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ISL1 loss-of-function mutation contributes to congenital heart defects

Heart and Vessels volume 34, pages 658–668 (2019)Cite this article

Abstract

Congenital heart defect (CHD) is the most common form of birth deformity and is responsible for substantial morbidity and mortality in humans. Increasing evidence has convincingly demonstrated that genetic defects play a pivotal role in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disorder and the genetic basis underpinning CHD in the vast majority of cases remains elusive. This study was sought to identify the pathogenic mutation in the ISL1 gene contributing to CHD. A cohort of 210 unrelated patients with CHD and a total of 256 unrelated healthy individuals used as controls were registered. The coding exons and splicing boundaries of ISL1 were sequenced in all study subjects. The functional effect of an identified ISL1 mutation was evaluated using a dual-luciferase reporter assay system. A novel heterozygous ISL1 mutation, c.409G > T or p.E137X, was identified in an index patient with congenital patent ductus arteriosus and ventricular septal defect. Analysis of the proband’s pedigree revealed that the mutation co-segregated with CHD, which was transmitted in the family in an autosomal dominant pattern with complete penetrance. The nonsense mutation was absent in 512 control chromosomes. Functional analysis unveiled that the mutant ISL1 protein failed to transactivate the promoter of MEF2C, alone or in synergy with TBX20. This study firstly implicates ISL1 loss-of-function mutation with CHD in humans, which provides novel insight into the molecular mechanism of CHD, implying potential implications for genetic counseling and individually tailored treatment of CHD patients.

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References

  1. Zaidi S, Brueckner M (2017) Genetics and genomics of congenital heart disease. Circ Res 120:923–940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O’Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee (2018) Heart disease and stroke statistics—2018 update: a report from the American Heart Association. Circulation 137:e67–e492

    Article  Google Scholar 

  3. Ernst MM, Marino BS, Cassedy A, Piazza-Waggoner C, Franklin RC, Brown K, Wray J (2018) Biopsychosocial predictors of quality of life outcomes in pediatric congenital heart disease. Pediatr Cardiol 39:79–88

    Article  PubMed  Google Scholar 

  4. Banks L, Rosenthal S, Manlhiot C, Fan CS, McKillop A, Longmuir PE, McCrindle BW (2017) Exercise capacity and self-efficacy are associated with moderate-to-vigorous intensity physical activity in children with congenital heart disease. Pediatr Cardiol 38:1206–1214

    Article  PubMed  Google Scholar 

  5. Morton PD, Ishibashi N, Jonas RA (2017) Neurodevelopmental abnormalities and congenital heart disease: insights into altered brain maturation. Circ Res 120:960–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Peyvandi S, Chau V, Guo T, Xu D, Glass HC, Synnes A, Poskitt K, Barkovich AJ, Miller SP, McQuillen PS (2018) Neonatal brain injury and timing of neurodevelopmental assessment in patients with congenital heart disease. J Am Coll Cardiol 71:1986–1996

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zorzanelli L, Maeda N, Clavé M, Thomaz A, Galas F, Rabinovitch M, Lopes A (2017) Relation of cytokine profile to clinical and hemodynamic features in young patients with congenital heart disease and pulmonary hypertension. Am J Cardiol 119:119–125

    Article  CAS  PubMed  Google Scholar 

  8. van der Feen DE, Bartelds B, de Boer RA, Berger RM (2017) Pulmonary arterial hypertension in congenital heart disease: translational opportunities to study the reversibility of pulmonary vascular disease. Eur Heart J 38:2034–2041

    Article  CAS  PubMed  Google Scholar 

  9. Schwartz SS, Madsen N, Laursen HB, Hirsch R, Olsen MS (2018) Incidence and mortality of adults with pulmonary hypertension and congenital heart disease. Am J Cardiol 121:1610–1616

    Article  PubMed  Google Scholar 

  10. Muneuchi J, Ochiai Y, Masaki N, Okada S, Iida C, Sugitani Y, Ando Y, Watanabe M (2018) Pulmonary arterial compliance is a useful predictor of pulmonary vascular disease in congenital heart disease. Heart Vessels. https://doi.org/10.1007/s00380-018-1263-9

    Article  PubMed  Google Scholar 

  11. Lanz J, Brophy JM, Therrien J, Kaouache M, Guo L, Marelli AJ (2015) Stroke in adults with congenital heart disease: incidence, cumulative risk, and predictors. Circulation 132:2385–2394

    Article  PubMed  Google Scholar 

  12. Masuda K, Ishizu T, Niwa K, Takechi F, Tateno S, Horigome H, Aonuma K (2017) Increased risk of thromboembolic events in adult congenital heart disease patients with atrial tachyarrhythmias. Int J Cardiol 234:69–75

    Article  PubMed  Google Scholar 

  13. Giang KW, Mandalenakis Z, Dellborg M, Lappas G, Eriksson P, Hansson PO, Rosengren A (2018) Long-term risk of hemorrhagic stroke in young patients with congenital heart disease. Stroke 49:1155–1162

    Article  PubMed  PubMed Central  Google Scholar 

  14. Forte A, Grossi M, Bancone C, Cipollaro M, De Feo M, Hellstrand P, Persson L, Nilsson BO, Della Corte A (2018) Polyamine concentration is increased in thoracic ascending aorta of patients with bicuspid aortic valve. Heart Vessels 33:327–339

    Article  PubMed  Google Scholar 

  15. Diller GP, Baumgartner H (2017) Endocarditis in adults with congenital heart disease: new answers-new questions. Eur Heart J 38:2057–2059

    Article  PubMed  Google Scholar 

  16. Mylotte D, Rushani D, Therrien J, Guo L, Liu A, Guo K, Martucci G, Mackie AS, Kaufman JS, Marelli A (2017) Incidence, predictors, and mortality of infective endocarditis in adults with congenital heart disease without prosthetic valves. Am J Cardiol 120:2278–2283

    Article  PubMed  Google Scholar 

  17. Kuijpers JM, Koolbergen DR, Groenink M, Peels KC, Reichert CL, Post MC, Bosker HA, Wajon EM, Zwinderman AH, Mulder BJ, Bouma BJ (2017) Incidence, risk factors, and predictors of infective endocarditis in adult congenital heart disease: focus on the use of prosthetic material. Eur Heart J 38:2048–2056

    Article  PubMed  Google Scholar 

  18. Tutarel O, Alonso-Gonzalez R, Montanaro C, Schiff R, Uribarri A, Kempny A, Grübler MR, Uebing A, Swan L, Diller GP, Dimopoulos K, Gatzoulis MA (2018) Infective endocarditis in adults with congenital heart disease remains a lethal disease. Heart 104:161–165

    Article  PubMed  Google Scholar 

  19. Ciepłucha A, Trojnarska O, Kociemba A, Łanocha M, Barczynski M, Rozmiarek S, Kramer L, Pyda M (2018) Clinical aspects of myocardial fibrosis in adults with Ebstein’s anomaly. Heart Vessels 33:1076–1085

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lluri G, Renella P, Finn JP, Vorobiof G, Aboulhosn J, Deb A (2017) Prognostic significance of left ventricular fibrosis in patients with congenital bicuspid aortic valve. Am J Cardiol 120:1176–1179

    Article  PubMed  PubMed Central  Google Scholar 

  21. Miyazaki A, Sakaguchi H, Noritake K, Hayama Y, Negishi J, Kagisaki K, Yasuda K, Ichikawa H, Ohuchi H (2017) Interventricular dyssynchrony in a patient with a biventricular physiology and a systemic right ventricle. Heart Vessels 32:234–239

    Article  PubMed  Google Scholar 

  22. Shiina Y, Inai K, Takahashi T, Taniguchi K, Watanabe E, Fukushima K, Niwa K, Nagao M (2018) Inter- and intra-ventricular dyssynchrony in the systemic right ventricle is a surrogate marker of major cardiac events in mildly symptomatic patients. Heart Vessels 33:1086–1093

    Article  PubMed  Google Scholar 

  23. Hinton RB, Ware SM (2017) Heart failure in pediatric patients with congenital heart disease. Circ Res 120:978–994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Isogai T, Matsui H, Tanaka H, Kohyama A, Fushimi K, Yasunaga H (2018) Clinical features and peripartum outcomes in pregnant women with cardiac disease: a nationwide retrospective cohort study in Japan. Heart Vessels 33:918–930

    Article  PubMed  Google Scholar 

  25. Shaddy RE, George AT, Jaecklin T, Lochlainn EN, Thakur L, Agrawal R, Solar-Yohay S, Chen F, Rossano JW, Severin T, Burch M (2018) Systematic literature review on the incidence and prevalence of heart failure in children and adolescents. Pediatr Cardiol 39:415–436

    Article  Google Scholar 

  26. Labombarda F, Hamilton R, Shohoudi A, Aboulhosn J, Broberg CS, Chaix MA, Cohen S, Cook S, Dore A, Fernandes SM, Fournier A, Kay J, Macle L, Mondésert B, Mongeon FP, Opotowsky AR, Proietti A, Rivard L, Ting J, Thibault B, Zaidi A, Khairy P, AARCC (2017) Increasing prevalence of atrial fibrillation and permanent atrial arrhythmias in congenital heart disease. J Am Coll Cardiol 70:857–865

    Article  PubMed  Google Scholar 

  27. McLeod CJ (2017) Acute arrhythmias in adults with congenital heart disease. Heart 103:1380–1388

    Article  PubMed  Google Scholar 

  28. Holst KA, Said SM, Nelson TJ, Cannon BC, Dearani JA (2017) Current interventional and surgical management of congenital heart disease: specific focus on valvular disease and cardiac arrhythmias. Circ Res 120:1027–1044

    Article  CAS  PubMed  Google Scholar 

  29. Hernández-Madrid A, Paul T, Abrams D, Aziz PF, Blom NA, Chen J, Chessa M, Combes N, Dagres N, Diller G, Ernst S, Giamberti A, Hebe J, Janousek J, Kriebel T, Moltedo J, Moreno J, Peinado R, Pison L, Rosenthal E, Skinner JR, Zeppenfeld K; ESC Scientific Document Group (2018) Arrhythmias in congenital heart disease: a position paper of the European Heart Rhythm Association (EHRA), Association for European Paediatric and Congenital Cardiology (AEPC), and the European Society of Cardiology (ESC) Working Group on Grown-up Congenital heart disease, endorsed by HRS, PACES, APHRS, and SOLAECE. Europace https://doi.org/10.1093/europace/eux380

  30. Koyak Z, de Groot JR, Bouma BJ, Zwinderman AH, Silversides CK, Oechslin EN, Budts W, Van Gelder IC, Mulder BJ, Harris L (2017) Sudden cardiac death in adult congenital heart disease: can the unpredictable be foreseen? Europace 19:401–406

    PubMed  Google Scholar 

  31. Moore B, Yu C, Kotchetkova I, Cordina R, Celermajer DS (2018) Incidence and clinical characteristics of sudden cardiac death in adult congenital heart disease. Int J Cardiol 254:101–106

    Article  Google Scholar 

  32. Lynge TH, Jeppesen AG, Winkel BG, Glinge C, Schmidt MR, Søndergaard L, Risgaard B, Tfelt-Hansen J (2018) Nationwide study of sudden cardiac death in people with congenital heart defects aged 0 to 35 years. Circ Arrhythm Electrophysiol 11:e005757

    Article  PubMed  Google Scholar 

  33. Izumi G, Senzaki H, Takeda A, Yamazawa H, Takei K, Furukawa T, Inai K, Shinohara T, Nakanishi T (2017) Significance of right atrial tension for the development of complications in patients after atriopulmonary connection Fontan procedure: potential indicator for Fontan conversion. Heart Vessels 32:850–855

    Article  PubMed  Google Scholar 

  34. Saito C, Fukushima N, Fukushima K, Matsumura G, Ashihara K, Hagiwara N (2017) Factors associated with aortic root dilatation after surgically repaired ventricular septal defect. Echocardiography 34:1203–1209

    Article  PubMed  Google Scholar 

  35. Shinkawa T, Chipman C, Holloway J, Tang X, Gossett JM, Imamura M (2017) Single center experience of aortic bypass graft for aortic arch obstruction in children. Heart Vessels 32:76–82

    Article  PubMed  Google Scholar 

  36. Henmi R, Ejima K, Yagishita D, Iwanami Y, Nishimura T, Takeuchi D, Toyohara K, Shoda M, Hagiwara N (2017) Long-term efficacy of implantable cardioverter defibrillator in repaired tetralogy of Fallot—role of anti-tachycardia pacing. Circ J 81:165–171

    Article  CAS  PubMed  Google Scholar 

  37. Kim J, Kuwata S, Kurishima C, Iwamoto Y, Ishido H, Masutani S, Senzaki H (2018) Importance of dynamic central venous pressure in Fontan circulation. Heart Vessels 33:664–670

    Article  PubMed  Google Scholar 

  38. Takahashi T, Shiina Y, Nagao M, Inai K (2018) Stroke volume ratio derived from magnetic resonance imaging as an indicator of interventricular dyssynchrony predicts future cardiac event in patients with biventricular Fontan circulation. Heart Vessels. https://doi.org/10.1007/s00380-018-1217-2

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hasegawa T, Masuda M, Okumura M, Arai H, Kobayashi J, Saiki Y, Tanemoto K, Nishida H, Motomura N (2017) Trends and outcomes in neonatal cardiac surgery for congenital heart disease in Japan from 1996 to 2010. Eur J Cardiothorac Surg 51:301–307

    PubMed  Google Scholar 

  40. Bouma BJ, Mulder BJ (2017) Changing landscape of congenital heart disease. Circ Res 120:908–922

    Article  CAS  PubMed  Google Scholar 

  41. Mandalenakis Z, Rosengren A, Skoglund K, Lappas G, Eriksson P, Dellborg M (2017) Survivorship in children and young adults with congenital heart disease in Sweden. JAMA Intern Med 177:224–230

    Article  PubMed  Google Scholar 

  42. Hayabuchi Y, Ono A, Homma Y, Kagami S (2018) Pulmonary annular motion velocity reflects right ventricular outflow tract function in children with surgically repaired congenital heart disease. Heart Vessels 33:316–326

    Article  PubMed  Google Scholar 

  43. Blue GM, Kirk EP, Giannoulatou E, Sholler GF, Dunwoodie SL, Harvey RP, Winlaw DS (2017) Advances in the genetics of congenital heart disease: a clinician’s guide. J Am Coll Cardiol 69:859–870

    Article  CAS  PubMed  Google Scholar 

  44. Akhirome E, Walton NA, Nogee JM, Jay PY (2017) The complex genetic basis of congenital heart defects. Circ J 81:629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li YJ, Yang YQ (2017) An update on the molecular diagnosis of congenital heart disease: focus on loss-of-function mutations. Expert Rev Mol Diagn 17:393–401

    Article  CAS  PubMed  Google Scholar 

  46. Fahed AC, Gelb BD, Seidman JG, Seidman CE (2013) Genetics of congenital heart disease: the glass half empty. Circ Res 112:707–720

    Article  CAS  Google Scholar 

  47. Wang X, Chang WL, Chen CA, Rosenfeld JA, Al Shamsi A, Al-Gazali L, McGuire M, Mew NA, Arnold GL, Qu C, Ding Y, Muzny DM, Gibbs RA, Eng CM, Walkiewicz M, Xia F, Plon SE, Lupski JR, Schaaf CP, Yang Y (2017) Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations. Nat Genet 49:613–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jin SC, Homsy J, Zaidi S, Lu Q, Morton S, DePalma SR, Zeng X, Qi H, Chang W, Sierant MC, Hung WC, Haider S, Zhang J, Knight J, Bjornson RD, Castaldi C, Tikhonoa IR, Bilguvar K, Mane SM, Sanders SJ, Mital S, Russell MW, Gaynor JW, Deanfield J, Giardini A, Porter GA Jr, Srivastava D, Lo CW, Shen Y, Watkins WS, Yandell M, Yost HJ, Tristani-Firouzi M, Newburger JW, Roberts AE, Kim R, Zhao H, Kaltman JR, Goldmuntz E, Chung WK, Seidman JG, Gelb BD, Seidman CE, Lifton RP, Brueckner M (2017) Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet 49:1593–1601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu X, Yagi H, Saeed S, Bais AS, Gabriel GC, Chen Z, Peterson KA, Li Y, Schwartz MC, Reynolds WT, Saydmohammed M, Gibbs B, Wu Y, Devine W, Chatterjee B, Klena NT, Kostka D, de Mesy Bentley KL, Ganapathiraju MK, Dexheimer P, Leatherbury L, Khalifa O, Bhagat A, Zahid M, Pu W, Watkins S, Grossfeld P, Murray SA, Porter GA Jr, Tsang M, Martin LJ, Benson DW, Aronow BJ, Lo CW (2017) The complex genetics of hypoplastic left heart syndrome. Nat Genet 49:1152–1159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tan TY, Gonzaga-Jauregui C, Bhoj EJ, Strauss KA, Brigatti K, Puffenberger E, Li D, Xie L, Das N, Skubas I, Deckelbaum RA, Hughes V, Brydges S, Hatsell S, Siao CJ, Dominguez MG, Economides A, Overton JD, Mayne V, Simm PJ, Jones BO, Eggers S, Le Guyader G, Pelluard F, Haack TB, Sturm M, Riess A, Waldmueller S, Hofbeck M, Steindl K, Joset P, Rauch A, Hakonarson H, Baker NL, Farlie PG (2017) Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions. Am J Hum Genet 101:985–994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hempel M, Casar Tena T, Diehl T, Burczyk MS, Strom TM, Kubisch C, Philipp M, Lessel D (2017) Compound heterozygous GATA5 mutations in a girl with hydrops fetalis, congenital heart defects and genital anomalies. Hum Genet 136:339–346

    Article  CAS  PubMed  Google Scholar 

  52. Wang J, Hu XQ, Guo YH, Gu JY, Xu JH, Li YJ, Li N, Yang XX, Yang YQ (2017) HAND1 loss-of-function mutation causes tetralogy of Fallot. Pediatr Cardiol 38:547–557

    Article  CAS  PubMed  Google Scholar 

  53. Li L, Wang J, Liu XY, Liu H, Shi HY, Yang XX, Li N, Li YJ, Huang RT, Xue S, Qiu XB, Yang YQ (2017) HAND1 loss-of-function mutation contributes to congenital double outlet right ventricle. Int J Mol Med 39:711–718

    Article  CAS  PubMed  Google Scholar 

  54. Xu YJ, Qiu XB, Yuan F, Shi HY, Xu L, Hou XM, Qu XK, Liu X, Huang RT, Xue S, Yang YQ, Li RG (2017) Prevalence and spectrum of NKX2.5 mutations in patients with congenital atrial septal defect and atrioventricular block. Mol Med Rep 15:2247–2254

    Article  CAS  PubMed  Google Scholar 

  55. Chen HX, Zhang X, Hou HT, Wang J, Yang Q, Wang XL, He GW (2017) Identification of a novel and functional mutation in the TBX5 gene in a patient by screening from 354 patients with isolated ventricular septal defect. Eur J Med Gene 60:385–390

    Article  CAS  Google Scholar 

  56. Ramond F, Duband S, Croisille P, Cavé H, Teyssier G, Adouard V, Touraine R (2017) Expanding the cardiac spectrum of Noonan syndrome with RIT1 variant: left main coronary artery atresia causing sudden death. Eur J Med Genet 60:299–302

    Article  PubMed  Google Scholar 

  57. Guo C, Wang Q, Wang Y, Yang L, Luo H, Cao XF, An L, Qiu Y, Du M, Ma X, Li H, Lu C (2017) Exome sequencing reveals novel IRXI mutation in congenital heart disease. Mol Med Rep 15:3193–3197

    Article  CAS  PubMed  Google Scholar 

  58. Huang RT, Wang J, Xue S, Qiu XB, Shi HY, Li RG, Qu XK, Yang XX, Liu H, Li N, Li YJ, Xu YJ, Yang YQ (2017) TBX20 loss-of-function mutation responsible for familial tetralogy of Fallot or sporadic persistent truncus arteriosus. Int J Med Sci 14:323–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Qiao XH, Wang F, Zhang XL, Huang RT, Xue S, Wang J, Qiu XB, Liu XY, Yang YQ (2017) MEF2C loss-of-function mutation contributes to congenital heart defects. Int J Med Sci 14:1143–1153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang M, Li FX, Liu XY, Huang RT, Xue S, Yang XX, Li YJ, Liu H, Shi HY, Pan X, Qiu XB, Yang YQ (2017) MESP1 loss–of–function mutation contributes to double outlet right ventricle. Mol Med Rep 16:2747–2754

    Article  CAS  PubMed  Google Scholar 

  61. Vaidya A, Flores SK, Cheng ZM, Nicolas M, Deng Y, Opotowsky AR, Lourenço DM Jr, Barletta JA, Rana HQ, Pereira MA, Toledo RA, Dahia PLM (2018) EPAS1 Mutations and Paragangliomas in Cyanotic Congenital Heart Disease. N Engl J Med 378:1259–1261

    Article  PubMed  PubMed Central  Google Scholar 

  62. Bashamboo A, Eozenou C, Jorgensen A, Bignon-Topalovic J, Siffroi JP, Hyon C, Tar A, Nagy P, Sólyom J, Halász Z, Paye-Jaouen A, Lambert S, Rodriguez-Buritica D, Bertalan R, Martinerie L, Rajpert-De Meyts E, Achermann JC, McElreavey K (2018) Loss of function of the nuclear receptor NR2F2, encoding COUP-TF2, causes testis development and cardiac defects in 46, XX children. Am J Hum Genet 102:487–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Qiao XH, Wang Q, Wang J, Liu XY, Xu YJ, Huang RT, Xue S, Li YJ, Zhang M, Qu XK, Li RG, Qiu XB, Yang YQ (2018) A novel NR2F2 loss-of-function mutation predisposes to congenital heart defect. Eur J Med Genet 61:197–203

    Article  PubMed  Google Scholar 

  64. Li RG, Xu YJ, Wang J, Liu XY, Yuan F, Huang RT, Xue S, Li L, Liu H, Li YJ, Qu XK, Shi HY, Zhang M, Qiu XB, Yang YQ (2018) GATA4 loss-of-function mutation and the congenitally bicuspid aortic valve. Am J Cardiol 121:469–474

    Article  CAS  PubMed  Google Scholar 

  65. Lu CX, Wang W, Wang Q, Liu XY, Yang YQ (2018) A novel MEF2C loss-of-function mutation associated with congenital double outlet right ventricle. Pediatr Cardiol 39:794–804

    Article  PubMed  Google Scholar 

  66. Yokoyama R, Kinoshita K, Hata Y, Abe M, Matsuoka K, Hirono K, Kano M, Nakazawa M, Ichida F, Nishida N, Tabata T (2018) A mutant HCN4 channel in a family with bradycardia, left bundle branch block, and left ventricular noncompaction. Heart Vessels 33:802–819

    Article  PubMed  Google Scholar 

  67. Li X, Shi L, Xu M, Zheng X, Yu Y, Jin J (2018) RCAN1 mutation and functional characterization in children with sporadic congenital heart disease. Pediatr Cardiol 39:226–235

    Article  PubMed  Google Scholar 

  68. Nijak A, Alaerts M, Kuiperi C, Corveleyn A, Suys B, Paelinck B, Saenen J, Van Craenenbroeck E, Van Laer L, Loeys B, Verstraeten A (2018) Left ventricular non-compaction with Ebstein anomaly attributed to a TPM1 mutation. Eur J Med Genet 61:8–10

    Article  PubMed  Google Scholar 

  69. Zhang M, Li FX, Liu XY, Hou JY, Ni SH, Wang J, Zhao CM, Zhang W, Kong Y, Huang RT, Xue S, Yang YQ (2018) TBX1 loss-of-function mutation contributes to congenital conotruncal defects. Exp Ther Med 15:447–453

    CAS  PubMed  Google Scholar 

  70. Jaouadi A, Tabebi M, Abdelhedi F, Abid D, Kamoun F, Chabchoub I, Maatoug S, Doukali H, Belghuith N, Ksentini MA, Keskes LA, Triki C, Hachicha M, Kamoun S, Kamoun H (2018) A novel TBX1 missense mutation in patients with syndromic congenital heart defects. Biochem Biophys Res Commun 499:563–569

    Article  CAS  PubMed  Google Scholar 

  71. Pu T, Liu Y, Xu R, Li F, Chen S, Sun K (2018) Identification of ZFPM2 mutations in sporadic conotruncal heart defect patients. Mol Genet Genomics 293:217–223

    Article  CAS  PubMed  Google Scholar 

  72. Xu YJ, Di RM, Qiao Q, Li XM, Huang RT, Xue S, Liu XY, Wang J, Yang YQ (2018) GATA6 loss-of-function mutation contributes to congenital bicuspid aortic valve. Gene 663:115–120

    Article  CAS  PubMed  Google Scholar 

  73. Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JX, Evans S, Chien KR (2005) Postnatal isl1 + cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:647–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Moretti A, Caron L, Nakano A, Lam JT, Bernshausen A, Chen Y, Qyang Y, Bu L, Sasaki M, Martin-Puig S, Sun Y, Evans SM, Laugwitz KL, Chien KR (2006) Multipotent embryonic isl1 + progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 127:1151–1165

    Article  CAS  PubMed  Google Scholar 

  75. Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, Chien KR (2009) Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 460:113–117

    Article  CAS  PubMed  Google Scholar 

  76. Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5:877–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Stevens KN, Hakonarson H, Kim CE, Doevendans PA, Koeleman BP, Mital S, Raue J, Glessner JT, Coles JG, Moreno V, Granger A, Gruber SB, Gruber PJ (2010) Common variation in ISL1 confers genetic susceptibility for human congenital heart disease. PLoS ONE 5:e10855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Luo ZL, Sun H, Yang ZQ, Ma YH, Gu Y, He YQ, Wei D, Xia LB, Yang BH, Guo T (2014) Genetic variations of ISL1 associated with human congenital heart disease in Chinese Han people. Genet Mol Res 13:1329–1338

    Article  CAS  PubMed  Google Scholar 

  79. Sun YM, Wang J, Xu YJ, Wang XH, Yuan F, Liu H, Li RG, Zhang M, Li YJ, Shi HY, Zhao L, Qiu XB, Qu XK, Yang YQ (2018) ZBTB17 loss-of-function mutation contributes to familial dilated cardiomyopathy. Heart Vessels 33:722–732

    Article  PubMed  Google Scholar 

  80. Dodou E, Verzi MP, Anderson JP, Xu SM, Black BL (2004) Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development 131:3931–3942

    Article  CAS  PubMed  Google Scholar 

  81. Takeuchi JK, Mileikovskaia M, Koshiba-Takeuchi K, Heidt AB, Mori AD, Arruda EP, Gertsenstein M, Georges R, Davidson L, Mo R, Hui CC, Henkelman RM, Nemer M, Black BL, Nagy A, Bruneau BG (2005) Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development. Development 132:2463–2474

    Article  CAS  PubMed  Google Scholar 

  82. Friedrich FW, Dilanian G, Khattar P, Juhr D, Gueneau L, Charron P, Fressart V, Vilquin JT, Isnard R, Gouya L, Richard P, Hammoudi N, Komajda M, Bonne G, Eschenhagen T, Dubourg O, Villard E, Carrier L (2013) A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity. Eur J Heart Fail 15:267–276

    Article  CAS  PubMed  Google Scholar 

  83. Zhang H, Wang WP, Guo T, Yang JC, Chen P, Ma KT, Guan YF, Zhou CY (2009) The LIM-homeodomain protein ISL1 activates insulin gene promoter directly through synergy with BETA2. J Mol Biol 392:566–577

    Article  CAS  PubMed  Google Scholar 

  84. Yuan F, Qiu ZH, Wang XH, Sun YM, Wang J, Li RG, Liu H, Zhang M, Shi HY, Zhao L, Jiang WF, Liu X, Qiu XB, Qu XK, Yang YQ (2018) MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy. Clin Chem Lab Med 56:502–511

    Article  CAS  PubMed  Google Scholar 

  85. Gong Q, Zhou Z (2018) Nonsense-mediated mRNA decay of hERG mutations in long QT syndrome. Methods Mol Biol 1684:37–49

    Article  CAS  PubMed  Google Scholar 

  86. Inácio A, Silva AL, Pinto J, Ji X, Morgado A, Almeida F, Faustino P, Lavinha J, Liebhaber SA, Romão L (2004) Nonsense mutations in close proximity to the initiation codon fail to trigger full nonsense-mediated mRNA decay. J Biol Chem 279:32170–32180

    Article  CAS  PubMed  Google Scholar 

  87. Huang RT, Xue S, Xu YJ, Zhou M, Yang YQ (2014) Somatic GATA5 mutations in sporadic tetralogy of Fallot. Int J Mol Med 33:1227–1235

    Article  CAS  PubMed  Google Scholar 

  88. Guo DF, Li RG, Yuan F, Shi HY, Hou XM, Qu XK, Xu YJ, Zhang M, Liu X, Jiang JQ, Yang YQ, Qiu XB (2016) TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome. Mol Med Rep 13:4349–4356

    Article  CAS  PubMed  Google Scholar 

  89. Lu CX, Gong HR, Liu XY, Wang J, Zhao CM, Huang RT, Xue S, Yang YQ (2016) A novel HAND2 loss-of-function mutation responsible for tetralogy of Fallot. Int J Mol Med 37:445–451

    Article  CAS  PubMed  Google Scholar 

  90. Sun YM, Wang J, Qiu XB, Yuan F, Xu YJ, Li RG, Qu XK, Huang RT, Xue S, Yang YQ (2016) PITX2 loss-of-function mutation contributes to tetralogy of Fallot. Gene 577:258–264

    Article  CAS  PubMed  Google Scholar 

  91. Qiu XB, Qu XK, Li RG, Liu H, Xu YJ, Zhang M, Shi HY, Hou XM, Liu X, Yuan F, Sun YM, Wang J, Huang RT, Xue S, Yang YQ (2017) CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy. Clin Chem Lab Med 55:1417–1425

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We are sincerely thankful to the study participants for their dedication to the investigation.

Funding

This study was funded by the grants from the National Natural Science Foundation of China (81470372, 81400244, and 81370400), the Medicine Guided Program of Shanghai, China (17411971000), the Experimental Animal Program of Shanghai, China (17140902400), the Clinical Research Plan of SHDC, Shanghai, China (16CR3005A), the Project Foundation of Health and Family Planning Commission of Shanghai, China (M20170348), and the Fundamental Research Funds for the Central Universities.

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Author notes

  1. Lan Ma, Juan Wang and Li Li have contributed equally to the work.

Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China

    Lan Ma & Xun Li

  2. Department of Ultrasound, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China

    Lan Ma

  3. Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Juan Wang

  4. Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Li Li

  5. Department of Cardiology, The Fifth People′s Hospital of Shanghai, Fudan University, Shanghai, 200240, China

    Qi Qiao, Ruo-Min Di, Xiu-Mei Li, Ying-Jia Xu & Yi-Qing Yang

  6. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China

    Min Zhang, Ruo-Gu Li & Xing-Biao Qiu

  7. Department of Cardiovascular Research Laboratory, The Fifth People′s Hospital of Shanghai, Fudan University, Shanghai, 200240, China

    Yi-Qing Yang

  8. Department of Central Laboratory, The Fifth People′s Hospital of Shanghai, Fudan University, Shanghai, 200240, China

    Yi-Qing Yang

Authors
  1. Lan Ma
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  2. Juan Wang
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  3. Li Li
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  4. Qi Qiao
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  7. Ying-Jia Xu
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  8. Min Zhang
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  9. Ruo-Gu Li
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  10. Xing-Biao Qiu
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  11. Xun Li
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  12. Yi-Qing Yang
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Corresponding authors

Correspondence to Xun Li or Yi-Qing Yang.

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Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study or their legal guardians.

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Ma, L., Wang, J., Li, L. et al. ISL1 loss-of-function mutation contributes to congenital heart defects. Heart Vessels 34, 658–668 (2019). https://doi.org/10.1007/s00380-018-1289-z

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  • DOI: https://doi.org/10.1007/s00380-018-1289-z

Keywords

  • Congenital heart defect
  • Patent ductus arteriosus
  • Molecular genetics
  • Transcription factor
  • ISL1
  • Reporter gene assay