perinatologyРоссийский вестник перинатологии и педиатрииRossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)1027-40652500-2228Ltd. “The National Academy of Pediatric Science and Innovation”10.21508/1027-4065-2023-68-2-29-38perinatology-1798Research ArticleОБЗОРЫ ЛИТЕРАТУРЫLITERATURE REVIEWSМолекулярно-генетические основы вариабельности клинических проявлений синдрома МарфанаMolecular and genetic basis of variability in clinical manifestations of Marfan syndromehttps://orcid.org/0000-0002-4628-5086ГрицевскаяД. Ю.GritsevskayaD. Yu.

 Грицевская Дарья Юрьевна — аспирант

125412 Москва, ул. Талдомская, д. 2

Moscow

gritsevskaya.d@pedklin.ruhttps://orcid.org/0000-0001-9030-3192СмирноваА. В.SmirnovaA. V.

Смирнова  Анна  Викторовна  —  лаборант-исследователь  лаборатории  клинической  геномики  и  биоинформатики  

125412 Москва, ул. Талдомская, д. 2

Moscow

https://orcid.org/0000-0001-8491-0228ВоиноваВ. Ю.VoinovaV. Yu.

Воинова Виктория Юрьевна — доктор медицинских наук, главный научный сотрудник отдела клинической генетики 

125412 Москва, ул. Талдомская, д. 2

Moscow

ОСП «Научно-исследовательский клинический институт педиатрии и детской хирургии им. академика Ю.Е. Вельтищева» ФГАОУ ВО РНИМУ им. Н.И. Пирогова Минздрава РоссииРоссияVeltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical UniversityRussian Federation2023270420236822938Copyright © Ltd. “The National Academy of Pediatric Science and Innovation”, 20232023Ltd. “The National Academy of Pediatric Science and Innovation”Ltd. “The National Academy of Pediatric Science and Innovation”https://www.ped-perinatology.ru/jour/about/submissions#copyrightNoticehttps://www.ped-perinatology.ru/jour/article/view/1798

Синдром Марфана — наследственное заболевание соединительной ткани с аутосомно-доминантным типом наследования. Заболевание отличается выраженной фенотипической вариабельностью, причиной которой, высоковероятно, служат генетические модификаторы. В обзоре дана информация о молекулярной характеристике фибриллина-1 — белкового продукта гена FBN1, связанного с возникновением синдрома Марфана. Представлены сведения об изученных к настоящему вемени корреляциях генотип–фенотип, а также результаты поиска возможных генетических модификаторов.

Marfan syndrome is an inherited connective tissue disease with autosomal dominant inheritance and pronounced phenotypic variability, which is highly likely to be caused by genetic modifiers. This review presents the molecular characterization of fibrillin-1, the protein product of the disease-associated FBN1 gene, the genotype-phenotype correlations studied to date, and the results of the search for possible genetic modifiers.

детисиндром Марфанафибриллин-1трансформирующий бета-фактор ростакорреляция генотип–фенотипгенетические модификаторыchildrenMarfan syndromefibrillin-1transforming growth factor-betagenotype-phenotype correlationsgenetic modifiersReferencesDietz H.C., Saraiva J.M., Pyeritz R.E., Cutting G.R., Francomano C.A. Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains. Hum Mutat 1992; 1(5): 366–374. DOI: 10.1002/humu.1380010504Dietz H.C., Saraiva J.M., Pyeritz R.E., Cutting G.R., Francomano C.A. Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains. Hum Mutat 1992; 1(5): 366–374. DOI: 10.1002/humu.1380010504Ramirez F., Dietz H.C. Fibrillin-rich microfibrils: Structural determinants of morphogenetic and homeostatic events. J Cell Physiol. 2007; 213(2): 326–330. DOI: 10.1002/jcp.21189Ramirez F., Dietz H.C. Fibrillin-rich microfibrils: Structural determinants of morphogenetic and homeostatic events. J Cell Physiol. 2007; 213(2): 326–330. DOI: 10.1002/jcp.21189Jensen S.A., Handford P.A. New insights into the structure, assembly and biological roles of 10–12 nm connective tissue microfibrils from fibrillin-1 studies. Biochem J 2016; 473(7): 827–838. DOI: 10.1042/BJ20151108Jensen S.A., Handford P.A. New insights into the structure, assembly and biological roles of 10–12 nm connective tissue microfibrils from fibrillin-1 studies. Biochem J 2016; 473(7): 827–838. DOI: 10.1042/BJ20151108Robinson P.N., Arteaga-Solis E., Baldock C., Collod-Béroud G., Booms P., De Paepe A. et al. The molecular genetics of Marfan syndrome and related disorders. J Med Genet 2006; 43(10): 769–787. DOI: 10.1136/jmg.2005.039669Robinson P.N., Arteaga-Solis E., Baldock C., Collod-Béroud G., Booms P., De Paepe A. et al. The molecular genetics of Marfan syndrome and related disorders. J Med Genet 2006; 43(10): 769–787. DOI: 10.1136/jmg.2005.039669Yin X., Wanga S., Fellows A.L., Barallobre-Barreiro J., Lu R., Davaapil H. et al. Glycoproteomic Analysis of the Aortic Extracellular Matrix in Marfan Patients. Arterioscler Thromb Vasc Biol 2019; 39(9): 1859–1873. DOI: 10.1161/ATVBAHA.118.312175Yin X., Wanga S., Fellows A.L., Barallobre-Barreiro J., Lu R., Davaapil H. et al. Glycoproteomic Analysis of the Aortic Extracellular Matrix in Marfan Patients. Arterioscler Thromb Vasc Biol 2019; 39(9): 1859–1873. DOI: 10.1161/ATVBAHA.118.312175Halper J., Kjaer M. Basic components of connective tissues and extracellular matrix: elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins. Adv Exp Med Biol 2014; 802: 31–47. DOI: 10.1007/978–94–007–7893–1Halper J., Kjaer M. Basic components of connective tissues and extracellular matrix: elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins. Adv Exp Med Biol 2014; 802: 31–47. DOI: 10.1007/978–94–007–7893–1Bobik A. Transforming growth factor-betas and vascular disorders. Arterioscler Thromb Vasc Biol 2006; 26(8): 1712–1720. DOI: 10.1161/01Bobik A. Transforming growth factor-betas and vascular disorders. Arterioscler Thromb Vasc Biol 2006; 26(8): 1712–1720. DOI: 10.1161/01Aubart M., Gazal S., Arnaud P., Benarroch L., Gross M.S., Buratti J. et al. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability. Eur J Hum Genet 2018; 26(12): 1759–1772. DOI: 10.1038/s41431–018–0164–9Aubart M., Gazal S., Arnaud P., Benarroch L., Gross M.S., Buratti J. et al. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability. Eur J Hum Genet 2018; 26(12): 1759–1772. DOI: 10.1038/s41431–018–0164–9Wahl S.M., Allen J.B., Weeks B.S., Wong H.L., Klotman P.E. Transforming growth factor beta enhances integrin expression and type IV collagenase secretion in human monocytes. Proc Natl Acad Sci USA 1993; 90(10): 4577–4581. DOI: 10.1073/pnas.90.10.4577Wahl S.M., Allen J.B., Weeks B.S., Wong H.L., Klotman P.E. Transforming growth factor beta enhances integrin expression and type IV collagenase secretion in human monocytes. Proc Natl Acad Sci USA 1993; 90(10): 4577–4581. DOI: 10.1073/pnas.90.10.4577Wheeler J.B., Ikonomidis J.S., Jones J.A. Connective tissue disorders and cardiovascular complications: the indomitable role of transforming growth factor-beta signaling. Adv Exp Med Biol 2014; 802: 107–127. DOI: 10.1007/978–94–007–7893–1_8Wheeler J.B., Ikonomidis J.S., Jones J.A. Connective tissue disorders and cardiovascular complications: the indomitable role of transforming growth factor-beta signaling. Adv Exp Med Biol 2014; 802: 107–127. DOI: 10.1007/978–94–007–7893–1_8Lima B.L., Santos E.J., Fernandes G.R., Merkel C., Mello M.R., Gomes J.P. et al. A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression. PLoS One 2010; 5(11): e14136. DOI: 10.1371/journal.pone.0014136Lima B.L., Santos E.J., Fernandes G.R., Merkel C., Mello M.R., Gomes J.P. et al. A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression. PLoS One 2010; 5(11): e14136. DOI: 10.1371/journal.pone.0014136Faivre L., Collod-Beroud G., Loeys B.L., 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(3): 454–466. DOI: 10.1086/520125Faivre L., Collod-Beroud G., Loeys B.L., 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(3): 454–466. DOI: 10.1086/520125Franken R., Groenink M., de Waard V., Feenstra H.M., Scholte A.J., van den Berg M.P. et al. Genotype impacts survival in Marfan syndrome. Eur Heart J 2016; 37(43): 3285– 3290. DOI: 10.1093/eurheartj/ehv739Franken R., Groenink M., de Waard V., Feenstra H.M., Scholte A.J., van den Berg M.P. et al. Genotype impacts survival in Marfan syndrome. Eur Heart J 2016; 37(43): 3285– 3290. DOI: 10.1093/eurheartj/ehv739Arnaud P., Hanna N., Aubart M., Leheup B., Dupuis-Girod S., Naudion S. et al. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome. J Med Genet 2017; 54(2): 100–103. DOI: 10.1136/jmedgenet-2016–103996Arnaud P., Hanna N., Aubart M., Leheup B., Dupuis-Girod S., Naudion S. et al. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome. J Med Genet 2017; 54(2): 100–103. DOI: 10.1136/jmedgenet-2016–103996Baudhuin L.M., Kotzer K.E., Lagerstedt S.A. Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events. Genet Med 2015; 17(3): 177–187. DOI: 10.1038/gim.2014.91Baudhuin L.M., Kotzer K.E., Lagerstedt S.A. Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events. Genet Med 2015; 17(3): 177–187. DOI: 10.1038/gim.2014.91Mátyás G., Alonso S., Patrignani A., Marti M., Arnold E., Magyar I. et al. Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome. Hum Genet 2007; 122(1): 23–32. DOI: 10.1007/ s00439–007–0371-xMátyás G., Alonso S., Patrignani A., Marti M., Arnold E., Magyar I. et al. Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome. Hum Genet 2007; 122(1): 23–32. DOI: 10.1007/ s00439–007–0371-xRobinson P.N., Booms P., Katzke S., Ladewig M., Neumann L., Palz M. et al. Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies. Hum Mutat 2002; 20(3): 153–161. DOI: 10.1002/humu.10113Robinson P.N., Booms P., Katzke S., Ladewig M., Neumann L., Palz M. et al. Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies. Hum Mutat 2002; 20(3): 153–161. DOI: 10.1002/humu.10113Garcia-Gonzalez M.A., Jones J.G., Allen S.K., Palatucci C.M., Batish S.D., Seltzer W.K. et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab 2007; 92(1–2): 160–167. DOI: 10.1016/j.ymgme.2007.05.004Garcia-Gonzalez M.A., Jones J.G., Allen S.K., Palatucci C.M., Batish S.D., Seltzer W.K. et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab 2007; 92(1–2): 160–167. DOI: 10.1016/j.ymgme.2007.05.004Gentilini D., Oliveri A., Fazia T., Pini A., Marelli S., Bernardinelli L., Di Blasio A.M. NGS analysis in Marfan syndrome spectrum: Combination of rare and common genetic variants to improve genotype-phenotype correlation analysis. PLoS One 2019; 14(9): e0222506. DOI: 10.1371/journal.pone.0222506Gentilini D., Oliveri A., Fazia T., Pini A., Marelli S., Bernardinelli L., Di Blasio A.M. NGS analysis in Marfan syndrome spectrum: Combination of rare and common genetic variants to improve genotype-phenotype correlation analysis. PLoS One 2019; 14(9): e0222506. DOI: 10.1371/journal.pone.0222506McGrory J., Cole W.G. Alternative splicing of exon 37 of FBN1 deletes part of an ‘eight-cysteine’ domain resulting in the Marfan syndrome. Clin Genet 1999; 55(2): 118–121. DOI: 10.1034/j.1399-0004.1999.550208.xMcGrory J., Cole W.G. Alternative splicing of exon 37 of FBN1 deletes part of an ‘eight-cysteine’ domain resulting in the Marfan syndrome. Clin Genet 1999; 55(2): 118–121. DOI: 10.1034/j.1399-0004.1999.550208.xDevereux R.B., Hilhorst-Hofstee Y., Jondeau G., Faivre L., Milewicz D.M., Pyeritz R.E. et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010; 47(7): 476–85. DOI: 10.1136/jmg.2009.072785Devereux R.B., Hilhorst-Hofstee Y., Jondeau G., Faivre L., Milewicz D.M., Pyeritz R.E. et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010; 47(7): 476–85. DOI: 10.1136/jmg.2009.072785Grange T., Aubart M., Langeois M., Benarroch L., Arnaud P., Milleron O. et al. Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability. Genes (Basel) 2020; 11(5): 574. DOI: 10.3390/genes11050574Grange T., Aubart M., Langeois M., Benarroch L., Arnaud P., Milleron O. et al. Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability. Genes (Basel) 2020; 11(5): 574. DOI: 10.3390/genes11050574Arnaud P., Milleron O., Hanna N., Ropers J., Ould Ouali N., Affoune A. et al. 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; 23(7): 1296–1304. DOI: 10.1038/s41436–021–01132-xArnaud P., Milleron O., Hanna N., Ropers J., Ould Ouali N., Affoune A. et al. 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; 23(7): 1296–1304. DOI: 10.1038/s41436–021–01132-xDu Q., Zhang D., Zhuang Y., Xia Q., Wen T., Jia H. The Molecular Genetics of Marfan Syndrome. Int J Med Sci 2021; 18(13): 2752–2766. DOI: 10.7150/ijms.60685Du Q., Zhang D., Zhuang Y., Xia Q., Wen T., Jia H. The Molecular Genetics of Marfan Syndrome. Int J Med Sci 2021; 18(13): 2752–2766. DOI: 10.7150/ijms.60685Najafi A., Caspar S.M., Meienberg J., Rohrbach M., Steinmann B., Matyas G. Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies. Clin Genet 2020; 97(2): 235–245. DOI: 10.1111/cge.13640Najafi A., Caspar S.M., Meienberg J., Rohrbach M., Steinmann B., Matyas G. Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies. Clin Genet 2020; 97(2): 235–245. DOI: 10.1111/cge.13640Gerdes Gyuricza I., Barbosa de Souza R., Farinha-Arcieri L.E., Ribeiro Fernandes G., Veiga Pereira L. Is HSPG2 a modifier gene for Marfan syndrome? Eur J Hum Genet 2020; 28(9): 1292–1296. DOI: 10.1038/s41431–020–0666–0Gerdes Gyuricza I., Barbosa de Souza R., Farinha-Arcieri L.E., Ribeiro Fernandes G., Veiga Pereira L. Is HSPG2 a modifier gene for Marfan syndrome? Eur J Hum Genet 2020; 28(9): 1292–1296. DOI: 10.1038/s41431–020–0666–0Tiedemann K., Sasaki T., Gustafsson E., Göhring W., Bätge B., Notbohm H. et al. Microfibrils at basement membrane zones interact with perlecan via fibrillin-1. J Biol Chem 2005; 280(12): 11404–11412. DOI: 10.1074/jbc.M409882200Tiedemann K., Sasaki T., Gustafsson E., Göhring W., Bätge B., Notbohm H. et al. Microfibrils at basement membrane zones interact with perlecan via fibrillin-1. J Biol Chem 2005; 280(12): 11404–11412. DOI: 10.1074/jbc.M409882200Zoeller J.J., McQuillan A., Whitelock J., Ho S.Y., Iozzo R.V. A central function for perlecan in skeletal muscle and cardiovascular development. J Cell Biol 2008; 181(2): 381–394. DOI: 10.1083/jcb.200708022Zoeller J.J., McQuillan A., Whitelock J., Ho S.Y., Iozzo R.V. A central function for perlecan in skeletal muscle and cardiovascular development. J Cell Biol 2008; 181(2): 381–394. DOI: 10.1083/jcb.200708022Wu Y., Sun H., Wang J., Wang X., Gong M., Han L. et al. Marfan syndrome: whole-exome sequencing reveals de novo mutations, second gene and genotype-phenotype correlations in the Chinese population. Biosci Rep 2020; 40(12): BSR20203356. DOI: 10.1042/BSR20203356Wu Y., Sun H., Wang J., Wang X., Gong M., Han L. et al. Marfan syndrome: whole-exome sequencing reveals de novo mutations, second gene and genotype-phenotype correlations in the Chinese population. Biosci Rep 2020; 40(12): BSR20203356. DOI: 10.1042/BSR20203356Jimenez Y., Paulsen C., Turner E., Iturra S., Cuevas O., LaySon G. et al. Exome Sequencing Identifies Genetic Variants Associated with Extreme Manifestations of the Cardiovascular Phenotype in Marfan Syndrome. Genes (Basel) 2022; 13(6): 1027. DOI: 10.3390/genes13061027Jimenez Y., Paulsen C., Turner E., Iturra S., Cuevas O., LaySon G. et al. Exome Sequencing Identifies Genetic Variants Associated with Extreme Manifestations of the Cardiovascular Phenotype in Marfan Syndrome. Genes (Basel) 2022; 13(6): 1027. DOI: 10.3390/genes13061027Chesneau B., Edouard T., Dulac Y., Colineaux H., Langeois M., Hanna N. et al. Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature. Mol Genet Genomic Med 2020; 8(5): e1132. DOI: 10.1002/mgg3.1132Chesneau B., Edouard T., Dulac Y., Colineaux H., Langeois M., Hanna N. et al. Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature. Mol Genet Genomic Med 2020; 8(5): e1132. DOI: 10.1002/mgg3.1132Fouillade C., Monet-Leprêtre M., Baron-Menguy C., Joutel A. Notch signalling in smooth muscle cells during development and disease. Cardiovasc Res 2012; 95(2): 138–146. DOI: 10.1093/cvr/cvs019Fouillade C., Monet-Leprêtre M., Baron-Menguy C., Joutel A. Notch signalling in smooth muscle cells during development and disease. Cardiovasc Res 2012; 95(2): 138–146. DOI: 10.1093/cvr/cvs019Guo D.C., Regalado E., Casteel D.E., Santos-Cortez R.L., Gong L., Kim J.J., et al; GenTAC Registry Consortium; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project; Kim C, Milewicz DM. Recurrent gain-offunction mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet 2013; 93(2): 398–404. DOI: 10.1016/j.ajhg.2013.06.019Guo D.C., Regalado E., Casteel D.E., Santos-Cortez R.L., Gong L., Kim J.J., et al; GenTAC Registry Consortium; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project; Kim C, Milewicz DM. Recurrent gain-offunction mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet 2013; 93(2): 398–404. DOI: 10.1016/j.ajhg.2013.06.019Lucarini L., Evangelisti L., Attanasio M., Lapini I., Chiarini F., Porciani M.C. et al. May TGFBR1 act also as low penetrance allele in Marfan syndrome? Int J Cardiol 2009; 131(2): 281– 284. DOI: 10.1016/j.ijcard.2007.07.048Lucarini L., Evangelisti L., Attanasio M., Lapini I., Chiarini F., Porciani M.C. et al. May TGFBR1 act also as low penetrance allele in Marfan syndrome? Int J Cardiol 2009; 131(2): 281– 284. DOI: 10.1016/j.ijcard.2007.07.048Somers A.E., Hinton R.B., Pilipenko V., Miller E., Ware S.M. Analysis of TGFBR1*6A variant in individuals evaluated for Marfan syndrome. Am J Med Genet A 2016; 170(7): 1786–1790. DOI: 10.1002/ajmg.a.37668Somers A.E., Hinton R.B., Pilipenko V., Miller E., Ware S.M. Analysis of TGFBR1*6A variant in individuals evaluated for Marfan syndrome. Am J Med Genet A 2016; 170(7): 1786–1790. DOI: 10.1002/ajmg.a.37668De Backer J., Loeys B., Leroy B., Coucke P., Dietz H., De Paepe A. Utility of molecular analyses in the exploration of extreme intrafamilial variability in the Marfan syndrome. Clin Genet 2007; 72(3): 188–198. DOI: 10.1111/j.1399–0004.2007.00845.xDe Backer J., Loeys B., Leroy B., Coucke P., Dietz H., De Paepe A. Utility of molecular analyses in the exploration of extreme intrafamilial variability in the Marfan syndrome. Clin Genet 2007; 72(3): 188–198. DOI: 10.1111/j.1399–0004.2007.00845.xLima B.L., Santos E.J., Fernandes G.R., Merkel C., Mello M.R., Gomes J.P. et al. A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression. PLoS One 2010; 5(11): e14136. DOI: 10.1371/journal.pone.0014136Lima B.L., Santos E.J., Fernandes G.R., Merkel C., Mello M.R., Gomes J.P. et al. A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression. PLoS One 2010; 5(11): e14136. DOI: 10.1371/journal.pone.0014136Carta L., Wagenseil J.E., Knutsen R.H., Mariko B., Faury G., Davis E.C. et al. Discrete contributions of elastic fiber components to arterial development and mechanical compliance. Arterioscler Thromb Vasc Biol 2009; 29(12): 2083–2089. DOI: 10.1161/ATVBAHA.109.193227Carta L., Wagenseil J.E., Knutsen R.H., Mariko B., Faury G., Davis E.C. et al. Discrete contributions of elastic fiber components to arterial development and mechanical compliance. Arterioscler Thromb Vasc Biol 2009; 29(12): 2083–2089. DOI: 10.1161/ATVBAHA.109.193227Aubart M., Gross M.S., Hanna N., Zabot M.T., Sznajder M., Detaint D. et al. The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele. Hum Mol Genet 2015; 24(10) :2764–2770. DOI: 10.1093/hmg/ddv037Aubart M., Gross M.S., Hanna N., Zabot M.T., Sznajder M., Detaint D. et al. The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele. Hum Mol Genet 2015; 24(10) :2764–2770. DOI: 10.1093/hmg/ddv037Hutchinson S., Furger A., Halliday D., Judge D.P., Jefferson A., Dietz H.C. et al. Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: a potential modifier of phenotype? Hum Mol Genet 2003; 12(18): 2269–2276. DOI: 10.1093/hmg/ddg241Hutchinson S., Furger A., Halliday D., Judge D.P., Jefferson A., Dietz H.C. et al. Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: a potential modifier of phenotype? Hum Mol Genet 2003; 12(18): 2269–2276. DOI: 10.1093/hmg/ddg241Fernandes G.R., Massironi S.M., Pereira L.V. Identification of Loci Modulating the Cardiovascular and Skeletal Phenotypes of Marfan Syndrome in Mice. Sci Rep 2016; 6: 22426. DOI: 10.1038/srep22426Fernandes G.R., Massironi S.M., Pereira L.V. Identification of Loci Modulating the Cardiovascular and Skeletal Phenotypes of Marfan Syndrome in Mice. Sci Rep 2016; 6: 22426. DOI: 10.1038/srep22426

The authors declare that there are no conflicts of interest present.