Journal of Otolaryngology and Ophthalmology of Shandong University ›› 2023, Vol. 37 ›› Issue (2): 98-103.doi: 10.6040/j.issn.1673-3770.0.2022.207

• 论著 • Previous Articles    

Analysis of a new-onset FBN1 gene mutation in a patient with Marfan syndrome

ZHAO Shuang1, ZHAO Jun2, XUE Youyu2, ZHANG Juanmei2   

  1. 1. Graduate Department, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250000, Shandong, China;
    2. Department of Ophthalmology, Linyi People's Hospital, Linyi 276000, Shandong, China
  • Published:2023-03-30

PDF (PC)

477

Abstract: Objective To identify the genetic etiology, sequencing analysis of the causative gene was performed in a child with a clinical diagnosis of Marfan syndrome. Methods Genomic DNA was extracted from the peripheral blood samples of the proband and his parents for whole exome sequencing analysis; the suspected loci were then verified using Sanger sequencing. The pathogenicity of the variants was assessed according to the guidelines issued by the American College of Medical Genetics and Genomics(ACMG), and predictive analysis was performed using REVEL-a bioinformatics software for the comprehensive prediction of the pathogenicity of missense variants. Results The results of whole exome sequencing analysis showed that the FBN1 gene was associated with the c. 4016G > T(p.C1339F)heterozygous missense mutation in the child. Results of Sanger sequencing showed that his parents had no variation at this locus and exhibited spontaneous mutations. According to the ACMG guidelines, this variant was tentatively determined to be a pathogenic variant. REVEL predicted the missense variant as harmful, and SIFT, PolyPhen 2, Mutation Taster, and GERP + predicted it to be deleterious. Conclusion The c.4016G > T(p.C1339F)heterozygous mutation in the FBN1 gene may be the cause of the disease in our patient with Marfan syndrome; this new variant further expands the FBN1 variant spectrum.

Key words: Marfan syndrome, FBN1 gene, Heterozygous mutation, Genes mutation, Whole exome sequencing

CLC Number: 

  • R596.1
[1] Seo GH, Kim YM, Kang E, et al. The phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums[J]. Medicine(Baltimore), 2018, 97(20): 10767. doi:10.1097/MD.0000000000010767
[2] Milewicz DM, Braverman AC, De Backer J, et al. Marfan syndrome[J]. Nat Rev Dis Primers, 2021, 7(1):64.doi: 10.1038/s41572-021-00298-7
[3] van Andel MM, Groenink M, van den Berg MP, et al. Genome-wide methylation patterns in Marfan syndrome[J]. Clin Epigenetics, 2021, 13(1): 217. doi:10.1186/s13148-021-01204-4
[4] Demolder A, Timmermans F, Duytschaever M, et al. Association of mitral annular disjunction with cardiovascular outcomes among patients with Marfan syndrome[J]. JAMA Cardiol, 2021, 6(10): 1177-1186. doi:10.1001/jamacardio.2021.2312
[5] Nayak SS, Schneeberger PE, Patil SJ, et al. Clinically relevant variants in a large cohort of Indian patients with Marfan syndrome and related disorders identified by next-generation sequencing[J]. Sci Rep, 2021, 11(1): 764. doi:10.1038/s41598-020-80755-7
[6] Fernández-álvarez P, Codina-Sola M, Valenzuela I, et al. A systematic study and literature review of parental somatic mosaicism of FBN1 pathogenic variants in Marfan syndrome[J]. J Med Genet, 2022, 59(6): 605-612. doi:10.1136/jmedgenet-2020-107604
[7] Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene[J]. Nature, 1991, 352(6333): 337-339. doi:10.1038/352337a0
[8] Lerner-Ellis JP, Aldubayan SH, Hernandez AL, et al. The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections(TAAD)[J]. Mol Genet Metab, 2014, 112(2): 171-176. doi:10.1016/j.ymgme.2014.03.011
[9] Groth KA, von Kodolitsch Y, Kutsche K, et al. Evaluating the quality of Marfan genotype-phenotype correlations in existing FBN1 databases[J]. Genet Med, 2017, 19(7): 772-777. doi:10.1038/gim.2016.181
[10] Franken R, Teixido-Tura G, Brion M, et al. Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome[J]. Heart, 2017, 103(22): 1795-1799. doi:10.1136/heartjnl-2016-310631
[11] Bitterman AD, Sponseller PD. Marfan syndrome: a clinical update[J]. J Am Acad Orthop Surg, 2017, 25(9): 603-609. doi:10.5435/JAAOS-D-16-00143
[12] Zeigler SM, Sloan B, Jones JA. Pathophysiology and pathogenesis of Marfan syndrome[J]. Adv Exp Med Biol, 2021, 1348: 185-206. doi:10.1007/978-3-030-80614-9_8
[13] 赵良慧, 蔡涛, 杜显丽. 圆锥角膜家系中ZEB1基因突变的致病性分析[J]. 山东大学耳鼻喉眼学报, 2021, 35(2): 98-104. doi:10.6040/j.issn.1673-3770.0.2020.358 ZHAO Lianghui, CAI Tao, DU Xianli. Mutation analysis of ZEB1 in a pedigree with keratoconus[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2021, 35(2): 98-104. doi:10.6040/j.issn.1673-3770.0.2020.358
[14] Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome[J]. J Med Genet, 2010, 47(7): 476-485. doi:10.1136/jmg.2009.072785
[15] Coelho SG, Almeida AG. Marfan syndrome revisited: from genetics to the clinic[J]. Rev Port Cardiol(Engl Ed), 2020, 39(4): 215-226. doi:10.1016/j.repc.2019.09.008
[16] Pollock L, Ridout A, Teh J, et al. The musculoskeletal manifestations of Marfan syndrome: diagnosis, impact, and management[J]. Curr Rheumatol Rep, 2021, 23(11): 81. doi:10.1007/s11926-021-01045-3
[17] Pogue RE, Cavalcanti DP, Shanker S, et al. Rare genetic diseases: update on diagnosis, treatment and online resources[J]. Drug Discov Today, 2018, 23(1): 187-195. doi:10.1016/j.drudis.2017.11.002
[18] Li JC, Zhao TT, Zhang Y, et al. Performance evaluation of pathogenicity-computation methods for missense variants[J]. Nucleic Acids Res, 2018, 46(15): 7793-7804. doi:10.1093/nar/gky678
[19] Ballester LY, Luthra R, Kanagal-Shamanna R, et al. Advances in clinical next-generation sequencing: target enrichment and sequencing technologies[J]. Expert Rev Mol Diagn, 2016, 16(3): 357-372. doi:10.1586/14737159.2016.1133298
[20] 康小翠, 徐昳, 林瑷琪, 等. FBN1基因与马凡综合征及其相关表型关系研究进展[J]. 临床内科杂志, 2021, 38(11): 724-727. doi: 10.3969/j.issn.1001-9057.2021.11.002 KANG Xiaocui, XU Yi, LIN Aiqi, et al. Association between FBN1, Marfan syndrome and the related phenotypes: an overview[J]. Journal of Clinical Internal Medicine, 2021, 38(11): 724-727. doi: 10.3969/j.issn.1001-9057.2021.11.002
[21] Ramirez F, Caescu C, Wondimu E, et al. Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness[J]. Matrix Biol, 2018(71/72): 82-89. doi:10.1016/j.matbio.2017.07.004
[22] Schrenk S, Cenzi C, Bertalot T, et al. Structural and functional failure of fibrillin?1 in human diseases(Review)[J]. Int J Mol Med, 2018, 41(3): 1213-1223. doi:10.3892/ijmm.2017.3343
[23] Groth KA, von Kodolitsch Y, Kutsche K, et al. Evaluating the quality of Marfan genotype-phenotype correlations in existing FBN1 databases[J]. Genet Med, 2017, 19(7): 772-777. doi:10.1038/gim.2016.181
[24] 杨岚, 郭小新, 蒋琳鑫, 等. 两个马凡综合征家系的FBN1基因突变分析[J]. 中华医学遗传学杂志, 2019, 36(6): 566-570. doi:10.3760/cma.j.issn.1003-9406.2019.06.008
[25] Wu YD, Sun HR, Wang JB, et al. Marfan syndrome: whole-exome sequencing reveals de novo mutations, second gene and genotype-phenotype correlations in the Chinese population[J]. Biosci Rep, 2020, 40(12): BSR20203356. doi:10.1042/BSR20203356
[26] Arnaud P, Milleron O, Hanna N, et al. Clinical relevance of genotype-phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants[J]. Genet Med, 2021, 23(7): 1296-1304. doi:10.1038/s41436-021-01132-x
[27] de Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic criteria for the Marfan syndrome[J]. Am J Med Genet, 1996, 62(4): 417-426. doi:10.1002/(SICI)1096-8628(19960424)62: 4<417: AID-AJMG15>3.0.CO;2-R
[1] ZHAO Lianghui, CAI Tao, DU Xianli. Mutation analysis of ZEB1 in a pedigree with keratoconus [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2021, 35(2): 98-104.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Website Copyright: Editorial Office of Journal of Otolaryngology and Ophthalmology of Shandong University
Address: No.27 Shanda South Road, Jinan, Shandong, China. Post code: 250100 Tel: +86-0531-88366912 Email: ebhxb@sdu.edu.cn Supported by Beijing Magtech Co.Ltd