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An integrated clinical and molecular study of a cohort of Turkish patients with Marfan syndrome harboring known and novel FBN1 variants

Journal of Human Genetics volume 66, pages 647–657 (2021)Cite this article

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Abstract

Marfan syndrome (MFS) is an autosomal dominant genetic condition that mainly affects connective tissue in many parts of the body. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. The diagnosis of MFS relies on the revised Ghent criteria, outlined by international expert opinion to facilitate accurate recognition of this syndrome as well as to improve patient management and counseling. However, it may not always be possible to make a definitive diagnosis according to these criteria in each patient and thus molecular confirmation is necessary in subjects with suspected MFS. This debilitating, if not fatal, disorder is caused by mutations in FBN1, which encodes a major constitutive element of extracellular microfibrils. Here, we present a detailed clinical and molecular analysis of 76 Turkish patients with definitive or suspected MFS diagnosed at our center between 2014 and 2019. We were able to identify a total of 51 different FBN1 variants in our cohort, 31 of which have previously been reported in the relevant scientific literature. The remaining 20 variants have not been documented to date. In one patient, we detected a large deletion including the entire FBN1 gene using the array CGH approach. Currently, there are very few studies on the genotype–phenotype correlation of patients with MFS, and no clear genotype–phenotype maps for MFS have been constructed so far, except for some cases. We believe that our findings will make a rich and peculiar contribution to the elusive genotype–phenotype relationship in MFS, especially in this large and populous ethnic group.

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References

  1. Verstraeten A, Alaerts M, Van Laer L, Loeys B. Marfan syndrome and related disorders: 25 years of gene discovery. Hum Mutat. 2016;37:524–31.

    Article  CAS  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. Becerra-Munoz VM, Gomez-Doblas JJ, Porras-Martin C, Such-Martinez M, Crespo-Leiro MG, Barriales-Villa R, et al. The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet J Rare Dis. 2018;13:16.

    Article  Google Scholar 

  4. Dietz HC, Pyeritz RE. Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet. 1995;4:1799–809. Spec No

    Article  CAS  Google Scholar 

  5. Zeyer KA, Reinhardt DP. Engineered mutations in fibrillin-1 leading to Marfan syndrome act at the protein, cellular and organismal levels. Mutat Res Rev Mutat Res. 2015;765:7–18.

    Article  CAS  Google Scholar 

  6. Jensen SA, Robertson IB, Handford PA. Dissecting the fibrillin microfibril: structural insights into organization and function. Structure 2012;20:215–25.

    Article  CAS  Google Scholar 

  7. Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77.

    Article  CAS  Google Scholar 

  8. Davis MR, Summers KM. Structure and function of the mammalian fibrillin gene family: implications for human connective tissue diseases. Mol Genet Metab. 2012;107:635–47.

    Article  CAS  Google Scholar 

  9. 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.

    Article  Google Scholar 

  10. Collod-Beroud 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.

    Article  CAS  Google Scholar 

  11. Henrie A, Hemphill SE, Ruiz-Schultz N, Cushman B, DiStefano MT, Azzariti D, et al. ClinVar miner: demonstrating utility of a Web-based tool for viewing and filtering ClinVar data. Hum Mutat. 2018;39:1051–60.

    Article  Google Scholar 

  12. Ittisoponpisan S, Islam SA, Khanna T, Alhuzimi E, David A, Sternberg MJE. Can predicted protein 3D structures provide reliable insights into whether missense variants are disease associated? J Mol Biol. 2019;431:2197–212.

    Article  CAS  Google Scholar 

  13. Biggin A, Holman K, Brett M, Bennetts B, Ades L. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat. 2004;23:99.

    Article  Google Scholar 

  14. Lee SS, Knott V, Jovanovic J, Harlos K, Grimes JM, Choulier L, et al. Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization. Structure 2004;12:717–29.

    Article  CAS  Google Scholar 

  15. Sali A, Overington JP. Derivation of rules for comparative protein modeling from a database of protein structure alignments. Protein Sci. 1994;3:1582–96.

    Article  CAS  Google Scholar 

  16. Tiecke F, Katzke S, Booms P, Robinson PN, Neumann L, Godfrey M, et al. Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40. Eur J Hum Genet. 2001;9:13–21.

    Article  CAS  Google Scholar 

  17. Attanasio M, Lapini I, Evangelisti L, Lucarini L, Giusti B, Porciani M, et al. FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clin Genet. 2008;74:39–46.

    Article  CAS  Google Scholar 

  18. Li J, Jia X, Li S, Fang S, Guo X. Mutation survey of candidate genes in 40 Chinese patients with congenital ectopia lentis. Mol Vis. 2014;20:1017–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Milewicz DM, Grossfield J, Cao SN, Kielty C, Covitz W, Jewett T. A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome. J Clin Investig. 1995;95:2373–8.

    Article  CAS  Google Scholar 

  20. Raghunath M, Putnam EA, Ritty T, Hamstra D, Park ES, Tschodrich-Rotter M, et al. Carboxy-terminal conversion of profibrillin to fibrillin at a basic site by PACE/furin-like activity required for incorporation in the matrix. J Cell Sci. 1999;112:1093–100.

    Article  CAS  Google Scholar 

  21. Dordoni C, Ciaccio C, Santoro G, Venturini M, Cavallari U, Ritelli M, et al. Marfan syndrome: report of a complex phenotype due to a 15q21.1 contiguos gene deletion encompassing FBN1, and literature review. Am J Med Genet Part A. 2017;173:200–6.

    Article  CAS  Google Scholar 

  22. Hilhorst-Hofstee Y, Hamel BC, Verheij JB, Rijlaarsdam ME, Mancini GM, Cobben JM, et al. The clinical spectrum of complete FBN1 allele deletions. Eur J Hum Genet. 2011;19:247–52.

    Article  Google Scholar 

  23. Colovati ME, da Silva LR, Takeno SS, et al. Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene. Mol Cytogenet. 2012;5:5.

    Article  CAS  Google Scholar 

  24. Furtado LV, Wooderchak-Donahue W, Rope AF, Yetman AT, Lewis T, Plant P, et al. Characterization of large genomic deletions in the FBN1 gene using multiplex ligation-dependent probe amplification. BMC Med Genet. 2011;12:119.

    Article  CAS  Google Scholar 

  25. Baetens M, Van Laer L, De Leeneer K, Hellemans J, De Schrijver J, Van De Voorde H, et al. Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat. 2011;32:1053–62.

    Article  CAS  Google Scholar 

  26. Faivre L, Collod-Beroud G, Loeys BL, Child A, Binquet C, Gautier E, et al. 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;81:454–66.

    Article  CAS  Google Scholar 

  27. Schrijver I, Liu W, Brenn T, Furthmayr H, Francke U. Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet. 1999;65:1007–20.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, 34480, Istanbul, Turkey

    Alper Gezdirici

  2. Department of Medical Biochemistry, Faculty of Medicine, Near East University, 99138, Nicosia, Cyprus

    Kerem Teralı

  3. Bioinformatics & Computational Biology Research Group, DESAM Institute, Near East University, 99138, Nicosia, Cyprus

    Kerem Teralı

  4. Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, 34303, Istanbul, Turkey

    Elif Yılmaz Gülec

  5. Department of Pediatric Cardiology, Kanuni Sultan Suleyman Training and Research Hospital, 34303, Istanbul, Turkey

    Helen Bornaun

  6. Department of Medical Genetics, Faculty of Medicine, Malatya Turgut Ozal University, 44300, Malatya, Turkey

    Mustafa Dogan

  7. Department of Medical Genetics, Faculty of Medicine, Duzce University, 81010, Düzce, Turkey

    Recep Eröz

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  1. Alper Gezdirici
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  3. Elif Yılmaz Gülec
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  4. Helen Bornaun
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  6. Recep Eröz
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Contributions

AG designed the study, analyzed and interpreted genetic data. AG, EYG, and HB collected clinical data and performed phenotyping of patients. AG, KT, MD and RE drafted the manuscript. KT helped bioinformatic analyses. MD and RE helped statistical analyses, conception and supervision of the study.

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Correspondence to Alper Gezdirici.

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The authors declare that they have no conflict of interest.

Ethical approval

The study protocol was conducted in accordance with the Declaration of Helsinki and was approved by ethics committee of Kanuni Sultan Suleyman Training and Research Hospital (KAEK/2019.05.134).

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Gezdirici, A., Teralı, K., Gülec, E.Y. et al. An integrated clinical and molecular study of a cohort of Turkish patients with Marfan syndrome harboring known and novel FBN1 variants. J Hum Genet 66, 647–657 (2021). https://doi.org/10.1038/s10038-021-00899-w

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  • DOI: https://doi.org/10.1038/s10038-021-00899-w

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