New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome

BMC Genetics

Jacob Tfelt-Hansen¹  Morten S Olesen¹  Jesper Hastrup Svendsen¹  Stig Haunsø¹  Ahmad Sajadieh²  Xu Chen³  Bjarke Risgaard³  Jonas B Nielsen³  Reza Jabbari³  Xiao-Shu Cheng⁴  Javad Jabbari³  Ren-Qiang Yang⁴ 

[1] Department of Medicine and Surgery, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark;Department of Cardiology, Copenhagen University Hospital of Bispebjerg, Bispebjerg, Denmark;The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark;Department of Cardiology, Institute of Cardiovascular Disease, the Heart Centre, the Second Affiliated Hospital, Nanchang University, Nanchang, China

关键词: Variant;    The NHLBI GO exome sequencing project;    HGMD;    Genetic testing;    Marfan syndrome;   

Others  :  866423
DOI  :  10.1186/1471-2156-15-74

 received in 2013-11-04, accepted in 2014-06-02,  发布年份 2014

【 摘 要 】

Background

Marfan syndrome (MFS) is a rare autosomal dominantly inherited connective tissue disorder with an estimated prevalence of 1:5,000. More than 1000 variants have been previously reported to be associated with MFS. However, the disease-causing effect of these variants may be questionable as many of the original studies used low number of controls. To study whether there are possible false-positive variants associated with MFS, four in silico prediction tools (SIFT, Polyphen-2, Grantham score, and conservation across species) were used to predict the pathogenicity of these variant.

Results

Twenty-three out of 891 previously MFS-associated variants were identified in the ESP. These variants were distributed on 100 heterozygote carriers in 6494 screened individuals. This corresponds to a genotype prevalence of 1:65 for MFS. Using a more conservative approach (cutoff value of >2 carriers in the EPS), 10 variants affected a total of 82 individuals. This gives a genotype prevalence of 1:79 (82:6494) in the ESP. A significantly higher frequency of MFS-associated variants not present in the ESP were predicted to be pathogenic with the agreement of ≥3 prediction tools, compared to the variants present in the ESP (p = 3.5 × 10⁻¹⁵).

Conclusions

This study showed a higher genotype prevalence of MFS than expected from the phenotype prevalence in the general population. The high genotype prevalence suggests that these variants are not the monogenic cause of MFS. Therefore, caution should be taken with regard to disease stratification based on these previously reported MFS-associated variants.

【 授权许可】

   
2014 Yang et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Arbustini E, Grasso M, Ansaldi S, Malattia C, Pilotto A, Porcu E, Disabella E, Marziliano N, Pisani A, Lanzarini L, Mannarino S, Larizza D, Mosconi M, Antoniazzi E, Zoia MC, Meloni G, Magrassi L, Brega A, Bedeschi MF, Torrente I, Mari F, Tavazzi L: Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies. Hum Mutat 2005, 26(5):1-15.
• [2]Judge DP, Dietz HC: Marfan’s syndrome. Lancet 2005, 366(9501):1965-1976.
• [3]Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM: ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. J Am Coll Cardiol 2010, 55(14):e27-e129.
• [4]Schoenhoff FS, Jungi S, Czerny M, Roost E, Reineke D, Matyas G, Steinmann B, Schmidli J, Kadner A, Carrel T: Acute aortic dissection determines the fate of initially untreated aortic segments in Marfan syndrome. Circulation 2013, 127(15):1569-1575.
• [5]Barrett PM, Topol EJ: The fibrillin-1 gene: unlocking new therapeutic pathways in cardiovascular disease. Heart 2013, 99(2):83-90.
• [6]Lacro RV, Guey LT, Dietz HC, Pearson GD, Yetman AT, Gelb BD, Loeys BL, Benson DW, Bradley TJ, De Backer J, Forbus GA, Klein GL, Lai WW, Levine JC, Lewin MB, Markham LW, Paridon SM, Pierpont ME, Radojewski E, Selamet Tierney ES, Sharkey AM, Wechsler SB, Mahony L: Pediatric Heart Network Investigators: characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy. Am Heart J 2013, 165(5):828-835.
• [7]Pati PK, George PV, Jose JV: Giant pulmonary artery aneurysm with dissection in a case of Marfan syndrome. J Am Coll Cardiol 2013, 61(6):685.
• [8]De Backer JF, Devos D, Segers P, Matthys D, François K, Gillebert TC, De Paepe AM, De Sutter J: Primary impairment of left ventricular function in Marfan syndrome. Int J Cardiol 2006, 112(3):353-358.
• [9]Halushka MK: Single gene disorders of the aortic wall. Cardiovasc Pathol 2012, 21(4):240-244.
• [10]Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM: The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010, 47(7):476-485.
• [11]Gillis E, Van Laer L, Loeys BL: Genetics of thoracic aortic aneurysm: at the crossroad of transforming growth factor-β signaling and vascular smooth muscle cell contractility. Circ Res 2013, 113(3):327-340.
• [12]Sawaki D, Suzuki T: Targeting transforming growth factor-β signaling in Aortopathies in Marfan syndrome. Circ J 2013, 77(4):898-899.
• [13]Stheneur C, Collod-Béroud G, Faivre L, Gouya L, Sultan G, Le Parc J-M, Moura B, Attias D, Muti C, Sznajder M, Claustres M, Junien C, Baumann C, Cormier-Daire V, Rio M, Lyonnet S, Plauchu H, Lacombe D, Chevallier B, Jondeau G, Boileau C: Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. Hum Mutat 2008, 29(11):E284-E295.
• [14]Singh KK, Rommel K, Mishra A, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M: TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat 2006, 27(8):770-777.
• [15]Fu W, O’Connor TD, Jun G, Kang HM, Abecasis G, Leal SM, Gabriel S, Altshuler D, Shendure J, Nickerson DA, Bamshad MJ, Akey JM: Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 2013, 493(7431):216-220.
• [16]Exome Variant Server. Retrieved from: http://evs.gs.washington.edu/EVS/ webcite
• [17]Biological Databases for Gene Expression, Pathway & NGS Analysis. Retrieved from: http://www.biobase-international.com/ webcite
• [18]Dong J, Bu J, Du W, Li Y, Jia Y, Li J, Meng X, Yuan M, Peng X, Zhou A, Wang L: A new novel mutation in FBN1 causes autosomal dominant Marfan syndrome in a Chinese family. Mol Vis 2012, 18:81-86.
• [19]Van Den Bossche MJA, Van Wallendael KLP, Strazisar M, Sabbe B, Del-Favero J: Co-occurrence of Marfan syndrome and schizophrenia: what can be learned? Eur J Med Genet 2012, 55(4):252-255.
• [20]Hogue J, Lee C, Jelin A, Strecker M, Cox V, Slavotinek A: Homozygosity for a FBN1 missense mutation causes a severe Marfan syndrome phenotype. Clin Genet 2013, 84(4):392-393.
• [21]Giudicessi JR, Kapplinger JD, Tester DJ, Alders M, Salisbury BA, Wilde AAM, Ackerman MJ: Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet 2012, 5(5):519-528.
• [22]Tjeldhorn L, Rand-Hendriksen S, Gervin K, Brandal K, Inderhaug E, Geiran O, Paus B: Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test 2006, 10(4):258-264.
• [23]Rommel K, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M: Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations. Hum Mutat 2002, 20(5):406-407.
• [24]Hung C-C, Lin S-Y, Lee C-N, Cheng H-Y, Lin S-P, Chen M-R, Chen C-P, Chang C-H, Lin C-Y, Yu C-C, Chiu H-H, Cheng W-F, Ho H-N, Niu D-M, Su Y-N: Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. Ann Hum Genet 2009, 73(Pt 6):559-567.
• [25]Comeglio P, Johnson P, Arno G, Brice G, Evans A, Aragon-Martin J, da Silva FP, Kiotsekoglou A, Child A: The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat 2007, 28(9):928.
• [26]Tiecke F, Katzke S, Booms P, Robinson PN, Neumann L, Godfrey M, Mathews KR, Scheuner M, Hinkel GK, Brenner RE, Hövels-Gürich HH, Hagemeier C, Fuchs J, Skovby F, Rosenberg T: Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24–40. Eur J Hum Genet 2001, 9(1):13-21.
• [27]Yuan B, Thomas JP, von Kodolitsch Y, Pyeritz RE: Comparison of heteroduplex analysis, direct sequencing, and enzyme mismatch cleavage for detecting mutations in a large gene, FBN1. Hum Mutat 1999, 14(5):440-446.
• [28]Hayward C, Porteous ME, Brock DJ: A novel mutation in the fibrillin gene (FBN1) in familial arachnodactyly. Mol Cell Probes 1994, 8(4):325-327.
• [29]Mátyás G, De Paepe A, Halliday D, Boileau C, Pals G, Steinmann B: Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel polymorphisms in the FBN1 gene. Hum Mutat 2002, 19(4):443-456.
• [30]Liu WO, Oefner PJ, Qian C, Odom RS, Francke U: Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders. Genet Test 1997, 1(4):237-242.
• [31]Collod-Béroud G, Béroud C, Ades L, Black C, Boxer M, Brock DJ, Holman KJ, de Paepe A, Francke U, Grau U, Hayward C, Klein HG, Liu W, Nuytinck L, Peltonen L, Alvarez Perez AB, Rantamäki T, Junien C, Boileau C: Marfan Database (third edition): new mutations and new routines for the software. Nucleic Acids Res 1998, 26(1):229-223.
• [32]Sheikhzadeh S, Kade C, Keyser B, Stuhrmann M, Arslan-Kirchner M, Rybczynski M, Bernhardt AM, Habermann CR, Hillebrand M, Mir T, Robinson PN, Berger J, Detter C, Blankenberg S, Schmidtke J, von Kodolitsch Y: Analysis of phenotype and genotype information for the diagnosis of Marfan syndrome. Clin Genet 2012, 82(3):240-247.
• [33]Sakai H, Visser R, Ikegawa S, Ito E, Numabe H, Watanabe Y, Mikami H, Kondoh T, Kitoh H, Sugiyama R, Okamoto N, Ogata T, Fodde R, Mizuno S, Takamura K, Egashira M, Sasaki N, Watanabe S, Nishimaki S, Takada F, Nagai T, Okada Y, Aoka Y, Yasuda K, Iwasa M, Kogaki S, Harada N, Mizuguchi T, Matsumoto N: Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes. Am J Med Genet A 2006, 140(16):1719-1725.
• [34]Howarth R, Yearwood C, Harvey JF: Application of dHPLC for mutation detection of the fibrillin-1 gene for the diagnosis of Marfan syndrome in a National Health Service Laboratory. Genet Test 2007, 11(2):146-152.
• [35]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 Invest 1995, 95(5):2373-2378.
• [36]Mátyás G, Arnold E, Carrel T, Baumgartner D, Boileau C, Berger W, Steinmann B: Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Hum Mutat 2006, 27(8):760-769.
• [37]Refsgaard L, Holst AG, Sadjadieh G, Haunsø S, Nielsen JB, Olesen MS: High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet 2012, 20(8):905-908.
• [38]Risgaard B, Jabbari R, Refsgaard L, Holst A, Haunsø S, Sadjadieh A, Winkel B, Olesen M, Tfelt-Hansen J: High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. Clin Genet 2013, 84(5):489-495.
• [39]Andreasen C, Nielsen JB, Refsgaard L, Holst AG, Christensen AH, Andreasen L, Sajadieh A, Haunsø S, Svendsen JH, Olesen MS: New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet 2013, 21(9):918-928.
• [40]Lucarini L, Evangelisti L, Attanasio M, Lapini I, Chiarini F, Porciani MC, Abbate R, Gensini G, Pepe G: May TGFBR1 act also as low penetrance allele in Marfan syndrome? Int J Cardiol 2009, 131(2):281-284.
• [41]Jabbari J, Jabbari R, Nielsen MW, Holst AG, Nielsen JB, Haunsø S, Tfelt-Hansen J, Svendsen JH, Olesen MS: New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. Circ Cardiovasc Genet 2013, 6(5):481-489.
• [42]Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H: Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 2013, 132(10):1077-1130.
• [43]Katsanis SH, Katsanis N: Molecular genetic testing and the future of clinical genomics. Nat Rev Genet 2013, 14(6):415-426.