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Marfan Syndrome and Related Disorders: Genetic Basis, Molecular Mechanisms, and...
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Marfan Syndrome and Related Disorders: Genetic Basis, Molecular Mechanisms, and Genotype–Phenotype Correlations

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 April 2021) | Viewed by 17425

Special Issue Editor

Prof. Dr. Guglielmina Pepe

E-Mail Website1 Website2
Guest Editor
Department of Experimental and Clinical Medicine (DMSC),Tuscany CRR Marfan Syndrome and Related Disorders, University of Florence, Careggi University Hospital, Florence, Italy
Interests: hereditary thoracic aortic aneurysms and dissections; inherited connective tissue disorders; congenital heart diseases; molecular mechanisms underlying hereditary diseases; genotype-phenotype correlation; clinical, biochemical and genetic biomarkers; early diagnosis comorbidities; guidelines implementation
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Special Issue Information

Dear Colleagues,

Marfan syndrome belongs, on one side, to the group of rare heritable connective tissue disorders (HCTD) and, on the other side, to the group of syndromic and non-syndromic hereditary thoracic aortic aneurysms/dissections (s/ns-HTAAD). The clinical and genetic features that allow the diagnosis of Marfan syndrome are aneurysm/dissection of thoracic aorta at the Valsalva’s sinus; subluxation/luxation of the eye lenses; and presence of systemic features with a score ≥7. Genetic signs are represented by first-degree familiarity for Marfan syndrome and characterization of a pathogenetic mutation in the propositus or in first-degree relatives. Marfan syndrome is associated with FBN1 in more than 90% of patients. The genetic analysis through the next-generation sequencing (NGS) technique allows a differential diagnosis with isolated TAAD, aortic bicuspid valve (VAB) Loeys–Dietz, arterial tortuosity, vascular Ehlers–Danlos, ectopia lentis, Weil–Marchesani syndromes, and homocystinuria. The various clinical phenotypes among relatives of the same family suggest the presence of modifier genes, some of which have been identified. NGS technology will hopefully help in detecting other modifying genes and other genes associated to Marfan syndrome and in distinguishing diseases associated with the same gene/different alleles vs. diseases present in comorbidity.

This Special Issue will focus on the current state-of-the-art and novel research findings concerning the molecular basis and pathogenesis of Marfan syndrome and related disorders, with particular interest in news regarding genotype–phenotype correlation, the discovery and characterization of modifier genes, and the patterns of mutations/genes associated to a clinical phenotype and and the techniques applied to these studies. A review regarding the aspects of hereditary transmission, of the genes associated with several pathologies or of the single gene underlying each pathology is also welcome, as well as a review regarding the cell-molecular physiopathology of Marfan syndrome and related disorders.

This issue is not meant to include papers reporting only clinical descriptions of Marfan syndrome and related disorders.

Prof. Dr. Guglielmina Pepe
Guest Editor

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Keywords

  • Inherited connective tissue disorders
  • Marfan syndrome and related disorders
  • Major genes
  • Modifier genes
  • Thoracic aortic aneurysm/dissection
  • TGFbetapathies
  • Genotype–phenotyype correlation
  • Fibrillinopathies
  • Collagenopathies
  • Bicuspid aortic valve

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Published Papers (4 papers)

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Research

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12 pages, 1971 KiB  
Article
Differential Diagnosis between Marfan Syndrome and Loeys–Dietz Syndrome Type 4: A Novel Chromosomal Deletion Covering TGFB2
by Stefano Nistri, Rosina De Cario, Elena Sticchi, Gaia Spaziani, Matteo Della Monica, Sabrina Giglio, Silvia Favilli, Betti Giusti, Pierluigi Stefano and Guglielmina Pepe
Genes 2021, 12(10), 1462; https://doi.org/10.3390/genes12101462 - 22 Sep 2021
Cited by 5 | Viewed by 3624
Abstract
Marfan syndrome (MFS) and Loeys–Dietz syndrome type 4 (LDS4) are two hereditary connective tissue disorders. MFS displays ectopia lentis as a distinguishing, characterising feature, and thoracic aortic ectasia, aneurysm, dissection, and systemic features as manifestations overlapping with LDS4. LDS4 is characterised by the [...] Read more.
Marfan syndrome (MFS) and Loeys–Dietz syndrome type 4 (LDS4) are two hereditary connective tissue disorders. MFS displays ectopia lentis as a distinguishing, characterising feature, and thoracic aortic ectasia, aneurysm, dissection, and systemic features as manifestations overlapping with LDS4. LDS4 is characterised by the presence of hypertelorism, cleft palate and/or bifid uvula, with possible ectasia or aneurysms in other arteries. The variable age of onset of clinical manifestations makes clinical diagnosis more difficult. In this study, we report the case of a patient with Marfan syndrome diagnosed at our centre at the age of 33 on the basis of typical clinical manifestations of this syndrome. At the age of 38, the appearance of ectasia of the left common iliac artery and tortuosity of the iliac arteries suggested the presence of LDS4. Next Generation Sequencing (NGS) analysis, followed by Array-CGH, allowed the detection of a novel chromosomal deletion including the entire TGFB2 gene, confirming not only the clinical suspicion of LDS4, but also the clinical phenotype associated with the haploinsufficiency mechanism, which is, in turn, associated with the deletion of the entire gene. The same mutation was detected in the two young sons. This emblematic case confirms that we must be very careful in the differential diagnosis of these two pathologies, especially before the age of 40, and that, in young subjects suspected to be affected by MFS in particular, we must verify the diagnosis, extending genetic analysis, when necessary, to the search for chromosomal alterations. Recently, ectopia lentis has been reported in a patient with LDS4, confirming the tight overlap between the two syndromes. An accurate revision of the clinical parameters both characterising and overlapping the two pathologies is highly desirable. Full article
(This article belongs to the Special Issue Marfan Syndrome and Related Disorders: Genetic Basis, Molecular Mechanisms, and Genotype–Phenotype Correlations)
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15 pages, 1047 KiB  
Article
Genotype–Phenotype Correlation in Children: The Impact of FBN1 Variants on Pediatric Marfan Care
by Veronika C. Stark, Flemming Hensen, Kerstin Kutsche, Fanny Kortüm, Jakob Olfe, Peter Wiegand, Yskert von Kodolitsch, Rainer Kozlik-Feldmann, Götz C. Müller and Thomas S. Mir
Genes 2020, 11(7), 799; https://doi.org/10.3390/genes11070799 - 15 Jul 2020
Cited by 15 | Viewed by 3660
Abstract
Currently, no reliable genotype–phenotype correlation is available for pediatric Marfan patients in everyday clinical practice. We investigated correlations of FBN1 variants with the prevalence and age of onset of Marfan manifestations in childhood and differentiated three groups: missense/in-frame, splice, and nonsense/frameshift variants. In [...] Read more.
Currently, no reliable genotype–phenotype correlation is available for pediatric Marfan patients in everyday clinical practice. We investigated correlations of FBN1 variants with the prevalence and age of onset of Marfan manifestations in childhood and differentiated three groups: missense/in-frame, splice, and nonsense/frameshift variants. In addition, we differentiated missense variants destroying or generating a cysteine (cys-missense) and alterations not affecting cysteine. We categorized 105 FBN1-positive pediatric patients. Patients with cys-missense more frequently developed aortic dilatation (p = 0.03) requiring medication (p = 0.003), tricuspid valve prolapse (p = 0.03), and earlier onset of myopia (p = 0.02) than those with other missense variants. Missense variants correlated with a higher prevalence of ectopia lentis (p = 0.002) and earlier onset of pulmonary artery dilatation (p = 0.03) than nonsense/frameshift, and dural ectasia was more common in the latter (p = 0.005). Pectus excavatum (p = 0.007) appeared more often in patients with splice compared with missense/in-frame variants, while hernia (p = 0.04) appeared earlier in the latter. Findings on genotype–phenotype correlations in Marfan-affected children can improve interdisciplinary therapy. In patients with cys-missense variants, early medical treatment of aortic dilatation seems reasonable and early regular ophthalmologic follow-up essential. Patients with nonsense/frameshift and splice variants require early involvement of orthopedic specialists to support the growing child. Full article
(This article belongs to the Special Issue Marfan Syndrome and Related Disorders: Genetic Basis, Molecular Mechanisms, and Genotype–Phenotype Correlations)
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14 pages, 1417 KiB  
Article
Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability
by Thomas Grange, Mélodie Aubart, Maud Langeois, Louise Benarroch, Pauline Arnaud, Olivier Milleron, Ludivine Eliahou, Marie-Sylvie Gross, Nadine Hanna, Catherine Boileau, Laurent Gouya and Guillaume Jondeau
Genes 2020, 11(5), 574; https://doi.org/10.3390/genes11050574 - 20 May 2020
Cited by 15 | Viewed by 4857
Abstract
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying FBN1 [...] Read more.
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying FBN1 mutations. We found strong correlations between features within the same system (i.e., ophthalmology vs. skeletal vs. cardiovascular) suggesting common underlying determinants, while features belonging to different systems were largely uncorrelated. We adapted a classical quantitative genetics model to estimate the heritability of each clinical feature from phenotypic correlations between relatives. Most clinical features showed strong familial aggregation and high heritability. We found a significant contribution by the major locus on the phenotypic variance only for ectopia lentis using a new strategy. Finally, we found evidence for the “Carter effect” in the MFS cardiovascular phenotype, which supports a polygenic model for MFS cardiovascular variability and indicates additional risk for children of MFS mothers with an aortic event. Our results demonstrate that an important part of the phenotypic variability in MFS is under the control of inherited modifiers, widely shared between features within the same system, but not among different systems. Further research must be performed to identify genetic modifiers of MFS severity. Full article
(This article belongs to the Special Issue Marfan Syndrome and Related Disorders: Genetic Basis, Molecular Mechanisms, and Genotype–Phenotype Correlations)
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Review

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10 pages, 514 KiB  
Review
LTBP4 in Health and Disease
by Chi-Ting Su and Zsolt Urban
Genes 2021, 12(6), 795; https://doi.org/10.3390/genes12060795 - 23 May 2021
Cited by 24 | Viewed by 4428
Abstract
Latent transforming growth factor β (TGFβ)-binding protein (LTBP) 4, a member of the LTBP family, shows structural homology with fibrillins. Both these protein types are characterized by calcium-binding epidermal growth factor-like repeats interspersed with 8-cysteine domains. Based on its domain composition and distribution, [...] Read more.
Latent transforming growth factor β (TGFβ)-binding protein (LTBP) 4, a member of the LTBP family, shows structural homology with fibrillins. Both these protein types are characterized by calcium-binding epidermal growth factor-like repeats interspersed with 8-cysteine domains. Based on its domain composition and distribution, LTBP4 is thought to adopt an extended structure, facilitating the linear deposition of tropoelastin onto microfibrils. In humans, mutations in LTBP4 result in autosomal recessive cutis laxa type 1C, characterized by redundant skin, pulmonary emphysema, and valvular heart disease. LTBP4 is an essential regulator of TGFβ signaling and is related to development, immunity, injury repair, and diseases, playing a central role in regulating inflammation, fibrosis, and cancer progression. In this review, we focus on medical disorders or diseases that may be manipulated by LTBP4 in order to enhance the understanding of this protein. Full article
(This article belongs to the Special Issue Marfan Syndrome and Related Disorders: Genetic Basis, Molecular Mechanisms, and Genotype–Phenotype Correlations)
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