The value of genetic analysis in the study of the nature of congenital malformations

Congenital malformations are the main cause of infant and child morbidity and mortality worldwide. Most congenital malformations are represented by non-syndromic forms, their etiology has not yet been studied. However, the latest genetic technologies have opened up new possibilities in the study of congenital malformations. The article presents latest achievements in the genetics of non-syndromic forms of congenital malformations. Genome-wide association study (GWAS) is an effective method for identifying gene variants associated with a predisposition to the congenital malformations; this method helps to identify correlations between single nucleotide polymorphism (SNP) and certain malformations. Numerous studies demonstrate that in addition to SNP the copy number variations (CNV) play an important role in the etiology of some birth defects (for example, congenital heart defects). It has been established that 5—10% of isolated congenital heart defects can be associated with rare CNV. Next-generation sequencing (NGS) is expected to play important role in the identification of birth defect etiology. The authors have obtained the first data on the genes involved in the development of malformations such as congenital heart defects, neural tube defects, facial clefts.

1. World Health Organization. Birth defects. Report by Secretariat. https://apps.who.int/gb/ebwha/pdf_files/WHA63/A63_10-en.pdf?ua=1. Ссылка активна на 29.05.2020 г.

2. Ardinger H.H., Buetow K.H., Bell G.I., Bardach J., VanDe-mark D.R., Murray J.C. Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. Am J Hum Genet 1989; 45: 348—353.

3. Lu X.C., Yu W., Tao Y., Zhao P.L., Li K., Tang L.J. et al. Contribution of transforming growth factor alpha polymorphisms to nonsyndromic orofacial clefts: a HuGE review and meta-analysis. Am J Epidemiol 2014; 179: 267—281. DOI: 10.1093/aje/kwt262

4. Shaw G.M., O’Malley C.D., Wasserman C.R., Tolarova M.M., Lammer E.J. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 1995; 59(4): 536-545. DOI: 10.1002/ajmg.1320590428

5. Yin M., DongL., Zheng J., Zhang H., Liu J., Hu Z. Meta-analysis of the association between MTHFR C677T polymorphism and the risk of congenital heart defects. Ann Hum Genet 2012; 76: 9-16. DOI: 10.1111/j.1469-1809.2011.00687.x

6. Leslie E., Murray J. Evaluating rare coding variants as contributing causes to non-syndromic cleft lip and palate. Clin Genet 2013; 84(5): 496-500. DOI: 10.1111/cge.12018

7. Gelb B., Brueckner M., Chung W., Goldmuntz E., Kaltman J., Kaski J.P. et al. The Congenital Heart Disease Genetic Network Study: rationale, design, and early results. Circ Res 2013; 112(4):698—706. DOI: 10.1161/CIRCRESAHA.111.300297

8. Van der Zanden L.F., van Rooij I.A., Feitz W.F., Knight Jo, Donders A.R., Renkema K.Y. et al. Common variants in DGKK are strongly associated with risk of hypospadias. Nat Genet 2011; 43(1): 48-50. DOI: 10.1038/ng.721

9. Ludwig K.U., Mangold E., Herms S., Nowak S., Reutter H., Paul A. et al. Genomewide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nat Genet 2012; 44(9): 968-971. DOI: 10.1038/ng.2360

10. Cordell H.J., Bentham J., Topf A., Zelenika D., Heath S., Ma-masoula C. et al. Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16. Nat Genet 2013; 45: 822-824. DOI: 10.1038/ng.2637

11. Hu Z., Shi Y., Mo X., Xu J., Zhao B., Lin Y. et al. A genome-wide association study identifies two risk loci for congenital heart malformations in Han Chinese populations. Nat Genet 2013; 45(7): 818-821. DOI: 10.1038/ng.2636

12. Greenway S.C., Pereira A.C., Lin J.C., DePalma S.R., Israel S.J., Mesquita S.M. et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet 2009; 41(8): 931-935. DOI: 10.1038/ng.415

13. Soemedi R., Wilson I.J., Bentham J., Darlay R., Topf A., Zelenika D. et al. Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. Am J Hum Genet 2012; 91: 489-501. DOI: 10.1016/j.ajhg.2012.08.003

14. Gelb B.D. Recent advances in understanding the genetics of congenital heart defects. Curr Opin Pediatr 2013; 25(5): 561-566. DOI: 10.1097/MOP.0b013e3283648826

15. Arrington C.B., Bleyl S.B., Matsunami N., Bonnell G.D., Otter-udB.E., Nielsen D.C. et al. Exome analysis of a family with pleio-tropic congenital heart disease. Circ Cardiovasc Genet 2012; 5: 175-182. DOI: 10.1161/CIRCGENETICS.111.961797

16. Zaidi S., Choi M., Wakimoto H., Ma L., Jiang J., Overton J.D. et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 2013; 498: 220-223. DOI: 10.1038/nature12141

17. Webber D.M., MacLeod S.L., Bamshad M.J., Shaw G.M., Fin-nell R.H., Shete S.S. et al. Developments in our understanding of the genetic basis of birth defects. Birth Defects Res A Clin Mol Teratol 2015; 103(8): 680-691. DOI: 10.1002/bdra.23385