Genetic study in congenital heart defects

Syed Abir Hussain, Nasir U din Wani, Tasneem Muzaffar, Abdul Majeed Dar, Mohammad Akbar Bhat, Roohi Rasool, Imtiyaz Ahmad Bhat, Shyam Singh


Background: Congenital heart diseases (CHD) are relatively common with a prevalence ranging from 3.7 to 17.5 per 1000 live births. Little is known about genetic link with respect to congenital heart disease. Iroquoise (Irx) homeobox genes have been widely studied and their expression in both developing and adult heart. Author tried to study the role of irx4 and irx5 genes in structural congenital heart disease, keeping the focus on study reported by Cheng Z et al.

Methods: Author studied reported mutation site sequences in 25 various congenital heart disease patients and control healthy relatives of patients. It is a unique study and there has not been such a study reported in literature till date. Besides comparison with healthy related controls, author took cardiac tissue biopsy in patients while doing corrective cardiac surgery. However, blood samples were taken from controls due to ease of feasibility.

Results: Although, there were no sequence variations in the studied exon regions, but author got a base pair sequence change at 6 bp intron region, which is near the exon splice site in irx4 gene. Besides two ASD patient’s male children (one child each) had ASD prompting us to believe some role of sex linkage. However later needs pedigree analysis and sex chromosome studies for further analysis.

Conclusions: Gene sequence in the Kashmiri population is unique. There is possibility of role of irx genes in CHD. ASD might have sex linkage in some.


Congenital, Heart disease, Genes Irx4, Irx5

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Ferencz C, Rubin JD, McCarter RJ, Brenner JI, Neil CA, Perry LW, et al. Congenital heart disease: prevalence at live birth. The Baltimore-Washington Infant Study. Am J Epidemiol. 1985;121:31-6.

Bolisetty S, Daftary A, Ewald D, Knight B, Wheaton G. Congenital heart defects in Central Australia. Med J Aust. 2004;180:614-7.

Kapoor R, Gupta S. Prevalence of congenital heart disease, Kanpur, India. Indian Pedia. 2008;45:309-11.

Brand T. Heart development: molecular insights into cardiac specification and early morphogenesis. Dev Biol. 2003;258;1-19.

Evans SM, Yelon D, Conlon FL, Kirby ML. Myocardial lineage development. Circ Res. 2010;107:1428-44.

Harvey RP. Patterning the vertebrate heart. Nat Rev Genet. 2002;3:544-56.

Gomez-Skarmeta JL, Modolell J. Araucan and caupolican provide a link between compartment subdivisions and patterning of sensory organs and veins in the drosophila wing. Genes Dev. 1996;10:2935-45.

Leyns L, Gomez-Skarmeta JL, Dambly-Chaudiere C. Iroquois: a prepattern gene that controls the formation of bristles on the thorax of drosophila. Mech Dev. 1996;59:63-72.

Gomez-Skarmeta JL, Modolell J. Iroquois genes: genomic organization and function in vertebrate neural development. Curr Opin Genet Dev. 2002;12:403-8.

Matsumoto K, Nishihara S, Kamimura M, Shiraishi T, Otoguro T, Uehara M, et al. The prepattern transcription factor irx2, a target of the fgf8/map kinase cascade, is involved in cerebellum formation. Nat Neurosci. 2004;7:605-12.

Gardner EJ, Simmons MJ, Snustad DP. Genetic control of development in drosophila. Principles of Genetics. 8th ed. 2006; 413-424.

Gehring WJ. Exploring the homeobox. Gene. 1993;135:215-21.

Burglin TR. Analysis of tale superclass homeobox genes (meis, pbc, knox, Iroquois, tgif) reveals a novel domain conserved between plants and animals. Nucleic Acids Res. 1997;25:4173-80.

Cavodeassi F, Modolell J, Gomez-Skarmeta JL. The Iroquois family of genes: from body building to neural patterning. Dev. 2001;128:2847-55.

Jordan KC, Clegg NJ, Blasi JA, Morimoto AM, Sen J, Stein D, et al. The homeobox gene mirror links EGF signalling to embryonic dorso-ventral axis formation through notch activation. Nat Genet. 2000;24:429-33.

Blin N, Stafford DW. A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res. 1976;3(9):2303-08.

Cheng Z, Wang J, Su D, Pan H, Huang G, Li X, et al. Two novel mutations of the irx4 gene in patients with congenital heart disease. Hum Genet. 2011;130:657-62.

Zhang WM, Li XF, Ma ZY, Zhang J, Zhou SH, Li T, et al. GATA4 and NKX2.5 gene analysis in Chinese Uygur patients with congenital heart disease. Chin Med J (Engl); 2009;122:416-19.

Peng T, Wang L, Zhou S F, Li X. Mutations of the GATA4 and NKX2.5 genes in Chinese pediatric patients with non-familial congenital heart disease. Genetica. 2010;138:1231-40.

Luca A, Sarkozy A, Ferese R, Consoli F, Lepri F, Dentici ML, et al. New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot and double outlet right ventricle. Clin. Genet. 2011;80:184-190.

Benson DW, Sharkey A, Fatkin D, Lang P, Basson CT, Barbara, et al. Reduced penetrance, variable expressivity, and genetic heterogeneity of familial atrial septal defects. Circulation. 1998;97:2043-8.

Bayrak F, Kömürcü-Bayrak E, Mutlu B, Kahveci G, Erginel-Ünaltuna N. Genetic analysis of the Irx4 gene in hypertrophic cardiomyopathy. Arch Turk Soc Cardiol. 2008;36(2):90-5.