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• W2912292022 abstract "HomeCirculation ResearchVol. 124, No. 4Another Notch in the Genetic Puzzle of Tetralogy of Fallot Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAnother Notch in the Genetic Puzzle of Tetralogy of Fallot Adrianna Matos-Nieves, Jun Yasuhara and Vidu Garg Adrianna Matos-NievesAdrianna Matos-Nieves From the Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital, Columbus, OH (A.M.-N., J.Y., V.G.) Search for more papers by this author , Jun YasuharaJun Yasuhara From the Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital, Columbus, OH (A.M.-N., J.Y., V.G.) Search for more papers by this author and Vidu GargVidu Garg Correspondence to Vidu Garg, MD, Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital, Room WB4221 Columbus, OH 43205. Email E-mail Address: [email protected] From the Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital, Columbus, OH (A.M.-N., J.Y., V.G.) Department of Pediatrics and Department of Molecular Genetics, Ohio State University, Columbus (V.G.). Search for more papers by this author Originally published14 Feb 2019https://doi.org/10.1161/CIRCRESAHA.118.314520Circulation Research. 2019;124:462–464This article is a commentary on the followingWhole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of FallotCongenital heart disease (CHD) is the most common type of birth defect, affecting ≈1% of live births, and with the inclusion of bicuspid aortic valve, the prevalence is estimated to be 2% to 3%.1 Remarkable improvements in the medical and surgical management of individuals affected by CHD have resulted in an ever-growing population of adult CHD survivors.2 As these children reach reproductive age, questions arise regarding the risk of having an infant with CHD as prior epidemiological studies have consistently demonstrated an increased recurrence risk supporting genetic contributors.3 Recently, a greater understanding of the complex genetic architecture that underlies CHD has been achieved, based on molecular discoveries defining cardiovascular developmental pathways and new genomic technologies that allow for detailed analysis of the human genome.1 The first successes were achieved using positional cloning approaches studying inherited forms of syndromic and nonsyndromic CHD, but the increasing use of genome-wide approaches is uncovering novel submicroscopic chromosomal abnormalities and pathogenic sequence variants associated with CHD. Currently, it is estimated that a genetic cause can be identified in nearly 30% of CHD cases.4Article, see p 553CHD encompasses a diverse group of cardiac malformations, and the majority of currently published studies have examined large populations of individuals with a spectrum of CHD.5,6 One of the earliest reports of cyanotic CHD was by Neils Stensen ≈350 years ago, with the description of tetralogy of Fallot (TOF) which represents ≈7% to 10% of CHD cases.7 In 1888, Dr Etienne-Louis Arthur Fallot described its 4 cardinal features of pulmonary outflow tract obstruction, ventricular septal defect, overriding aorta, and right ventricular hypertrophy.7 In the current era, infants with TOF undergo corrective surgical repair and whereas the majority survive to adulthood, a subset suffer from long-term cardiovascular morbidity related to arrhythmias and right ventricular dysfunction because of pulmonary regurgitation. TOF can occur in the setting of additional noncardiac anomalies (syndromic) or in isolation (nonsyndromic). Syndromic TOF accounts for ≈20% of cases, primarily related to 22q11.2 deletion syndrome (22q11del), and has been shown to have worse clinical outcomes.4,8 Several etiologic genes have been implicated in nonsyndromic TOF, but these studies have been performed in small populations.8 Defining the genetic contributors for nonsyndromic TOF may identify potential subpopulations at risk for long-term morbidity. In this issue of Circulation Research, Page et al9 investigate the genetic contributors for nonsyndromic TOF by performing exome sequencing of 829 patients with nonsyndromic TOF, representing the largest cohort sequenced to date.The investigative team, from 9 institutions in Europe and Australia, recruited 867 adults and children with TOF of Northern European ancestry. After screening for 22q11del using targeted genetic testing, the remaining 829 individuals with nonsyndromic TOF underwent whole exome sequencing. Following standard approaches for annotating nucleotide variants, pathogenic variants were defined as those that predicted premature truncation of protein coding sequence (eg, nonsense and frameshift mutations) or those that predicted a deleterious nonsynonymous amino acid substitution (missense mutation), defined by a combined annotation-dependent depletion score ≥20. In addition, the potentially pathogenic variants had to be absent in the publicly available gnomAD database, which contains >140 000 reference genomes, and in a private reference exome database of 1252 individuals. Clustering analysis, a case-only approach that calculates if a statistically significant excess of pathogenic variants is present in the coding sequence of particular gene as compared with expected, was used to identify TOF-causing genes.Using this genome-wide approach, the investigators found that 37 probands harbored 31 unique, deleterious NOTCH1 variants accounting for 4.5% of the nonsyndromic TOF cohort. Of the NOTCH1 variants identified, 7 were loss-of-function, 2 were in-frame indels, and 22 were missense variants. The second most frequent locus of variant clustering was in the gene, FLT4/VEGFR3, which encodes a receptor in the VEGF (vascular endothelial growth factor) signaling pathway linked to congenital lymphedema (Milroy disease).10 Twenty-two unique, deleterious FLT4 variants were identified in 21 probands, accounting for 2.4% of cases, and unlike NOTCH1, the majority were loss-of-function (16) versus missense (6) variants. Not surprisingly, TBX1, the gene implicated in 22q11del, was among the top 9 genes identified, whereas pathogenic variants in previously implicated cardiac transcription factors (eg, NKX2.5, GATA4, HAND2, and GATA6) were present in only 1.2% of the population. Several other genes, that are biologically plausible, were also implicated among the top 9.A challenge in this type of large-scale sequencing study is establishing pathogenicity of identified sequence variants. Although it is generally accepted that extremely rare, loss-of-function, and de novo variants are highly likely to be pathogenic, further investigation is often necessary to establish pathogenicity of identified missense variants. Because of the study design, parental DNA was only available for 7 and 4 patients with NOTCH1 and FLT4 pathogenic variants, respectively. Sanger sequencing of these trios demonstrated that 5 of 7 probands harbored de novo NOTCH1 mutations. Of the 5 NOTCH1 missense mutations tested, 3 were de novo and 2 were inherited from an unaffected parent. Of the 4 FLT4 mutations, 3 were inherited.Another method to define pathogenicity is performing functional testing of mutant protein, which was done for 3 NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S). Notch1 encodes a receptor that functions in a highly conserved signaling pathway critical for cardiovascular development. Upon binding to its cognate ligands, members of the Jagged and Delta families, the Notch receptor undergoes a series of cleavages before translocating to the nucleus where it activates downstream target genes. In vitro testing of these mutant proteins using a luciferase reporter assay demonstrated that the p.C607Y and p.N1875S mutants displayed deficits in activation with Jagged1 stimulation. However, immunoblotting demonstrated that only C607Y mutant exhibited a perturbed ligand-independent cleavage, potentially contributing to the transactivation deficit.The finding that pathogenic variants in NOTCH1 are a cause of TOF is supported by several case reports in humans. NOTCH1 pathogenic variants were first described in individuals with CHD affecting the aortic valve and other left-sided structures,11 but recently pathogenic copy number or sequence variants in NOTCH1 have been found in TOF and other right-sided CHD.12 Interestingly, Jin et al5 did not find an abundance of NOTCH1 pathogenic variants in a population of 426 individuals with TOF, but this is likely related to defining only loss-of-function as pathogenic. This work also supports recent publications showing FLT4 pathogenic variants as a cause of nonsyndromic TOF.13 However, none of the FLT4 missense or in-frame variants identified in this cohort were located in the protein kinase domain of FLT4, a hallmark of Milroy disease, suggesting an important genotype-phenotype correlation. The question if other Notch and VEGF signaling pathway members contribute to TOF remains unclear. Although potentially pathogenic variants in VEGF-related genes have been reported in nonsyndromic TOF, this was neither seen in this TOF cohort nor were pathogenic variants in other members of the Notch signaling pathway.As mentioned, the authors identified potentially deleterious variants in only 16% of cases of nonsyndromic TOF when examining the top 9 genes. It calls into question how many other genes are involved and if other cases could be explained by whole genome sequencing. Whole genome sequencing would allow for the discovery of variants in regulatory and noncoding regions of identified TOF genes along with other CHD genes. As relatively strict criteria were used to define pathogenic variants, it is possible that additional variants with less deleterious effects contribute in an oligogenic manner or with environmental factors to cause disease.The strength of this work lies in the sheer number of exomes sequenced in a population affected by a single type of nonsyndromic CHD. A genome-wide, versus candidate gene, approach facilitated the process of gene discovery and provided stronger support of the conclusions. Statistical analysis demonstrated that NOTCH1 and FLT4 were among the most frequent genes predisposing to nonsyndromic TOF contributing to ≈7% of disease. This large population also has the potential for genotype-phenotype correlation. TOF has a variable phenotype with degrees of pulmonary outflow tract obstruction from pulmonary stenosis to pulmonary atresia; aortic arch and coronary artery abnormalities; and aortic root dilation, and Notch signaling is implicated in the development of these structures in animal models.14 Although VEGF signaling pathway has been linked to a variety of different aspects of cardiovascular development, the role of FLT4/VEGFR3 in the embryonic heart is less well studied as the focus has been the lymphatic vasculature.10,15 Additional studies are necessary to understand the distinct mechanistic roles of FLT4 pathogenic variants in the context of TOF using in vitro or in vivo approaches. Ultimately, identifying specific genotype-phenotype associations between NOTCH1 or FLT4 variants and TOF subtypes may provide clinical insights for the long-term outcomes of TOF patients.AcknowledgmentsWe thank Dr Madhumita Basu for her helpful comments on the article.Sources of FundingJ. Yasuhara is supported by a Fellowship from the Japan Heart Foundation, and V. Garg is supported by National Institutes of Health Grants R01HL121797 and R01HL132801.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Vidu Garg, MD, Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital, Room WB4221 Columbus, OH 43205. Email vidu.[email protected]orgReferences1. Pierpont ME, Brueckner M, Chung WK, Garg V, Lacro RV, McGuire AL, Mital S, Priest JR, Pu WT, Roberts A, Ware SM, Gelb BD, Russell MW; American Heart Association Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Genomic and Precision Medicine. Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association.Circulation. 2018; 138:e653–e711. doi: 10.1161/CIR.0000000000000606LinkGoogle Scholar2. Warnes CA. Adult congenital heart disease: the challenges of a lifetime.Eur Heart J. 2017; 38:2041–2047. doi: 10.1093/eurheartj/ehw529MedlineGoogle Scholar3. Øyen N, Poulsen G, Boyd HA, Wohlfahrt J, Jensen PK, Melbye M. Recurrence of congenital heart defects in families.Circulation. 2009; 120:295–301. doi: 10.1161/CIRCULATIONAHA.109.857987LinkGoogle Scholar4. Russell MW, Chung WK, Kaltman JR, Miller TA. Advances in the understanding of the genetic determinants of congenital heart disease and their impact on clinical outcomes.J Am Heart Assoc. 2018; 7:e006906. doi: 10.1161/JAHA.117.006906LinkGoogle Scholar5. Jin SC, Homsy J, Zaidi S, et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.Nat Genet. 2017; 49:1593–1601. doi: 10.1038/ng.3970CrossrefMedlineGoogle Scholar6. Sifrim A, Hitz MP, Wilsdon A, et al; INTERVAL Study; UK10K Consortium; Deciphering Developmental Disorders Study. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.Nat Genet. 2016; 48:1060–1065. doi: 10.1038/ng.3627CrossrefMedlineGoogle Scholar7. Van Praagh R. The first Stella van Praagh memorial lecture: the history and anatomy of tetralogy of Fallot.Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2009;19–38. doi: 10.1053/j.pcsu.2009.01.004CrossrefMedlineGoogle Scholar8. Morgenthau A, Frishman WH. Genetic origins of tetralogy of Fallot.Cardiol Rev. 2018; 26:86–92. doi: 10.1097/CRD.0000000000000170CrossrefMedlineGoogle Scholar9. Page DJ, Miossec MJ, Williams SG, et al. Whole exome sequencing reveals the major genetic contributors to nonsyndromic tetralogy of Fallot.Circ Res. 2019; 124:553–563. doi: 10.1161/CIRCRESAHA.118.313250LinkGoogle Scholar10. Gordon K, Spiden SL, Connell FC, Brice G, Cottrell S, Short J, Taylor R, Jeffery S, Mortimer PS, Mansour S, Ostergaard P. FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update.Hum Mutat. 2013; 34:23–31. doi: 10.1002/humu.22223CrossrefMedlineGoogle Scholar11. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in NOTCH1 cause aortic valve disease.Nature. 2005; 437:270–274. doi: 10.1038/nature03940CrossrefMedlineGoogle Scholar12. Kerstjens-Frederikse WS, van de Laar IM, Vos YJ, et al. Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families.Genet Med. 2016; 18:914–923. doi: 10.1038/gim.2015.193CrossrefMedlineGoogle Scholar13. Reuter MS, Jobling R, Chaturvedi R, et alet al. Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.Genet Med. 2018. doi: 10.1038/s41436-018-0260-9CrossrefGoogle Scholar14. Luxán G, D’Amato G, MacGrogan D, de la Pompa JL. Endocardial notch signaling in cardiac development and disease.Circ Res. 2016. 118(1):e1–e18. doi: 10.1161/CIRCRESAHA.115.305350LinkGoogle Scholar15. Lambrechts D, Carmeliet P. Genetics in zebrafish, mice, and humans to dissect congenital heart disease: insights in the role of VEGF.Curr Top Dev Biol. 2004; 62:189–224. doi: 10.1016/S0070-2153(04)62007-2CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Yu H, Wang X and Cao H (2021) Construction and investigation of a circRNA-associated ceRNA regulatory network in Tetralogy of Fallot, BMC Cardiovascular Disorders, 10.1186/s12872-021-02217-w, 21:1, Online publication date: 1-Dec-2021. Xiaodi L, Ming Y, Hongfei X, Yanjie Z, Ruoyi G, Ma X, Wei S and Guoying H (2020) DNA methylation at CpG island shore and RXRα regulate NR2F2 in heart tissues of tetralogy of Fallot patients, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2020.06.110, 529:4, (1209-1215), Online publication date: 1-Sep-2020. Related articlesWhole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of FallotDonna J. Page, et al. Circulation Research. 2019;124:553-563 February 15, 2019Vol 124, Issue 4 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.314520PMID: 30763217 Originally publishedFebruary 14, 2019 Keywordsgeneticsheart defectscongenitalexomeEditorialtetralogy of FallotPDF download Advertisement SubjectsCongenital Heart DiseaseGenetics" @default.
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