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01-02-2017 | Original Paper

Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals

Authors: Elham Kayvanpour, Farbod Sedaghat-Hamedani, Ali Amr, Alan Lai, Jan Haas, Daniel B. Holzer, Karen S. Frese, Andreas Keller, Katrin Jensen, Hugo A. Katus, Benjamin Meder

Published in: Clinical Research in Cardiology | Issue 2/2017

Abstract

Aims

Routine genetic testing in Dilated Cardiomyopathy (DCM) has recently become reality using Next-Generation Sequencing. Several studies have explored the relationship between genotypes and clinical phenotypes to support risk estimation and therapeutic decisions, however, most studies are small or restricted to a few genes. This study provides to our knowledge the first systematic meta-analysis on genotype-phenotype associations in DCM.

Methods and results

We retrieved PubMed/Medline literature on genotype–phenotype associations in patients with DCM and mutations in LMNA, PLN, RBM20, MYBPC3, MYH7, TNNT2 and TNNI3. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Together, 48 studies with 8097 patients were included. Furthermore, we reviewed recent studies investigating genotype-phenotype associations in DCM patients with TTN mutations. The average frequency of mutations in the investigated genes was between 1 and 5 %. The mean age of DCM onset was the beginning of the fifth decade for all genes. Heart transplantation (HTx) rate was highest in LMNA mutation carriers (27 %), while RBM20 mutation carriers were transplanted at a markedly younger age (mean 28.5 years). While 73 % of DCM patients with LMNA mutations showed cardiac conduction diseases, low voltage was the reported ECG hallmark in PLN mutation carriers. The frequency of ventricular arrhythmia in DCM patients with LMNA (50 %) and PLN (43 %) mutations was significantly higher. The penetrance of DCM phenotype in subjects with TTN truncating variants increased with age and reached 100 % by age of 70.

Conclusion

A pooled analysis of available genotype-phenotype data shows a higher prevalence of sudden cardiac death (SCD), cardiac transplantation, or ventricular arrhythmias in LMNA and PLN mutation carriers compared to sarcomeric gene mutations. This study will further support the clinical interpretation of genetic findings.

Available only for authorised users

Mestroni L, Maisch B, McKenna WJ, Schwartz K, Charron P, Rocco C, Tesson F, Richter A, Wilke A, Komajda M (1999) Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur Heart J 20(2):93–102CrossRefPubMed

Hershberger RE, Cowan J, Morales A, Siegfried JD (2009) Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Heart Fail 2(3):253–261CrossRefPubMedPubMedCentral

/CIRCHEARTFAILURE.108.817346

Kayvanpour E, Katus HA, Meder B (2015) Determined to fail-the role of genetic mechanisms in heart failure. Curr Heart Fail Rep. doi:10.1007/s11897-015-0264-6 PubMed

Watkins H, Ashrafian H, Redwood C (2011) Inherited cardiomyopathies. N Engl J Med 364(17):1643–1656. doi:10.1056/NEJMra0902923 CrossRefPubMed

Harakalova M, Kummeling G, Sammani A, Linschoten M, Baas AF, van der Smagt J, Doevendans PA, van Tintelen JP, Dooijes D, Mokry M, Asselbergs FW (2015) A systematic analysis of genetic dilated cardiomyopathy reveals numerous ubiquitously expressed and muscle-specific genes. Eur J Heart Fail 17(5):484–493. doi:10.1002/ejhf.255 CrossRefPubMed

Taylor MR, Fain PR, Sinagra G, Robinson ML, Robertson AD, Carniel E, Di Lenarda A, Bohlmeyer TJ, Ferguson DA, Brodsky GL, Boucek MM, Lascor J, Moss AC, Li WL, Stetler GL, Muntoni F, Bristow MR, Mestroni L, Familial Dilated Cardiomyopathy Registry Research G (2003) Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 41(5):771–780CrossRefPubMed

Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Peterson A, Li D, Jakobs P, Litt M, Porter CB, Rahko PS, Hershberger RE (2008) Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J 156(1):161–169. doi:10.1016/j.ahj.2008.01.026 CrossRefPubMedPubMedCentral

Perrot A, Sigusch HH, Nagele H, Genschel J, Lehmkuhl H, Hetzer R, Geier C, Leon Perez V, Reinhard D, Dietz R, Josef Osterziel K, Schmidt HH (2006) Genetic and phenotypic analysis of dilated cardiomyopathy with conduction system disease: demand for strategies in the management of presymptomatic lamin A/C mutant carriers. Eur J Heart Fail 8(5):484–493. doi:10.1016/j.ejheart.2005.11.004 CrossRefPubMed

10.

Perrot A, Hussein S, Ruppert V, Schmidt HH, Wehnert MS, Duong NT, Posch MG, Panek A, Dietz R, Kindermann I, Bohm M, Michalewska-Wludarczyk A, Richter A, Maisch B, Pankuweit S, Ozcelik C (2009) Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy. Basic Res Cardiol 104(1):90–99. doi:10.1007/s00395-008-0748-6 CrossRefPubMed

11.

Millat G, Bouvagnet P, Chevalier P, Sebbag L, Dulac A, Dauphin C, Jouk PS, Delrue MA, Thambo JB, Le Metayer P, Seronde MF, Faivre L, Eicher JC, Rousson R (2011) Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy. Euro J Med Genet 54(6):e570–575. doi:10.1016/j.ejmg.2011.07.005 CrossRef

12.

Lakdawala NK, Funke BH, Baxter S, Cirino AL, Roberts AE, Judge DP, Johnson N, Mendelsohn NJ, Morel C, Care M, Chung WK, Jones C, Psychogios A, Duffy E, Rehm HL, White E, Seidman JG, Seidman CE, Ho CY (2012) Genetic testing for dilated cardiomyopathy in clinical practice. J Cardiac Fail 18(4):296–303. doi:10.1016/j.cardfail.2012.01.013 CrossRef

13.

Saj M, Bilinska ZT, Tarnowska A, Sioma A, Bolongo P, Sobieszczanska-Malek M, Michalak E, Golen D, Mazurkiewicz L, Malek L, Walczak E, Fidzianska A, Grzybowski J, Przybylski A, Zielinski T, Korewicki J, Tesson F, Ploski R (2013) LMNA mutations in Polish patients with dilated cardiomyopathy: prevalence, clinical characteristics, and in vitro studies. BMC Med Genet 14:55. doi:10.1186/1471-2350-14-55 CrossRefPubMedPubMedCentral

14.

van Spaendonck-Zwarts KY, van Rijsingen IA, van den Berg MP, Lekanne Deprez RH, Post JG, van Mil AM, Asselbergs FW, Christiaans I, van Langen IM, Wilde AA, de Boer RA, Jongbloed JD, Pinto YM, van Tintelen JP (2013) Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years’ experience. Eur J Heart Fail 15(6):628–636. doi:10.1093/eurjhf/hft013 CrossRefPubMed

15.

van Tintelen JP, Hofstra RM, Katerberg H, Rossenbacker T, Wiesfeld AC, du Marchie Sarvaas GJ, Wilde AA, van Langen IM, Nannenberg EA, van der Kooi AJ, Kraak M, van Gelder IC, van Veldhuisen DJ, Vos Y, van den Berg MP, Working Group on Inherited Cardiac Disorders lICIoTN (2007) High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. Am Heart J 154(6):1130–1139. doi:10.1016/j.ahj.2007.07.038 CrossRef

16.

Stallmeyer B, Koopmann M, Schulze-Bahr E (2012) Identification of novel mutations in LMNA associated with familial forms of dilated cardiomyopathy. Genetic testing and molecular biomarkers 16(6):543–549. doi:10.1089/gtmb.2011.0214 CrossRefPubMed

17.

Brodt C, Siegfried JD, Hofmeyer M, Martel J, Rampersaud E, Li D, Morales A, Hershberger RE (2013) Temporal relationship of conduction system disease and ventricular dysfunction in LMNA cardiomyopathy. J Cardiac Fail 19(4):233–239. doi:10.1016/j.cardfail.2013.03.001 CrossRef

18.

Arbustini E, Pilotto A, Repetto A, Grasso M, Negri A, Diegoli M, Campana C, Scelsi L, Baldini E, Gavazzi A, Tavazzi L (2002) Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol 39(6):981–990CrossRefPubMed

19.

Karkkainen S, Helio T, Miettinen R, Tuomainen P, Peltola P, Rummukainen J, Ylitalo K, Kaartinen M, Kuusisto J, Toivonen L, Nieminen MS, Laakso M, Peuhkurinen K (2004) A novel mutation, Ser143Pro, in the lamin A/C gene is common in finnish patients with familial dilated cardiomyopathy. Eur Heart J 25(10):885–893. doi:10.1016/j.ehj.2004.01.020 CrossRefPubMed

20.

Karkkainen S, Reissell E, Helio T, Kaartinen M, Tuomainen P, Toivonen L, Kuusisto J, Kupari M, Nieminen MS, Laakso M, Peuhkurinen K (2006) Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy. Heart 92(4):524–526. doi:10.1136/hrt.2004.056721 CrossRefPubMedPubMedCentral

21.

Hasselberg NE, Edvardsen T, Petri H, Berge KE, Leren TP, Bundgaard H, Haugaa KH (2014) Risk prediction of ventricular arrhythmias and myocardial function in Lamin A/C mutation positive subjects. Euro Euro Pacing Arrhyth Cardiac Electrophysiol J Working Groups card Pacing Arrhyth Card Cellul Electrophysiol Euro Soc Cardiol 16(4):563–571. doi:10.1093/europace/eut291 CrossRef

22.

Meune C, Van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D (2006) Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med 354(2):209–210. doi:10.1056/NEJMc052632 CrossRefPubMed

23.

Hermida-Prieto M, Monserrat L, Castro-Beiras A, Laredo R, Soler R, Peteiro J, Rodriguez E, Bouzas B, Alvarez N, Muniz J, Crespo-Leiro M (2004) Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations. Am J Cardiol 94(1):50–54. doi:10.1016/j.amjcard.2004.03.029 CrossRefPubMed

24.

Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, Feng Z, Muller S, Kayvanpour E, Vogel B, Sedaghat-Hamedani F, Lim WK, Zhao X, Fradkin D, Kohler D, Fischer S, Franke J, Marquart S, Barb I, Li DT, Amr A, Ehlermann P, Mereles D, Weis T, Hassel S, Kremer A, King V, Wirsz E, Isnard R, Komajda M, Serio A, Grasso M, Syrris P, Wicks E, Plagnol V, Lopes L, Gadgaard T, Eiskjaer H, Jorgensen M, Garcia-Giustiniani D, Ortiz-Genga M, Crespo-Leiro MG, Deprez RH, Christiaans I, van Rijsingen IA, Wilde AA, Waldenstrom A, Bolognesi M, Bellazzi R, Morner S, Bermejo JL, Monserrat L, Villard E, Mogensen J, Pinto YM, Charron P, Elliott P, Arbustini E, Katus HA, Meder B (2015) Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 36(18):1123–1135a. doi:10.1093/eurheartj/ehu301 CrossRefPubMed

25.

Sebillon P, Bouchier C, Bidot LD, Bonne G, Ahamed K, Charron P, Drouin-Garraud V, Millaire A, Desrumeaux G, Benaiche A, Charniot JC, Schwartz K, Villard E, Komajda M (2003) Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. J Med Genet 40(8):560–567CrossRefPubMedPubMedCentral

26.

van Rijsingen IA, Arbustini E, Elliott PM, Mogensen J, Hermans-van Ast JF, van der Kooi AJ, van Tintelen JP, van den Berg MP, Pilotto A, Pasotti M, Jenkins S, Rowland C, Aslam U, Wilde AA, Perrot A, Pankuweit S, Zwinderman AH, Charron P, Pinto YM (2012) Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study. J Am Coll Cardiol 59(5):493–500. doi:10.1016/j.jacc.2011.08.078 CrossRefPubMed

27.

Rampersaud E, Siegfried JD, Norton N, Li D, Martin E, Hershberger RE (2011) Rare variant mutations identified in pediatric patients with dilated cardiomyopathy. Prog Pediatr Cardiol 31(1):39–47. doi:10.1016/j.ppedcard.2010.11.008 CrossRefPubMedPubMedCentral

28.

Shimizu M, Ino H, Yasuda T, Fujino N, Uchiyama K, Mabuchi T, Konno T, Kaneda T, Fujita T, Masuta E, Katoh M, Funada A, Mabuchi H (2005) Gene mutations in adult Japanese patients with dilated cardiomyopathy. Circ J 69(2):150–153CrossRefPubMed

29.

Haghighi K, Kolokathis F, Pater L, Lynch RA, Asahi M, Gramolini AO, Fan GC, Tsiapras D, Hahn HS, Adamopoulos S, Liggett SB, Dorn GW 2nd, MacLennan DH, Kremastinos DT, Kranias EG (2003) Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J Clin Investig 111(6):869–876. doi:10.1172/JCI17892 CrossRefPubMedPubMedCentral

30.

Schmitt JP, Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, Kranias EG, MacLennan DH, Seidman JG, Seidman CE (2003) Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 299(5611):1410–1413. doi:10.1126/science.1081578 CrossRefPubMed

31.

Villard E, Duboscq-Bidot L, Charron P, Benaiche A, Conraads V, Sylvius N, Komajda M (2005) Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene. Eur Heart J 26(8):794–803. doi:10.1093/eurheartj/ehi193 CrossRefPubMed

32.

DeWitt MM, MacLeod HM, Soliven B, McNally EM (2006) Phospholamban R14 deletion results in late-onset, mild, hereditary dilated cardiomyopathy. J Am Coll Cardiol 48(7):1396–1398. doi:10.1016/j.jacc.2006.07.016 CrossRefPubMed

33.

Haghighi K, Kolokathis F, Gramolini AO, Waggoner JR, Pater L, Lynch RA, Fan GC, Tsiapras D, Parekh RR, Dorn GW 2nd, MacLennan DH, Kremastinos DT, Kranias EG (2006) A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy. Proc Natl Acad Sci USA 103(5):1388–1393. doi:10.1073/pnas.0510519103 CrossRefPubMedPubMedCentral

34.

Medeiros A, Biagi DG, Sobreira TJ, de Oliveira PS, Negrao CE, Mansur AJ, Krieger JE, Brum PC, Pereira AC (2011) Mutations in the human phospholamban gene in patients with heart failure. American heart journal 162(6):1088–1095 e1081. doi:10.1016/j.ahj.2011.07.028

35.

van der Zwaag PA, van Rijsingen IA, Asimaki A, Jongbloed JD, van Veldhuisen DJ, Wiesfeld AC, Cox MG, van Lochem LT, de Boer RA, Hofstra RM, Christiaans I, van Spaendonck-Zwarts KY, Lekanne dit Deprez RH, Judge DP, Calkins H, Suurmeijer AJ, Hauer RN, Saffitz JE, Wilde AA, van den Berg MP, van Tintelen JP, (2012) Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail 14(11):1199–1207. doi:10.1093/eurjhf/hfs119 CrossRefPubMedPubMedCentral

36.

Hirtle-Lewis M, Desbiens K, Ruel I, Rudzicz N, Genest J, Engert JC, Giannetti N (2013) The genetics of dilated cardiomyopathy: a prioritized candidate gene study of LMNA, TNNT2, TCAP, and PLN. Clin Cardiol 36(10):628–633. doi:10.1002/clc.22193 PubMed

37.

Truszkowska GT, Bilinska ZT, Kosinska J, Sleszycka J, Rydzanicz M, Sobieszczanska-Malek M, Franaszczyk M, Bilinska M, Stawinski P, Michalak E, Malek LA, Chmielewski P, Foss-Nieradko B, Machnicki MM, Stoklosa T, Poninska J, Szumowski L, Grzybowski J, Piwonski J, Drygas W, Zielinski T, Ploski R (2015) A study in Polish patients with cardiomyopathy emphasizes pathogenicity of phospholamban (PLN) mutations at amino acid position 9 and low penetrance of heterozygous null PLN mutations. BMC Med Genet 16:21. doi:10.1186/s12881-015-0167-0 CrossRefPubMedPubMedCentral

38.

Liu GS, Morales A, Vafiadaki E, Lam CK, Cai WF, Haghighi K, Adly G, Hershberger RE, Kranias EG (2015) A novel human R25C-phospholamban mutation is associated with super-inhibition of calcium cycling and ventricular arrhythmia. Cardiovasc Res 107(1):164–174. doi:10.1093/cvr/cvv127 CrossRefPubMedPubMedCentral

39.

Posch MG, Perrot A, Geier C, Boldt LH, Schmidt G, Lehmkuhl HB, Hetzer R, Dietz R, Gutberlet M, Haverkamp W, Ozcelik C (2009) Genetic deletion of arginine 14 in phospholamban causes dilated cardiomyopathy with attenuated electrocardiographic R amplitudes. Heart rhythm: the official journal of the Heart Rhythm Society 6(4):480–486. doi:10.1016/j.hrthm.2009.01.016 CrossRef

40.

Brauch KM, Karst ML, Herron KJ, de Andrade M, Pellikka PA, Rodeheffer RJ, Michels VV, Olson TM (2009) Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J Am Coll Cardiol 54(10):930–941. doi:10.1016/j.jacc.2009.05.038 CrossRefPubMedPubMedCentral

41.

Li D, Morales A, Gonzalez-Quintana J, Norton N, Siegfried JD, Hofmeyer M, Hershberger RE (2010) Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. Clin Trans Sci 3(3):90–97. doi:10.1111/j.1752-8062.2010.00198.x CrossRef

42.

Wells QS, Becker JR, Su YR, Mosley JD, Weeke P, D’Aoust L, Ausborn NL, Ramirez AH, Pfotenhauer JP, Naftilan AJ, Markham L, Exil V, Roden DM, Hong CC (2013) Whole exome sequencing identifies a causal RBM20 mutation in a large pedigree with familial dilated cardiomyopathy. Circulation Cardiovascular genetics 6(4):317–326. doi:10.1161/CIRCGENETICS.113.000011 CrossRefPubMedPubMedCentral

43.

Waldmuller S, Schroeder C, Sturm M, Scheffold T, Imbrich K, Junker S, Frische C, Hofbeck M, Bauer P, Bonin M, Gawaz M, Gramlich M (2015) Targeted 46-gene and clinical exome sequencing for mutations causing cardiomyopathies. Mol Cell Probes. doi:10.1016/j.mcp.2015.05.004 PubMed

44.

Ehlermann P, Weichenhan D, Zehelein J, Steen H, Pribe R, Zeller R, Lehrke S, Zugck C, Ivandic BT, Katus HA (2008) Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. BMC Med Genet 9:95. doi:10.1186/1471-2350-9-95 CrossRefPubMedPubMedCentral

45.

Daehmlow S, Erdmann J, Knueppel T, Gille C, Froemmel C, Hummel M, Hetzer R, Regitz-Zagrosek V (2002) Novel mutations in sarcomeric protein genes in dilated cardiomyopathy. Biochem Biophys Res Commun 298(1):116–120CrossRefPubMed

46.

Moller DV, Andersen PS, Hedley P, Ersboll MK, Bundgaard H, Moolman-Smook J, Christiansen M, Kober L (2009) The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy. Eur J Hum Genet 17(10):1241–1249. doi:10.1038/ejhg.2009.34 CrossRefPubMedPubMedCentral

47.

Hershberger RE, Norton N, Morales A, Li D, Siegfried JD, Gonzalez-Quintana J (2010) Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circulation Cardiovascular genetics 3(2):155–161. doi:10.1161/CIRCGENETICS.109.912345 CrossRefPubMedPubMedCentral

48.

Merlo M, Sinagra G, Carniel E, Slavov D, Zhu X, Barbati G, Spezzacatene A, Ramani F, Salcedo E, Di Lenarda A, Mestroni L, Taylor MR (2013) Poor prognosis of rare sarcomeric gene variants in patients with dilated cardiomyopathy. Clinical and translational science 6(6):424–428. doi:10.1111/cts.12116 CrossRefPubMed

49.

Waldmuller S, Erdmann J, Binner P, Gelbrich G, Pankuweit S, Geier C, Timmermann B, Haremza J, Perrot A, Scheer S, Wachter R, Schulze-Waltrup N, Dermintzoglou A, Schonberger J, Zeh W, Jurmann B, Brodherr T, Borgel J, Farr M, Milting H, Blankenfeldt W, Reinhardt R, Ozcelik C, Osterziel KJ, Loeffler M, Maisch B, Regitz-Zagrosek V, Schunkert H, Scheffold T (2011) Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure. Eur J Heart Fail 13(11):1185–1192. doi:10.1093/eurjhf/hfr074 CrossRefPubMed

50.

Hershberger RE, Parks SB, Kushner JD, Li D, Ludwigsen S, Jakobs P, Nauman D, Burgess D, Partain J, Litt M (2008) Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clinical and translational science 1(1):21–26. doi:10.1111/j.1752-8062.2008.00017.x CrossRefPubMedPubMedCentral

51.

Rai TS, Ahmad S, Bahl A, Ahuja M, Ahluwalia TS, Singh B, Talwar KK, Khullar M (2009) Genotype phenotype correlations of cardiac beta-myosin heavy chain mutations in Indian patients with hypertrophic and dilated cardiomyopathy. Mol Cell Biochem 321(1–2):189–196. doi:10.1007/s11010-008-9932-0 CrossRefPubMed

52.

Mogensen J, Murphy RT, Shaw T, Bahl A, Redwood C, Watkins H, Burke M, Elliott PM, McKenna WJ (2004) Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 44(10):2033–2040. doi:10.1016/j.jacc.2004.08.027 CrossRefPubMed

53.

Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62(10):1006–1012. doi:10.1016/j.jclinepi.2009.06.005 CrossRef

54.

Cassese S, Byrne RA, Ndrepepa G, Schunkert H, Fusaro M, Kastrati A (2015) Prolonged dual antiplatelet therapy after drug-eluting stenting: meta-analysis of randomized trials. Clin Res Cardiol 104(10):887–901. doi:10.1007/s00392-015-0860-1 CrossRefPubMed

55.

Xue YT, Tan QW, Li P, Mou SF, Liu SJ, Bao Y, Jiao HC, Su WG (2015) Investigating the role of acute mental stress on endothelial dysfunction: a systematic review and meta-analysis. Clin Res Cardiol 104(4):310–319. doi:10.1007/s00392-014-0782-3 CrossRefPubMed

56.

van Rijsingen IA, van der Zwaag PA, Groeneweg JA, Nannenberg EA, Jongbloed JD, Zwinderman AH, Pinto YM, Dit Deprez RH, Post JG, Tan HL, de Boer RA, Hauer RN, Christiaans I, van den Berg MP, van Tintelen JP, Wilde AA (2014) Outcome in phospholamban R14del carriers: results of a large multicentre cohort study. Circulation Cardiovascular genetics 7(4):455–465. doi:10.1161/CIRCGENETICS.113.000374 CrossRefPubMed

57.

van Berlo JH, de Voogt WG, van der Kooi AJ, van Tintelen JP, Bonne G, Yaou RB, Duboc D, Rossenbacker T, Heidbuchel H, de Visser M, Crijns HJ, Pinto YM (2005) Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med (Berl) 83(1):79–83. doi:10.1007/s00109-004-0589-1 CrossRef

58.

Luo YB, Mastaglia FL, Wilton SD (2014) Normal and aberrant splicing of LMNA. J Med Genet 51(4):215–223. doi:10.1136/jmedgenet-2013-102119 CrossRefPubMed

59.

Capell BC, Collins FS (2006) Human laminopathies: nuclei gone genetically awry. Nat Rev Genet 7(12):940–952. doi:10.1038/nrg1906 CrossRefPubMed

60.

Hegele R (2005) LMNA mutation position predicts organ system involvement in laminopathies. Clin Genet 68(1):31–34. doi:10.1111/j.1399-0004.2005.00447.x CrossRefPubMed

61.

Ceholski DK, Trieber CA, Young HS (2012) Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy. J Biol Chem 287(20):16521–16529. doi:10.1074/jbc.M112.360859 CrossRefPubMedPubMedCentral

62.

Young HS, Ceholski DK, Trieber CA (2015) Deception in simplicity: hereditary phospholamban mutations in dilated cardiomyopathy. Biochemistry and cell biology =. Biochimie et biologie cellulaire 93(1):1–7. doi:10.1139/bcb-2014-0080 CrossRefPubMed

63.

Guo W, Schafer S, Greaser ML, Radke MH, Liss M, Govindarajan T, Maatz H, Schulz H, Li S, Parrish AM, Dauksaite V, Vakeel P, Klaassen S, Gerull B, Thierfelder L, Regitz-Zagrosek V, Hacker TA, Saupe KW, Dec GW, Ellinor PT, MacRae CA, Spallek B, Fischer R, Perrot A, Ozcelik C, Saar K, Hubner N, Gotthardt M (2012) RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat Med 18(5):766–773. doi:10.1038/nm.2693 CrossRefPubMedPubMedCentral

64.

Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, Sasse-Klaassen S, Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux M, Thierfelder L (2002) Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 30(2):201–204CrossRefPubMed

65.

Gramlich M, Pane LS, Zhou Q, Chen Z, Murgia M, Schotterl S, Goedel A, Metzger K, Brade T, Parrotta E, Schaller M, Gerull B, Thierfelder L, Aartsma-Rus A, Labeit S, Atherton JJ, McGaughran J, Harvey RP, Sinnecker D, Mann M, Laugwitz KL, Gawaz MP, Moretti A (2015) Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy. EMBO molecular medicine 7(5):562–576. doi:10.15252/emmm.201505047 CrossRefPubMedPubMedCentral

66.

Kamisago M, Sharma SD, DePalma SR, Solomon S, Sharma P, McDonough B, Smoot L, Mullen MP, Woolf PK, Wigle ED, Seidman JG, Seidman CE (2000) Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 343(23):1688–1696. doi:10.1056/NEJM200012073432304 CrossRefPubMed

67.

Houston BA, Stevens GR (2014) Hypertrophic cardiomyopathy: a review. Clinical Medicine Insights Cardiology 8(Suppl 1):53–65. doi:10.4137/CMC.S15717 PubMed

68.

Ho CY, Charron P, Richard P, Girolami F, Van Spaendonck-Zwarts KY, Pinto Y (2015) Genetic advances in sarcomeric cardiomyopathies: state of the art. Cardiovasc Res 105(4):397–408. doi:10.1093/cvr/cvv025 CrossRefPubMedPubMedCentral

69.

Lakdawala NK, Thune JJ, Colan SD, Cirino AL, Farrohi F, Rivero J, McDonough B, Sparks E, Orav EJ, Seidman JG, Seidman CE, Ho CY (2012) Subtle abnormalities in contractile function are an early manifestation of sarcomere mutations in dilated cardiomyopathy. Circul Cardiovas Genet 5(5):503–510. doi:10.1161/CIRCGENETICS.112.962761 CrossRef

70.

McNally EM, Golbus JR, Puckelwartz MJ (2013) Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Investig 123(1):19–26. doi:10.1172/JCI62862 CrossRefPubMedPubMedCentral

71.

Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE (2012) Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366(7):619–628. doi:10.1056/NEJMoa1110186 CrossRefPubMedPubMedCentral

72.

Page SP, Kounas S, Syrris P, Christiansen M, Frank-Hansen R, Andersen PS, Elliott PM, McKenna WJ (2012) Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circul Cardiovas Genet 5(2):156–166. doi:10.1161/CIRCGENETICS.111.960831 CrossRef

73.

Haas J, Frese KS, Park YJ, Keller A, Vogel B, Lindroth AM, Weichenhan D, Franke J, Fischer S, Bauer A, Marquart S, Sedaghat-Hamedani F, Kayvanpour E, Kohler D, Wolf NM, Hassel S, Nietsch R, Wieland T, Ehlermann P, Schultz JH, Dosch A, Mereles D, Hardt S, Backs J, Hoheisel JD, Plass C, Katus HA, Meder B (2013) Alterations in cardiac DNA methylation in human dilated cardiomyopathy. EMBO Mole Med 5(3):413–429. doi:10.1002/emmm.201201553 CrossRef

74.

Becane HM, Bonne G, Varnous S, Muchir A, Ortega V, Hammouda EH, Urtizberea JA, Lavergne T, Fardeau M, Eymard B, Weber S, Schwartz K, Duboc D (2000) High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing and clinical electrophysiology: PACE 23(11 Pt 1):1661–1666CrossRefPubMed

75.

Pethig K, Genschel J, Peters T, Wilhelmi M, Flemming P, Lochs H, Haverich A, Schmidt HH (2005) LMNA mutations in cardiac transplant recipients. Cardiology 103(2):57–62. doi:10.1159/000082048 CrossRefPubMed

76.

Pasotti M, Klersy C, Pilotto A, Marziliano N, Rapezzi C, Serio A, Mannarino S, Gambarin F, Favalli V, Grasso M, Agozzino M, Campana C, Gavazzi A, Febo O, Marini M, Landolina M, Mortara A, Piccolo G, Vigano M, Tavazzi L, Arbustini E (2008) Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 52(15):1250–1260. doi:10.1016/j.jacc.2008.06.044 CrossRefPubMed

77.

Anselme F, Moubarak G, Savoure A, Godin B, Borz B, Drouin-Garraud V, Gay A (2013) Implantable cardioverter-defibrillators in lamin A/C mutation carriers with cardiac conduction disorders. Heart Rhyth Off J Heart Rhyth Soc 10(10):1492–1498. doi:10.1016/j.hrthm.2013.06.020 CrossRef

78.

van der Zwaag PA, van Rijsingen IA, de Ruiter R, Nannenberg EA, Groeneweg JA, Post JG, Hauer RN, van Gelder IC, van den Berg MP, van der Harst P, Wilde AA, van Tintelen JP (2013) Recurrent and founder mutations in the Netherlands-Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy. Netherlands Heart J Month J Netherlands Soc Cardiol Netherlands Heart Foundat 21(6):286–293. doi:10.1007/s12471-013-0401-3

79.

Meder B, Haas J, Keller A, Heid C, Just S, Borries A, Boisguerin V, Scharfenberger-Schmeer M, Stahler P, Beier M, Weichenhan D, Strom TM, Pfeufer A, Korn B, Katus HA, Rottbauer W (2011) Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circul Cardiovas Genet 4(2):110–122. doi:10.1161/CIRCGENETICS.110.958322 CrossRef

80.

Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O’Regan DP, San TR, de Marvao A, Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O’Donnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SA (2015) Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 7(270):270ra276. doi:10.1126/scitranslmed.3010134

81.

Akinrinade O, Ollila L, Vattulainen S, Tallila J, Gentile M, Salmenpera P, Koillinen H, Kaartinen M, Nieminen MS, Myllykangas S, Alastalo TP, Koskenvuo JW, Helio T (2015) Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. Eur Heart J 36(34):2327–2337. doi:10.1093/eurheartj/ehv253 CrossRefPubMedPubMedCentral

82.

Akinrinade O, Alastalo TP, Koskenvuo JW (2016) Relevance of truncating titin mutations in dilated cardiomyopathy. Clin Genet 90(1):49–54. doi:10.1111/cge.12741 CrossRefPubMed

Title: Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals
Authors: Elham Kayvanpour
Farbod Sedaghat-Hamedani
Ali Amr
Alan Lai
Jan Haas
Daniel B. Holzer
Karen S. Frese
Andreas Keller
Katrin Jensen
Hugo A. Katus
Benjamin Meder
Publication date: 01-02-2017
Publisher: Springer Berlin Heidelberg
Published in: Clinical Research in Cardiology / Issue 2/2017
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI: https://doi.org/10.1007/s00392-016-1033-6

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Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals

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