[2]
Abnormal morphology of fibrillin microfibrils in fibroblast cultures from patients with neonatal Marfan syndrome.

Am J Pathol. 1995-6

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