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

Abstract

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?