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Review

Congenital heart disease and genetic syndromes: new insights into molecular mechanisms

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Pages 861-870 | Received 28 Apr 2017, Accepted 25 Jul 2017, Published online: 03 Aug 2017

References

  • Ferencz C, Loffredo CA, Correa-Villasenor A, et al. Categorization of cardiovascular malformations for risk factor analysis. In: Ferencz C, Loffredo CA, Correa-Villasenor A, Wilson PD, editors. Genetic and environmental risk factors of major cardiovascular malformation: the Baltimore-Washington study 1981—1989. Armonk, NY: Futura; 1997. p.13–28.
  • Greenwood RD, Rosenthal A, Parisi L, et al. Extracardiac abnormalities in infants with congenital heart disease. Pediatrics. 1975;55:485–492.
  • Nora JJ. Causes of congenital heart diseases: old and new modes, mechanisms, and models. Am Heart J. 1993;125:1409–1419.
  • Pritchard MA, Kola I. The “gene dosage effect” hypothesis versus the “amplified developmental instability” hypothesis in Down syndrome. J Neural Transm Suppl. 1999;57:293–303.
  • Nora JJ. Multifactorial inheritance hypothesis for the etiology of congenital heart diseases. The genetic-environmental interaction. Circulation. 1968;38:604–617.
  • Digilio MC, Marino B, Cicini MP, et al. Risk of congenital heart defects in relatives of patients with atrioventricular canal. Am J Dis Child. 1993;147:1295–1297.
  • Digilio MC, Dallapiccola B, Marino B. Atrioventricular canal defect as a sign of laterality defect in Ellis-van Creveld and polydactyly syndromes with ciliary and Hedgehog signaling dysfunction. Pediatr Cardiol. 2012;33:874–875.
  • Marino B, Digilio MC. Congenital heart disease and genetic syndromes: specific correlation between cardiac phenotype and genotype. Cardiovasc Pathol. 2000;9:303–315.
  • Marino B. Congenital heart disease in patients with Down’s syndrome: anatomic and genetic aspects. Biomed Pharmacother. 1993;47:197–200.
  • Marino B, Vairo U, Corno A, et al. Atrioventricular canal in Down syndrome. Prevalence of associated cardiac malformations compared with patients without Down syndrome. Am J Dis Child. 1990;144:1120–1122.
  • Marino B, Papa M, Guccione P, et al. Ventricular septal defect in Down syndrome. Anatomic types and associated malformations. Am J Dis Child. 1990;144:544–545.
  • Marino B, Digilio MC, Toscano A, et al. Anatomic patterns of conotruncal defects associated with deletion 22q11. Genet Med. 2001;3:45–48.
  • Momma K. Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome. Am J Cardiol. 2010;105:1617–1624.
  • Marino B, Digilio MC, Toscano A, et al. Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr. 1999;135:703–706.
  • Wren C, Oslizlok P, Bull C. Natural history of supravalvular aortic stenosis and pulmonary artery stenosis. J Am Coll Cardiol. 1990;15:1625–1630.
  • Bonnet D, Pelet A, Legeai-Mallet L, et al. A gene for Holt-Oram syndrome maps to the distal long arm of chromosome 12. Nat Genet. 1994;6:405–408.
  • Digilio MC, Marino B, Ammirati A, et al. Cardiac malformations in patients with oral-facial-skeletal syndromes: clinical similarities with heterotaxia. Am J Med Genet. 1999;84:350–356.
  • Digilio MC, Bernardini L, Lepri F, et al. Ebstein anomaly: genetic heterogeneity and association with microdeletions 1p36 and 8p23.1. Am J Med Genet A. 2011;155A:2196–2202.
  • Fregeau B, Kim BJ, Hernandez-Garcia A, et al. De novo mutations of RERE cause a genetic syndrome with features that overlap those associated with proximal 1p36 deletions. Am J Hum Genet. 2016;98:963–970.
  • Digilio MC, Marino B. What is new in genetics of congenital heart defects? Front Pediatr. 2016;4:120.
  • Vetrini F, D’Alessandro LC, Akdemir ZC, et al. Bi-allelic mutations in PKD1L1 are associated with laterality defects in humans. Am J Hum Genet. 2016;99:886–893.
  • Boyle L, Wamelink MM, Salomons GS, et al. Mutations in TKT are the cause of a syndrome including short stature, developmental delay, and congenital heart defects. Am J Hum Genet. 2016;98:1235–1242.
  • Li YJ, Yang YQ. An update on the molecular diagnosis of congenital heart disease: focus on loss-of-function mutations. Expert Rev Mol Diagn. 2017;17:393–401.
  • Waldo KL, Kumiski DH, Wallis KT, et al. Conotruncal myocardium arises from a secondary heart field. Development. 2001;128:3179–3188.
  • Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R, et al. The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol. 2001;238:97–109.
  • Zaffran S, Kelly RG, Meilhac SM, et al. Right ventricular myocardium derives from the anterior heart field. Circ Res. 2004;95:261–268.
  • de la Cruz MV, Sanchez Gomez C, Arteaga MM, et al. Experimental study of the development of the truncus and the conus in the chick embryo. J Anat. 1977;123:661–686.
  • Kirby ML, Waldo KL. Neural crest and cardiovascular patterning. Circ Res. 1995;77:211–215.
  • Waldo K, Miyagawa-Tomita S, Kumiski D, et al. Cardiac neural crest cells provide new insight into septation of the cardiac outflow tract: aortic sac to ventricular septal closure. Dev Biol. 1998;196:129–144.
  • Bardawil T, Khalil S, Bergqvist C, et al. Genetics of inherited cardiocutaneous syndromes: a review. Open Heart. 2016;3:e000442.
  • De Biase L, Di Ciommo V, Ballerini L, et al. Prevalence of left-sided obstructive lesions in patients with atrioventricular canal without Down’s syndrome. J Thorac Cardiovasc Surg. 1986;91:467–469.
  • Formigari R, Di Donato RM, Gargiulo G, et al. Better surgical prognosis for patients with complete atrioventricular septal defect and Down’s syndrome. Ann Thorac Surg. 2004;78:666,72. discussion 672.
  • Michielon G, Marino B, Formigari R, et al. Genetic syndromes and outcome after surgical correction of tetralogy of Fallot. Ann Thorac Surg. 2006;81:968–975.
  • Jongewaard IN, Lauer RM, Behrendt DA, et al. Beta 1 integrin activation mediates adhesive differences between trisomy 21 and non-trisomic fibroblasts on type VI collagen. Am J Med Genet. 2002;109:298–305.
  • Arron JR, Winslow MM, Polleri A, et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature. 2006;441:595–600.
  • Ackerman C, Locke AE, Feingold E, et al. An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects. Am J Hum Genet. 2012;91:646–659.
  • Park SC, Mathews RA, Zuberbuhler JR, et al. Down syndrome with congenital heart malformation. Am J Dis Child. 1977;131:29–33.
  • Lo NS, Leung PM, Lau KC, et al. Congenital cardiovascular malformations in Chinese children with Down’s syndrome. Chin Med J (Engl). 1989;102:382–386.
  • Li H, Cherry S, Klinedinst D, et al. Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population. Circ Cardiovasc Genet. 2012;5:301–308.
  • Sailani MR, Makrythanasis P, Valsesia A, et al. The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome. Genome Res. 2013;23:1410–1421.
  • Pierpont ME, Markwald RR, Lin AE. Genetic aspects of atrioventricular septal defects. Am J Med Genet. 2000;97:289–296.
  • Blom NA, Ottenkamp J, Wenink AG, et al. Deficiency of the vestibular spine in atrioventricular septal defects in human fetuses with down syndrome. Am J Cardiol. 2003;91:180–184.
  • Gittenberger-de Groot AC, Calkoen EE, Poelmann RE, et al. Morphogenesis and molecular considerations on congenital cardiac septal defects. Ann Med. 2014;46:640–652.
  • Snarr BS, Wirrig EE, Phelps AL, et al. A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development. Dev Dyn. 2007;236:1287–1294.
  • Briggs LE, Kakarla J, Wessels A. The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion. Differentiation. 2012;84:117–130.
  • Goddeeris MM, Rho S, Petiet A, et al. Intracardiac septation requires hedgehog-dependent cellular contributions from outside the heart. Development. 2008;135:1887–1895.
  • Burnicka-Turek O, Steimle JD, Huang W, et al. Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms. Hum Mol Genet. 2016;25:3011–3028.
  • Fuchs C, Ciani E, Guidi S, et al. Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression. Lab Invest. 2012;92:1648–1660.
  • Trazzi S, Mitrugno VM, Valli E, et al. APP-dependent up-regulation of Ptch1 underlies proliferation impairment of neural precursors in Down syndrome. Hum Mol Genet. 2011;20:1560–1573.
  • Das I, Park JM, Shin JH, et al. Hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model. Sci Transl Med. 2013;5:201ra120.
  • McDonald-McGinn DM, Sullivan KE, Marino B, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:15071.
  • Goodship J, Cross I, LiLing J, et al. A population study of chromosome 22q11 deletions in infancy. Arch Dis Child. 1998;79:348–351.
  • Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics. 2003;112:101–107.
  • Oskarsdottir S, Vujic M, Fasth A. Incidence and prevalence of the 22q11 deletion syndrome: a population-based study in Western Sweden. Arch Dis Child. 2004;89:148–151.
  • Kelly D, Goldberg R, Wilson D, et al. Confirmation that the velo-cardio-facial syndrome is associated with haplo-insufficiency of genes at chromosome 22q11. Am J Med Genet. 1993;45:308–312.
  • Burn J, Takao A, Wilson D, et al. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11. J Med Genet. 1993;30:822–824.
  • Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997;34:798–804.
  • McDonald-McGinn DM, Kirschner R, Goldmuntz E, et al. The Philadelphia story: the 22q11.2 deletion: report on 250 patients. Genet Couns. 1999;10:11–24.
  • Philip N, Bassett A. Cognitive, behavioural and psychiatric phenotype in 22q11.2 deletion syndrome. Behav Genet. 2011;41:403–412.
  • Cancrini C, Puliafito P, Digilio MC, et al. Clinical features and follow-up in patients with 22q11.2 deletion syndrome. J Pediatr. 2014;164:1475, 80.e2.
  • Swillen A, McDonald-McGinn D. Developmental trajectories in 22q11.2 deletion. Am J Med Genet C Semin Med Genet. 2015;169:172–181.
  • McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore). 2011;90:1–18.
  • Repetto GM, Guzman ML, Delgado I, et al. Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study. BMJ Open. 2014;4:e005041,2014–005041.
  • Marino B, Digilio MC, Persiani M, et al. Deletion 22q11 in patients with interrupted aortic arch. Am J Cardiol. 1999;84:360,1, A9.
  • McElhinney DB, Clark BJ III, Weinberg PM, et al. Association of chromosome 22q11 deletion with isolated anomalies of aortic arch laterality and branching. J Am Coll Cardiol. 2001;37:2114–2119.
  • Momma K, Ando M, Matsuoka R. Truncus arteriosus communis associated with chromosome 22q11 deletion. J Am Coll Cardiol. 1997;30:1067–1071.
  • Marino B, Digilio MC, Toscano A, et al. Deficiency of the infundibular septum in patients with interrupted aortic arch and del 22q11. Cardiol Young. 2000;10:428–429.
  • Zhang J, Ma D, Wang Y, et al. Analysis of chromosome 22q11 copy number variations by multiplex ligation-dependent probe amplification for prenatal diagnosis of congenital heart defect. Mol Cytogenet. 2015;8:100,015-0209-5. eCollection 2015.
  • Melchionda S, Digilio MC, Mingarelli R, et al. Transposition of the great arteries associated with deletion of chromosome 22q11. Am J Cardiol. 1995;75:95–98.
  • Halford S, Lindsay E, Nayudu M, et al. Low-copy-number repeat sequences flank the DiGeorge/velo-cardio-facial syndrome loci at 22q11. Hum Mol Genet. 1993;2:191–196.
  • Saitta SC, Harris SE, Gaeth AP, et al. Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum Mol Genet. 2004;13:417–428.
  • Rump P, De Leeuw N, van Essen AJ, et al. Central 22q11.2 deletions. Am J Med Genet A. 2014;164A:2707–2723.
  • Driscoll DA, Salvin J, Sellinger B, et al. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. J Med Genet. 1993;30:813–817.
  • Lindsay EA, Halford S, Wadey R, et al. Molecular cytogenetic characterization of the DiGeorge syndrome region using fluorescence in situ hybridization. Genomics. 1993;17:403–407.
  • Vorstman JA, Jalali GR, Rappaport EF, et al. MLPA: a rapid, reliable, and sensitive method for detection and analysis of abnormalities of 22q. Hum Mutat. 2006;27:814–821.
  • Emanuel BS. Molecular mechanisms and diagnosis of chromosome 22q11.2 rearrangements. Dev Disabil Res Rev. 2008;14:11–18.
  • Lindsay EA, Botta A, Jurecic V, et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature. 1999;401:379–383.
  • Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet. 2001;27:286–291.
  • Lindsay EA, Vitelli F, Su H, et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature. 2001;410:97–101.
  • Merscher S, Funke B, Epstein JA, et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell. 2001;104:619–629.
  • Yagi H, Furutani Y, Hamada H, et al. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362:1366–1373.
  • Baldini A, Fulcoli FG, Illingworth E. Tbx1: transcriptional and developmental functions. Curr Top Dev Biol. 2017;122:223–243.
  • Xu H, Morishima M, Wylie JN, et al. Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development. 2004;131:3217–3227.
  • Vitelli F, Lindsay EA, Baldini A. Genetic dissection of the DiGeorge syndrome phenotype. Cold Spring Harb Symp Quant Biol. 2002;67:327–332.
  • Maeda J, Yamagishi H, McAnally J, et al. Tbx1 is regulated by forkhead proteins in the secondary heart field. Dev Dyn. 2006;235:701–710.
  • Ward C, Stadt H, Hutson M, et al. Ablation of the secondary heart field leads to tetralogy of Fallot and pulmonary atresia. Dev Biol. 2005;284:72–83.
  • Zhang Z, Baldini A. In vivo response to high-resolution variation of Tbx1 mRNA dosage. Hum Mol Genet. 2008;17:150–157.
  • Van Praagh R, Van Praagh S, Nebesar RA, et al. Tetralogy of Fallot: underdevelopment of the pulmonary infundibulum and its sequelae. Am J Cardiol. 1970;26:25–33.
  • Lania G, Bresciani A, Bisbocci M, et al. Vitamin B12 ameliorates the phenotype of a mouse model of DiGeorge syndrome. Hum Mol Genet. 2016;25:4369–4375.
  • Nowotschin S, Liao J, Gage PJ, et al. Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Development. 2006;133:1565–1573.
  • Peyvandi S, Lupo PJ, Garbarini J, et al. 22q11.2 deletions in patients with conotruncal defects: data from 1,610 consecutive cases. Pediatr Cardiol. 2013;34:1687–1694.
  • Moon AM, Guris DL, Seo JH, et al. Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes. Dev Cell. 2006;10:71–80.
  • Racedo SE, McDonald-McGinn DM, Chung JH, et al. Mouse and human CRKL is dosage sensitive for cardiac outflow tract formation. Am J Hum Genet. 2015;96:235–244.
  • Lopez-Rivera E, Liu YP, Verbitsky M, et al. Genetic drivers of kidney defects in the DiGeorge syndrome. N Engl J Med. 2017;376:742–754.
  • Goldmuntz E, Driscoll DA, Emanuel BS, et al. Evaluation of potential modifiers of the cardiac phenotype in the 22q11.2 deletion syndrome. Birth Defects Res A Clin Mol Teratol. 2009;85:125–129.
  • Chung JH, Cai J, Suskin BG, et al. Whole-genome sequencing and integrative genomic analysis approach on two 22q11.2 deletion syndrome family trios for genotype to phenotype correlations. Hum Mutat. 2015;36:797–807.
  • Mlynarski EE, Xie M, Taylor D, et al. Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome. Hum Genet. 2016;135:273–285.
  • Mlynarski EE, Sheridan MB, Xie M, et al. Copy-number variation of the glucose transporter gene SLC2A3 and congenital heart defects in the 22q11.2 deletion syndrome. Am J Hum Genet. 2015;96:753–764.
  • Guo T, Chung JH, Wang T, et al. Histone modifier genes alter conotruncal heart phenotypes in 22q11.2 deletion syndrome. Am J Hum Genet. 2015;97:869–877.
  • Newbern J, Zhong J, Wickramasinghe RS, et al. Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development. Proc Natl Acad Sci U S A. 2008;105:17115–17120.
  • Maynard TM, Gopalakrishna D, Meechan DW, et al. 22q11 Gene dosage establishes an adaptive range for sonic hedgehog and retinoic acid signaling during early development. Hum Mol Genet. 2013;22:300–312.
  • Dykes IM, Van Bueren KL, Ashmore RJ, et al. HIC2 is a novel dosage-dependent regulator of cardiac development located within the distal 22q11 deletion syndrome region. Circ Res. 2014;115:23–31.
  • Chen L, Fulcoli FG, Ferrentino R, et al. Transcriptional control in cardiac progenitors: tbx1 interacts with the BAF chromatin remodeling complex and regulates Wnt5a. PLoS Genet. 2012;8:e1002571.
  • Vitelli F, Taddei I, Morishima M, et al. A genetic link between Tbx1 and fibroblast growth factor signaling. Development. 2002;129:4605–4611.
  • Digilio MC, Marino B, Capolino R, et al. Familial recurrence of nonsyndromic congenital heart defects in first degree relatives of patients with deletion 22q11.2. Am J Med Genet A. 2005;134A:158–164.
  • Swaby JA, Silversides CK, Bekeschus SC, et al. Complex congenital heart disease in unaffected relatives of adults with 22q11.2 deletion syndrome. Am J Cardiol. 2011;107:466–471.
  • van Rooij E, Olson EN. MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets. J Clin Invest. 2007;117:2369–2376.
  • Shiohama A, Sasaki T, Noda S, et al. Molecular cloning and expression analysis of a novel gene DGCR8 located in the DiGeorge syndrome chromosomal region. Biochem Biophys Res Commun. 2003;304:184–190.
  • Sellier C, Hwang VJ, Dandekar R, et al. Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome. PLoS One. 2014;9:e103884.
  • Merico D, Costain G, Butcher NJ, et al. MicroRNA dysregulation, gene networks, and risk for schizophrenia in 22q11.2 deletion syndrome. Front Neurol. 2014;5:238.
  • Lee DA, Portnoy S, Hill P, et al. Psychological profile of children with Noonan syndrome. Dev Med Child Neurol. 2005;47:35–38.
  • Pierpont EI, Pierpont ME, Mendelsohn NJ, et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009;8:275–282.
  • Noonan JA. Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am J Dis Child. 1968;116:373–380.
  • Roberts AE, Allanson JE, Tartaglia M, et al. Noonan syndrome. Lancet. 2013;381:333–342.
  • Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29:465–468.
  • Pandit B, Sarkozy A, Pennacchio LA, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39:1007–1012.
  • Tartaglia M, Pennacchio LA, Zhao C, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39:75–79.
  • Cordeddu V, Di Schiavi E, Pennacchio LA, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41:1022–1026.
  • Sarkozy A, Carta C, Moretti S, et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009;30:695–702.
  • Cirstea IC, Kutsche K, Dvorsky R, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010;42:27–29.
  • Martinelli S, De Luca A, Stellacci E, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010;87:250–257.
  • Lepri F, De Luca A, Stella L, et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011;32:760–772.
  • Flex E, Jaiswal M, Pantaleoni F, et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum Mol Genet. 2014;23:4315–4327.
  • Yamamoto GL, Aguena M, Gos M, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015;52:413–421.
  • Gripp KW, Aldinger KA, Bennett JT, et al. A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair. Am J Med Genet A. 2016;170:2237–2247.
  • Aoki Y, Niihori T, Inoue S, et al. Recent advances in RASopathies. J Hum Genet. 2016;61:33–39.
  • Tartaglia M, Gelb BD. Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms. Ann N Y Acad Sci. 2010;1214:99–121.
  • Digilio MC, Lepri F, Baban A, et al. RASopathies: clinical diagnosis in the first year of life. Mol Syndromol. 2011;1:282–289.
  • Zambrano RM, Marble M, Chalew SA, et al. Further evidence that variants in PPP1CB cause a rasopathy similar to Noonan syndrome with loose anagen hair. Am J Med Genet A. 2017;173:565–567.
  • Digilio MC, Marino B, Giannotti A, et al. Noonan syndrome with cardiac left-sided obstructive lesions. Hum Genet. 1997;99:289.
  • Tartaglia M, Kalidas K, Shaw A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002;70:1555–1563.
  • Razzaque MA, Nishizawa T, Komoike Y, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007;39:1013–1017.
  • Aoki Y, Niihori T, Banjo T, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013;93:173–180.
  • Limongelli G, Pacileo G, Marino B, et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol. 2007;100:736–741.
  • Calcagni G, Baban A, De Luca E, et al. Coronary artery ectasia in Noonan syndrome: report of an individual with SOS1 mutation and literature review. Am J Med Genet A. 2016;170:665–669.
  • Muenke M, Kruszka PS, Sable CA, et al. Chapter 9: Gelb G.D., Roberts A.E., Tartaglia M. Noonan syndrome and other RAS/MAPK pathways syndromes. In: Muenke M.; Kruszka PS, Sable CA, editors. Congenital heart disease molecular genetics, principles of diagnosis and treatment. Karger Medical and Scientific Publishers; 2015.
  • Krenz M, Yutzey KE, Robbins J. Noonan syndrome mutation Q79R in Shp2 increases proliferation of valve primordia mesenchymal cells via extracellular signal-regulated kinase 1/2 signaling. Circ Res. 2005;97:813–820.
  • Gelb BD, Roberts AE, Tartaglia M. Cardiomyopathies in Noonan syndrome and the other RASopathies. Prog Pediatr Cardiol. 2015;39:13–19.
  • Wu X, Simpson J, Hong JH, et al. MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation. J Clin Invest. 2011;121:1009–1025.
  • Edouard T, Combier JP, Nedelec A, et al. Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling. Mol Cell Biol. 2010;30:2498–2507.
  • Marin TM, Keith K, Davies B, et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 2011;121:1026–1043.
  • Dhandapany PS, Razzaque MA, Muthusami U, et al. RAF1 mutations in childhood-onset dilated cardiomyopathy. Nat Genet. 2014;46:635–639.
  • Formigari R, Michielon G, Digilio MC, et al. Genetic syndromes and congenital heart defects: how is surgical management affected? Eur J Cardiothorac Surg. 2009;35:606–614.

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