Portal de Periódicos da CAPES

The Heritable Basis of Congenital Heart Disease

2016; Lippincott Williams & Wilkins; Volume: 9; Issue: 4 Linguagem: Inglês

10.1161/circgenetics.116.001559

1942-325X

Julie M. Nogee, Patrick Y. Jay,

Cardiac Structural Anomalies and Repair

HomeCirculation: Cardiovascular GeneticsVol. 9, No. 4The Heritable Basis of Congenital Heart Disease Free AccessEditorialPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Heritable Basis of Congenital Heart DiseasePast, Present, and Future Julie M. Nogee, MD and Patrick Y. Jay, MD, PhD Julie M. NogeeJulie M. Nogee From the Department of Pediatrics (J.M.N., P.Y.J.) and Department of Genetics (P.Y.J.), Washington University School of Medicine, St. Louis, MO. and Patrick Y. JayPatrick Y. Jay From the Department of Pediatrics (J.M.N., P.Y.J.) and Department of Genetics (P.Y.J.), Washington University School of Medicine, St. Louis, MO. Originally published1 Aug 2016https://doi.org/10.1161/CIRCGENETICS.116.001559Circulation: Cardiovascular Genetics. 2016;9:315–317A heritable basis for congenital heart disease was probably first suggested more than a century ago by a report of 3 cyanotic siblings.1 In the early 1960s, Zetterqvist in Sweden and Pitt in Australia convincingly demonstrated autosomal dominant inheritance in 2 large, extended families who had atrial septal defects (ASDs) and tetralogy of Fallot, respectively.2,3 Of note, Pitt ascertained the diagnosis in 215 of 275 descendants of one man spanning 6 generations, many of whom he personally examined! In contrast, it took at least 2 dozen people to identify a missense mutation of α-cardiac actin (ACTC1) as the cause of ASDs in the Swedish family.4 Their work, published in 2008, used linkage analysis, positional cloning, and Sanger DNA sequencing to diagnose one genetic mutation. Just 8 years later, White, Garg, and colleagues report in this issue their whole-exome sequencing (WES) analyses of 9 families. They identify the likely mutation in 3 families who had either ASDs or patent ductus arteriosus. Their stated goal was to demonstrate the clinical utility of WES in familial congenital heart disease.5 More broadly, their results highlight how far the field has come and how far it has to go in bringing genetics to pediatric cardiology.Article, see p 320WES evaluates the ≈1% of the genome that encodes proteins. If a person's disease is caused by a mutation in the exome, the sequence variant should be present in the WES output file of ≈3×107 nucleotides. A well-considered experimental design and bioinformatic pipeline are needed to filter the most plausible candidates from thousands of irrelevant variants. The investigators began by selecting families that demonstrate Mendelian patterns of a specific congenital heart defect, such as tetralogy of Fallot. Whether requiring the same defect in every affected family member increases the chance of finding a mutation is uncertain. Mutations of the same gene are generally associated with pleiotropic cardiac phenotypes due at least in part to the effect of modifier genes.6–8 Variants that were shared by all affected members of a family and that fit the expected inheritance pattern, for example, autosomal dominant or homozygous recessive, were then passed to the next filtering step.Close relatives share a large number of irrelevant variants, so common variants were excluded from further analysis. Common was defined as occurring in >1% of the general population. The filter relies on the premise that negative selection eliminates variants that have a deleterious effect on reproductive fitness. The assumption is reasonable, although the optimal threshold could be higher or lower than 1%. Deleterious variants that are associated with incomplete penetrance or mild defects would likely be more frequent than ones that have strong or severe effect. The population frequencies of the variants that the authors found for familial ASD and patent ductus arteriosus were 50 years ago. Where can we go from here? One may first ask what the genetic basis is in the other 6 families for whom WES yielded no candidate genes. Inherited chromosomal microdeletions or duplications or copy number variants occur in roughly 10% of isolated congenital heart disease.17 Mutations of regulatory DNA have not been explored; this would require whole-genome sequencing and the development of methods to estimate the pathogenicity of noncoding variants. Less often considered is an oligogenic basis: multiple mutations may contribute to the development of a heart defect. In fact, 2 of the families in the present article suggest this mechanism. The family that carried the GATA4 mutation also carried a mutation of EVC2, mutations of which cause Ellis van Creveld syndrome. Although the family did not have the syndrome, it is clear that mutations of syndromic genes can cause isolated congenital heart disease.10,14 Another family that had tetralogy of Fallot carried mutations of MYBPC3 and SOS1; mutations of the latter gene cause Noonan syndrome. Two recent genomic analyses provide compelling evidence for an oligogenic basis of tetralogy of Fallot and atrioventricular septal defects in humans.18,19Finally, one can ask how we can make genetics relevant to the practice of pediatric cardiology. Specific counseling regarding the risk for future offspring is an obvious application, but there may be even more meaningful emotional benefits for parents and patients. A genetic diagnosis may alleviate the parents' worry that they did something to cause their child's heart defect, and a certain diagnosis can in general help individuals cope with their disease. Of course, the nature of pediatric cardiologists and congenital heart surgeons is to intervene. For them, genetics will only be relevant if the information can guide the management of their patients. Recent evidence suggests a common genetic basis for congenital heart disease and neurodevelopmental disability.10 Children who carry such mutations may, hence, benefit from early intervention and individualized education programs. Certain genetic mutations may affect cardiac outcomes.20 High-risk patients might, thus, benefit from early and aggressive medical management. Personalized medicine—now that would be a laudable goal for the field in the next 50 years.DisclosuresJ.M. Nogee is supported by a National Institutes of Health (NIH) training grant (T32 HD043010, Training of the Pediatric Physician-Scientist). P.Y. Jay is an Established Investigator of the American Heart Association and the Lawrence J. and Florence A. DeGeorge Charitable Trust. P.Y. Jay is also supported by the Children's Discovery Institute of Washington University and St. Louis Children's Hospital and the NIH (R01 HL105857).FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Patrick Y. Jay, MD, PhD, Departments of Pediatrics and Genetics, Washington University School of Medicine, Box 8208, 660 S Euclid Ave, St. Louis, MO 63110. E-mail [email protected]References1. Weber FP.Congenital Heart Disease without Murmur, and with a Family History of Congenital Cyanosis.Proc R Soc Med. 1911; 4(Sect Study Dis Child):159–160.MedlineGoogle Scholar2. Zetterqvist P.Multiple occurrence of atrial septal defect in a family. Acta Paediatr. 1960; 49:741–747.CrossrefMedlineGoogle Scholar3. Pitt DB.A family study of Fallot's tetrad.Australas Ann Med. 1962; 11:179–183.CrossrefMedlineGoogle Scholar4. Matsson H, Eason J, Bookwalter CS, Klar J, Gustavsson P, Sunnegårdh J, et al. Alpha-cardiac actin mutations produce atrial septal defects.Hum Mol Genet. 2008; 17:256–265. doi: 10.1093/hmg/ddm302.CrossrefMedlineGoogle Scholar5. LaHaye S, Corsemeier D, Basu M, Bowman JL, Fitzgerald-Butt S,, Zender G, et al. Utilization of whole exome sequencing to identify causative mutations in familial congenital heart disease.Circ Cardiovasc Genet. 2016; 9:320–329. doi: 10.1161/CIRCGENETICS.115.001324.LinkGoogle Scholar6. Rajagopal SK, Ma Q, Obler D, Shen J, Manichaikul A, Tomita-Mitchell A, et al. Spectrum of heart disease associated with murine and human GATA4 mutation.J Mol Cell Cardiol. 2007; 43:677–685. doi: 10.1016/j.yjmcc.2007.06.004.CrossrefMedlineGoogle Scholar7. Sakata Y, Koibuchi N, Xiang F, Youngblood JM, Kamei CN, Chin MT.The spectrum of cardiovascular anomalies in CHF1/Hey2 deficient mice reveals roles in endocardial cushion, myocardial and vascular maturation.J Mol Cell Cardiol. 2006; 40:267–273. doi: 10.1016/j.yjmcc.2005.09.006.CrossrefMedlineGoogle Scholar8. Winston JB, Erlich JM, Green CA, Aluko A, Kaiser KA, Takematsu M, et al. Heterogeneity of genetic modifiers ensures normal cardiac development.Circulation. 2010; 121:1313–1321. doi: 10.1161/CIRCULATIONAHA.109.887687.LinkGoogle Scholar9. Hoffman JI, Kaplan S.The incidence of congenital heart disease.J Am Coll Cardiol. 2002; 39:1890–1900.CrossrefMedlineGoogle Scholar10. Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.Science. 2015; 350:1262–1266. doi: 10.1126/science.aac9396.CrossrefMedlineGoogle Scholar11. Wang K, Li M, Hakonarson H.ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res. 2010; 38:e164. doi: 10.1093/nar/gkq603.CrossrefMedlineGoogle Scholar12. Yang H, Wang K.Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR.Nat Protoc. 2015; 10:1556–1566. doi: 10.1038/nprot.2015.105.CrossrefMedlineGoogle Scholar13. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J.A general framework for estimating the relative pathogenicity of human genetic variants.Nat Genet. 2014; 46:310–315. doi: 10.1038/ng.2892.CrossrefMedlineGoogle Scholar14. Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, et al. De novo mutations in histone-modifying genes in congenital heart disease.Nature. 2013; 498:220–223. doi: 10.1038/nature12141.CrossrefMedlineGoogle Scholar15. Tu S, Chi NC.Zebrafish models in cardiac development and congenital heart birth defects.Differentiation. 2012; 84:4–16. doi: 10.1016/j.diff.2012.05.005.CrossrefMedlineGoogle Scholar16. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F.Genome engineering using the CRISPR-Cas9 system.Nat Protoc. 2013; 8:2281–2308. doi: 10.1038/nprot.2013.143.CrossrefMedlineGoogle Scholar17. Lander J, Ware SM.Copy number variation in congenital heart defects. Curr Genet Med Rep. 2014; 2:168–179.CrossrefGoogle Scholar18. Grunert M, Dorn C, Schueler M, Dunkel I, Schlesinger J, Mebus S, et al. Rare and private variations in neural crest, apoptosis and sarcomere genes define the polygenic background of isolated Tetralogy of Fallot.Hum Mol Genet. 2014; 23:3115–3128. doi: 10.1093/hmg/ddu021.CrossrefMedlineGoogle Scholar19. D'Alessandro LC, Al Turki S, Manickaraj AK, Manase D, Mulder BJ, Bergin L, et al. Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect.Genet Med. 2016; 18:189–198. doi: 10.1038/gim.2015.60.CrossrefMedlineGoogle Scholar20. Carey AS, Liang L, Edwards J, Brandt T, Mei H, Sharp AJ, et al. Effect of copy number variants on outcomes for infants with single ventricle heart defects.Circ Cardiovasc Genet. 2013; 6:444–451. doi: 10.1161/CIRCGENETICS.113.000189.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Wang B, Li J and Yin J (2019) Diagnostic value of echocardiography in fetal cardiac malformation and clinical classification, Experimental and Therapeutic Medicine, 10.3892/etm.2019.7732 August 2016Vol 9, Issue 4 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCGENETICS.116.001559 Originally publishedAugust 1, 2016 KeywordsEditorialscongenital heart diseasefamily studygene mutationexomePDF download Advertisement SubjectsGenetics