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Table of Contents
Year : 2020  |  Volume : 38  |  Issue : 2  |  Page : 98-101

A 45-year-old Italian male with p.(Gly1815Ser) FBN1 mutation causing a mild variant of Marfan syndrome: A case study

1 Department of Clinical Sciences and Community Health, University of Milan, IRCCS Ca' Granda Foundation Via San Barnaba 8; UOC Occupational Medicine, Department of Medicine Preventive Services, IRCCS Ca' Granda Foundation Ospedale Maggiore Policlinico, via San Barnaba 8, Milan, Italy
2 Department of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, Monza, Italy
3 Department of Clinical Sciences and Community Health, University of Milan, IRCCS Ca' Granda Foundation Via San Barnaba 8, Milan, Italy
4 Regional Center of Ehlers-Danlos Syndrome, UOC Occupational Medicine, Department of Medicine Preventive Services, IRCCS Ca' Granda Foundation Ospedale Maggiore Policlinico, via San Barnaba 8, Milan, Italy
5 UOC Occupational Medicine, Department of Medicine Preventive Services, IRCCS Ca' Granda Foundation Ospedale Maggiore Policlinico, via San Barnaba 8, Milan, Italy

Date of Submission07-Oct-2018
Date of Decision02-Aug-2019
Date of Acceptance14-Aug-2019
Date of Web Publication29-May-2020

Correspondence Address:
Dr. Francesca Cortini
Department of Clinical Sciences and Community Health, University of Milan, Via San Barnaba 8, 20122, Milan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ds.ds_16_19

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A 45-year-old Italian male was referred as suspected of having a heritable connective tissue disorders by clinical findings, including joint hyperlaxity and soft, smooth, velvety, and slightly elastic skin. Using a specific custom panel including genes involved in these disorders, next-generation sequencing (NGS) analysis led to the identification of the c. 5443G>A, p.(Gly1815Ser), (rs745680336) variant in fibrillin-1 (FBN1) gene, encoding the FBN1. Mutations in this protein are responsible for different connective tissue disorders, collectively known as type 1 fibrillinopathies, including Marfan syndrome (MFS). Multiple sequencing alignment of human FBN1 protein with various species revealed that the mutation occurred within a highly conserved region of the calcium-binding epidermal growth factor-like domain and affected the protein structure/function, suggesting its pathogenic role. NGS techniques successfully identified the molecular defect in this patient, clinically resembling as MFS, even if a clear genotype–phenotype correlation remains still challenging.

Keywords: Fibrillin-1 gene, heritable connective tissue disorders, Marfan syndrome, next-generation sequencing

How to cite this article:
Cortini F, Villa C, Marinelli B, Franchetti S, Riboldi L, Bassotti A. A 45-year-old Italian male with p.(Gly1815Ser) FBN1 mutation causing a mild variant of Marfan syndrome: A case study. Dermatol Sin 2020;38:98-101

How to cite this URL:
Cortini F, Villa C, Marinelli B, Franchetti S, Riboldi L, Bassotti A. A 45-year-old Italian male with p.(Gly1815Ser) FBN1 mutation causing a mild variant of Marfan syndrome: A case study. Dermatol Sin [serial online] 2020 [cited 2023 Mar 21];38:98-101. Available from: https://www.dermsinica.org/text.asp?2020/38/2/98/285349

  Introduction Top

Heritable connective tissue disorders (HCTDs) are widespread through the body, affecting the skin; eyes; and musculoskeletal, cardiovascular, and pulmonary systems. To date, more than 200 are known and they can present common clinical features as: joint laxity, hypotonia, vascular events, short stature, and hernias.[1] Mutations in a wide range of genes encoding collagen, extracellular matrix (ECM) proteins, or modifying enzymes are found in most of the HCTD patients. Three typical examples of them include Ehlers–Danlos syndrome (EDS), osteogenesis imperfecta (OI), and Marfan syndrome (MFS). Clinical diagnosis of these syndromes can be difficult because of the variability and overlapping phenotypes, which highlights the importance of molecular diagnostic confirmation. Concerning EDS, the term refers to a group of clinically and genetically heterogeneous connective tissue disorders, characterized by joint hypermobility, tissue fragility, and skin hyperextensibility. The latest EDS nosology recognized 13 EDS subtypes, based on the clinical findings, inheritance pattern, and molecular defects.[2] OI is a rare hereditary bone disorder usually caused by defects in the production or processing of type I collagen, a major protein of the bone matrix. The disease is characterized by an increased predisposition to recurrent fractures, bone deformities, and short stature.[3] Finally, MFS is mostly characterized by ocular, cardiovascular, and skeletal manifestation and caused by mutations in fibrillin-1 (FBN1), encoding for the ECM protein FBN1.[4]

Here, we report a case of a male suspected of having a connective tissue disorder based on clinical findings of soft and slightly elastic skin with atrophic scars and myopathy.

  Case Report Top

We report a case of 45-year-old Italian male, followed at the Regional Center of EDS, located at the IRCCS Ca' Granda Foundation, Milan, Italy. Family history delineated a relevant delay development in the prepubertal phase. There were not any parents that explained his development problems. His grandparents died for vascular events. He had three brothers: the first died after few days of life; the second, a 40-year-old Italian male, presented underdevelopment of the larynx; and the third, a 35-year-old Italian male, had hearing loss and arthralgia at lower limbs and kyphoscoliosis. The patient presented soft, smooth, velvety, and slightly elastic skin with small spontaneous hematomas [Figure 1]. Moreover, he had joint hyperlaxity that caused pain during daily tasks; an increase in the episodes of patella and glenohumeral articulation subluxations has been happened in the past years. He referred hypotrophic and hypotonic muscles at the level of lower limbs. He also described small fiber neuropathy connected to myopathy at the girdles and lower limbs.
Figure 1: Particular of clinical phenotype of the patient: (a and b) details of slightly elastic skin at cheeks and eyes level; (c and d) details of spontaneous hematomas at arm and leg; (e and f) details of atrophic scars

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After obtaining written informed consent, genomic DNA was extracted from peripheral blood of the patient using an automated platform (QIAGEN). Next generation sequencing (NGS) was performed on DNA using a specific custom panel designed to sequence the exons and exon–intron boundaries of genes commonly associated with EDS and overlapping phenotypes.[5] A precise pipeline was constructed by Galaxy software (https://usegalaxy.org/).[6] All genomic variants were analyzed by specific software and confirmed on independent DNA extraction by Sanger sequencing.[7]In silico analyses were performed with PolyPhen-2, Align-GVGD, and MutationTaster bioinformatic tools to predict the pathogenicity of the identified variants.

Bioinformatic pipeline,[6] considering and analyzing exonic and intronic (±20 bp surrounding exons) nucleotide alterations, identified 73 missense variants. These were filtered based on allelic frequency, effect of amino acid substitution on the primary amino acid sequence, protein tridimensional structure, and evolutionary conservation protein;[7] causative variants were confirmed by Sanger sequencing on independent DNA extraction.[7] Considering these parameters, we identified the missense variant c.5443G>A, p.(Gly1815Ser), and rs745680336 in heterozygous state in the exon 45 of FBN1 gene. The p.(Gly1815Ser) was located on a calcium-binding epidermal growth factor-like domain (cbEGF)[8],[9] and consisted of a replacement of glycine to serine. Its possible pathogenic role was supported by the in silico analyses by three different bioinformatics tools (PolyPhen-2, Align-GVGD, and MutationTaster). The Gly-Ser substitution at codon 1815 of FBN1 damaged protein function and affected a highly evolutionary conserved amino acid [Figure 2]b. This variant has been already reported, but clinical or frequency data were not available. More than 600 mutations were identified throughout the entire length of the gene, and only 12% of all reported FBN1 mutations were recurrent[10] [Figure 2]a.
Figure 2: (a) Schematic representation of fibrillin-1 protein reporting the most recurrent mutations, the p.(Gly1815Ser) variant is indicated with asterisk; (b) amino acid multiple alignment of fibrillin-1 sequence displaying evolutionary conservation of glycine (G) residue across species

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  Discussion Top

In this report, we described a case of an Italian man referred with suspected connective tissue disorder, based on clinical findings. NGS approach led to the identification of the missense variant p.(Gly1815Ser) harboring the NFB1 gene. The p.(Gly1815Ser), identified in heterozygosis, has already been reported as with uncertain significance, and no data about its molecular information or its clinical associated phenotype were available, hypothesizing thus its possible pathogenic role. Furthermore, this variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, providing further evidence that it is not common in these populations. Mutations in nearby residues, such as p.(Glu1811 Lys), p.(Cys1812Arg), p.(Cys1818Gly), and p.(Cys1818Tyr), have been reported in association with MFS, supporting the functional importance of this region of the protein. The replacement of a highly conserved nonpolar amino acid glycine (Gly) with a polar serine (Ser) has been predicted to damage protein function/structure by three different bioinformatic tools. More specifically, this substitution is located on a cbEGF, a conserved sequence of about 40 amino acids found in a large number of extracellular proteins with different functions, including cell fate, blood coagulation, cell adhesion, and connective tissue architecture. It has been shown that calcium plays a key role in the maintenance of microfibril architecture, so mutations occurring in this region may impair the direct ligation to calcium or its stabilization to the binding site.[11]

Although numerous FBN1 mutations have been identified, a strong genotype–phenotype correlation remains elusive. Pathogenic variants in FBN1 cause a range of connective tissue disorders, collectively known as type 1 fibrillinopathies, including MFS.[9] The patient presented with partial clinical features of MFS, such as joint laxity, but he did not completely fulfill the current diagnostic criteria,[12] rather suggesting a mild variant of MFS. It cannot be excluded that the same mutation is also carried in other members of the family showing some clinical aspects related to HCTDs, such as orthopedic disease, hearing loss, and hypodeveloped larynx. Unfortunately, these individuals were not compliant with the study, so a cosegregation analysis of the mutation was not feasible.

The introduction of NGS techniques has substantially increased the identification of new genetic variants and hence the necessity of accurate variant interpretation. Although there is no clear genotype–phenotype correlation in this patient, the discovery of a mutation in FBN1 gene may help clinicians in making a differential diagnosis from the other HCTDs and understanding the molecular defect. Nevertheless, further studies on in vitro cell culture will be necessary to clarify its pathogenicity.

Ethical statement

This study was carried out from routine diagnostic activity and does not request formal ethics review. The study follows the principles outlined in the Helsinki Declaration. The patient gave written informed consent for molecular study and publication.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.


The authors would like to thank Italian Association of Ehlers-Danlos Syndrome (AISED) for support.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Jobling R, D'Souza R, Baker N, Lara-Corrales I, Mendoza-Londono R, Dupuis L, et al. The collagenopathies: Review of clinical phenotypes and molecular correlations. Curr Rheumatol Rep 2014;16:394.  Back to cited text no. 1
Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 2017;175:8-26.  Back to cited text no. 2
Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004;363:1377-85.  Back to cited text no. 3
Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337-9.  Back to cited text no. 4
Cortini F, Villa C, Marinelli B, Combi R, Pesatori AC, Bassotti A, et al. Understanding the basis of Ehlers-Danlos syndrome in the era of the next-generation sequencing. Arch Dermatol Res 2019;311:265-75.  Back to cited text no. 5
Bhargava M, Viken K, Wang Q, Jagtap P, Bitterman P, Ingbar D, et al. Bronchoalveolar lavage fluid protein expression in acute respiratory distress syndrome provides insights into pathways activated in subjects with different outcomes. Sci Rep 2017;7:7464.  Back to cited text no. 6
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.  Back to cited text no. 7
Pundir S, Magrane M, Martin MJ, O'Donovan C, UniProt Consortium. Searching and navigating uniProt databases. Curr Protoc Bioinformatics 2015;50:1.27.1-10.  Back to cited text no. 8
Sakai LY, Keene DR, Renard M, De Backer J. FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders. Gene 2016;591:279-91.  Back to cited text no. 9
Collod-Béroud G, Le Bourdelles S, Ades L, Ala-Kokko L, Booms P, Boxer M, et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 2003;22:199-208.  Back to cited text no. 10
Downing AK, Knott V, Werner JM, Cardy CM, Campbell ID, Handford PA, et al. Solution structure of a pair of calcium-binding epidermal growth factor-like domains: Implications for the Marfan syndrome and other genetic disorders. Cell 1996;85:597-605.  Back to cited text no. 11
Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised GHENT nosology for the Marfan syndrome. J Med Genet 2010;47:476-85.  Back to cited text no. 12


  [Figure 1], [Figure 2]


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