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Letter to the EditorDOI Number : 10.36811/ijgmgt.2019.110002Article Views : 3268Article Downloads : 35

Unproven causal relation between a de novo NKX2.5 insertion and left ventricular noncompaction

Finsterer J1 and Stöllberger C2

1Krankenanstalt Rudolfstiftung, Messerli Institute, Veterinary University of Vienna, Vienna, Austria, Europe
2Second Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria, Europe

*Corresponding author: Josef Finsterer, MD, PhD, Krankenanstalt Rudolfstiftung, Messerli Institute, Veterinary University of Vienna, Postfach 20 1180 Vienna, Austria, Europe, Tel: +43-1-71165-72085; Fax: +43-1-4781711; Email: fifigs1@yahoo.de

Article Information

Aritcle Type: Letter to the Editor

Citation: Finsterer J, Stöllberger C, 2019. Pathogenicity of low heteroplasmic m.3243A>G variants requires confirmation. Int J Genet Med Gene Ther. 1: 04-05.

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright © 2019; Finsterer J

Publication history:

Received date: 17 December, 2018
Accepted date: 07 January, 2019
Published date: 08 January, 2019

Keywords: Mitochondrial disorder; Multisystem; mtDNA; Phenotype; Genotype

Letter to the Editor

In their article, Ouyong et al. reported about a three-generation family, of which three members carried a heterozygous 2bp insertion at c.512 from the translation start point in exon 2 of the NKX2.5 gene [1]. Mutations in the NKX2.5 have been shown to be associated with atrial septal defects (ASDs), congenital heart disease (CHD), and occasionally left-ventricular hypertrabeculation / noncompaction (LVHT) [2-4]. We have the following comments and concerns. Though three family members carried the mutation only one of them (III/2) presented with (LVHT). How do the authors explain this finding particularly with regard to the proposed causal relation between LVHT and the mutation? How to explain the interfamilial heterogeneity? Were family members not carrying the mutation also screened for LVHT? Since LVHT frequently occurs familiarly and since a causal relation between the mutation and LVHT remains unproven, LVHT might have been due to other causes. Since LVHT is frequently associated with neuromuscular disorders (NMDs) [5], it is worthwhile to investigate affected and non-affected family members for clinically manifesting or subclinical NMD. There is no comprehensive clinical description of the presented cases. Were there any indications for an extra-cardiac disease?

LVHT is usually also seen on cardiac MRI [6]. Was LVHT in the index patient also confirmed by cMRI? Was cMRI also carried out in other family members, which is recommended, since LVHT may be missed on echocardiography? As many others, the authors seem to believe that LVHT is exclusively congenital. Though most of the cases are probably congenital, there are reports about single cases in which LVHT developed during life (acquired LVHT) [7]. Acquired LVHT suggests that factors other than the genetic background may contribute to the development of the phenomenon. The authors also state that LVHT is „a cardiac disorder associated with mutations in sarcomer genes. However, LVHT has been reported in association with mutated genes encoding for non-sarcomeric proteins, such as DMD, SCN5A, LMNA, PMP22, respiratory chain complex components, or LAMP2 [8]. Additionally, LVHT is frequently found in chromosomal disorders. In conclusion, the view that upregulation of sarcomeric proteins by mutated NKX2.3 causes LVHT is so far unproven and does not explain why mutations in a number of other genes, not involved in sarcomere organization, are also associated with LVHT. Despite increasing awareness of LVHT, the pathogenic mechanism remains elusive.


  1. Ouyang P, Saarel E, Bai Y, et al. 2011. A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death. Clin Chim Acta. 412: 170-175.[Ref.]
  2. Ellesøe SG, Johansen MM, Bjerre JV, et al. 2016. Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature. Congenit Heart Dis. 11: 283-290.[Ref.]
  3. Ashraf H, Pradhan L, Chang EI, et al. 2014. A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation. Circ Cardiovasc Genet. 7: 423-433.[Ref.]
  4. Palomino Doza J, Salguero-Bodes R, de la Parte M, et al. 2018. Association Between Mutations in the NKX2.5 Homeobox, Atrial Septal Defects, Ventricular Noncompaction and Sudden Cardiac Death. Rev Esp Cardiol (Engl Ed). 71: 53-55.[Ref.]
  5. Finsterer J, Stöllberger C, Fazio G. 2010. Neuromuscular disorders in left ventricular hypertrabeculation / noncompaction. Curr Pharm Des. 16: 2895-2904.[Ref.]
  6. Thuny F, Jacquier A, Jop B, et al. 2010. Assessment of left ventricular non-compaction in adults: side-by-side comparison of cardiac magnetic resonance imaging with echocardiography. Arch Cardiovasc Dis. 103: 150-159.[Ref.]
  7. Finsterer J, Stöllberger C, Schubert B. 2008. Acquired left ventricular noncompaction as a cardiac manifestation of neuromuscular disorders. Scand Cardiovasc J. 42: 25-30.[Ref.]
  8. Finsterer J. 2009. Cardiogenetics, neurogenetics, and pathogenetics of left ventricular hypertrabeculation/noncompaction. Pediatr Cardiol. 30: 659-681.[Ref.]

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