A Novel Missense Heterozygous Mutation in NKX2-5 Gene in a Family with Congenital Septal Defects and Cardiomyopathy: Case Series and Literature Review

Abstract

Single-gene mutations are important causes of congenital heart defects in children. Mutations in the NKX2-5 gene have been recently described in the literature as a cause of septal defects and cardiomyopathy. However, the spectrum of cardiac disease associated with NKX2-5 gene mutations is variable, ranging from asymptomatic septal defects to cardiomyopathy and sudden death. In this case report, we describe a case of 2-year-old child, along with two other family members, with a novel missense heterozygous (c.544G > T p.[Val182Phe]) mutation in NKX2-5 gene consistent with the diagnosis of autosomal dominant atrial septal defects with cardiomyopathy. This report can contribute to the understanding of genotype–phenotype correlations; it emphasizes the significant clinical relevance of NKX2-5 gene defects for congenital heart defects, sudden death, and cardiomyopathy, especially in multiple affected family members. It also suggests that individuals with NKX2-5 mutations are at risk of lethal arrhythmias and conduction disorders, that is why they should be evaluated routinely to assess the need for implantable cardioverter-defibrillator or pacemaker implantation.

Keywords

NKX2-5 gene - congenital heart diseases - atrial septal defect - ventricular septal defect - cardiomyopathy

Consent for Publication

Consent for publication was obtained from the reported family.

Ethical Compliance

This study was approved by our regional research ethics committee. Ref. No.: KD/AJ/88

Authors' Contributions

The authors contributed to the conception and design. All authors contributed to the acquisition and revised manuscript and agreed to be accountable for all aspects of the work, ensuring integrity and accuracy. All authors read and approved the final manuscript.

Publication History

Received: 14 May 2023

Accepted: 10 June 2024

Article published online:
10 July 2024

• References

• 1 Bassili A, Mokhtar SA, Dabous NI, Zaher SR, Mokhtar MM, Zaki A. Risk factors for congenital heart diseases in Alexandria, Egypt. Eur J Epidemiol 2000; 16 (09) 805-814
• 2 van der Linde D, Konings EE, Slager MA. et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011; 58 (21) 2241-2247
• 3 Ellesøe SG, Johansen MM, Bjerre JV, Hjortdal VE, Brunak S, Larsen LA. Familial atrial septal defect and sudden cardiac death: identification of a novel NKX2-5 mutation and a review of the literature. Congenit Heart Dis 2016; 11 (03) 283-290
• 4 Ware SM, Jefferies JL. New genetic insights into congenital heart disease. J Clin Exp Cardiolog 2012; S8 (21) 003
• 5 Behiry EG, Al-Azzouny MA, Sabry D, Behairy OG, Salem NE. Association of NKX2-5, GATA4, and TBX5 polymorphisms with congenital heart disease in Egyptian children. Mol Genet Genomic Med 2019; 7 (05) e612
• 6 Stanley EG, Biben C, Elefanty A. et al. Efficient Cre-mediated deletion in cardiac progenitor cells conferred by a 3'UTR-ires-Cre allele of the homeobox gene Nkx2-5. Int J Dev Biol 2002; 46 (04) 431-439
• 7 Dentice M, Cordeddu V, Rosica A. et al. Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J Clin Endocrinol Metab 2006; 91 (04) 1428-1433
• 8 Elliott DA, Kirk EP, Schaft D, Harvey RP. NK-2 class homeodomain proteins: conserved regulators of cardiogenesis. In: Amack DJ, Amendt BA, Anderson RH. eds. Heart Development and Regeneration. Amsterdam:: Academic Press; 2010: 569-597
• 9 Stallmeyer B, Fenge H, Nowak-Göttl U, Schulze-Bahr E. Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease. Clin Genet 2010; 78 (06) 533-540
• 10 Pradhan L, Genis C, Scone P, Weinberg EO, Kasahara H, Nam HJ. Crystal structure of the human NKX2.5 homeodomain in complex with DNA target. Biochemistry 2012; 51 (32) 6312-6319
• 11 Kalayinia S, Ghasemi S, Mahdieh N. A comprehensive in silico analysis, distribution and frequency of human Nkx2-5 mutations; a critical gene in congenital heart disease. J Cardiovasc Thorac Res 2019; 11 (04) 287-299
• 12 Dixit R, Narasimhan C, Balekundri VI, Agrawal D, Kumar A, Mohapatra B. Functional analysis of novel genetic variants of NKX2-5 associated with nonsyndromic congenital heart disease. Am J Med Genet A 2021; 185 (12) 3644-3663
• 13 Morlanes-Gracia P, Antoniutti G, Alvarez-Rubio J, Torres-Juan L, Heine-Suñer D, Ripoll-Vera T. Case report: a novel NKX2-5 mutation in a family with congenital heart defects, left ventricular non-compaction, conduction disease, and sudden cardiac death. Front Cardiovasc Med 2021; 8: 691203
• 14 Yuan F, Qiu XB, Li RG. et al. A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias. Int J Mol Med 2015; 35 (02) 478-486
• 15 Hirono K, Hata Y, Miyao N. et al; LVNC study collaborates*. Increased burden of ion channel gene variants is related to distinct phenotypes in pediatric patients with left ventricular noncompaction. Circ Genom Precis Med 2020; 13 (04) e002940
• 16 Yamada Y, Yasuda K, Hata Y, Nishida N, Hirono K. A novel NKX2-5 variant in a child with left ventricular noncompaction, atrial septal defect, atrioventricular conduction disorder, and syncope. J Clin Med 2022; 11 (11) 3171
• 17 Xu YJ, Qiu XB, Yuan F. et al. Prevalence and spectrum of NKX2.5 mutations in patients with congenital atrial septal defect and atrioventricular block. Mol Med Rep 2017; 15 (04) 2247-2254
• 18 Perera JL, Johnson NM, Judge DP, Crosson JE. Novel and highly lethal NKX2.5 missense mutation in a family with sudden death and ventricular arrhythmia. Pediatr Cardiol 2014; 35 (07) 1206-1212
• 19 Rozqie R, Satwiko MG, Anggrahini DW. et al. NKX2-5 variants screening in patients with atrial septal defect in Indonesia. BMC Med Genomics 2022; 15 (01) 91
• 20 Ross SB, Singer ES, Driscoll E. et al. Genetic architecture of left ventricular noncompaction in adults. Hum Genome Var 2020; 7: 33
• 21 Palomino Doza J, Salguero-Bodes R, de la Parte M, Arribas-Ynsaurriaga F. Association between mutations in the NKX2.5 homeobox, atrial septal defects, ventricular noncompaction and sudden cardiac death. Rev Esp Cardiol (Engl Ed) 2018; 71 (01) 53-55
• 22 Bermúdez-Jiménez FJ, Jiménez-Jáimez J, López-Fernández S. Overlap of arrhythmogenic cardiomyopathy, spongiform cardiomyopathy, and congenital heart disease. Rev Esp Cardiol (Engl Ed) 2017; 70 (01) 51
• 23 el bouchikhi I, Bouguenouch L, Zohra Moufid F. et al. NKX2–5 molecular screening and assessment of variant rate and risk factors of secundum atrial septal defect in a Moroccan population. Anatol J Cardiol 2017; 17 (03) 217-223
• 24 Guntheroth W, Chun L, Patton KK, Matsushita MM, Page RL, Raskind WH. Wenckebach periodicity at rest that normalizes with tachycardia in a family with a NKX2.5 mutation. Am J Cardiol 2012; 110 (11) 1646-1650
• 25 Ouyang P, Saarel E, Bai Y. et al. A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death. Clin Chim Acta 2011; 412 (1-2) 170-175
• 26 Goldmuntz E, Geiger E, Benson DW. NKX2.5 mutations in patients with tetralogy of Fallot. Circulation 2001; 104 (21) 2565-2568