A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death

Abstract

Background Mutations in transcription factor NKX2.5 cause congenital heart disease (CHD). We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death. Our objective is to identify the disease-causing mutation in the CHD family. Methods Direct DNA sequence analysis was used to identify the CHD mutation. The functional effects of the mutation were characterized by a luciferase reporter assay and immunostaining. Results A novel, de novo 2-bp insertion (c.512insGC) was identified in exon 2 of NKX2.5. Mutation c.512insGC co-segregates with CHD in the family, and is not present in 200 controls. Functional studies indicate that the c.512insGC mutation impedes nuclear localization of NKX2.5 and causes a total loss of transactivation activity of NKX2.5. Furthermore, no NKX2.5 mutation was identified in 125 sporadic Chinese CHD patients. Conclusions (1) NKX2.5 mutation c.512insGC is associated with ASDs, syncope and sudden death. It is the second de novo mutation identified in NKX2.5. (2) NKX2.5 mutations are rare in sporadic CHD patients. (3) This study for the first time identifies association between a NKX2.5 mutation and ventricular noncompaction. Our results significantly expand the phenotypic spectrum of NKX2.5 mutations.

Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association

“…500,503 In some families with autosomal dominant LVNC associated with CHD, affected members may have very minor forms of CHD (eg, small ventricular septal defects, atrial septal defects, and patent ductus arteriosus) that may have normalized spontaneously, whereas other family members may have severe forms of CHD (eg, hypoplastic left heart syndrome, Ebstein anomaly). 504 Penetrance may be reduced in some e618 families. Ichida et al 502 reported that 44% of LVNC patients in their study had inherited LVNC, with 70% having autosomal dominant and 30% having X-linked inheritance.…”

Inherited progressive cardiac conduction disorders

“…Since then, numerous mutations in this transcription factor have been reported with various congenital heart defect phenotypes, such as secundum ASD, tetralogy of Fallot, truncus arteriosus, double-outlet right ventricle, L-transposition of great arteries, interrupted aortic arch and hypoplastic left heart syndrome, with or without conduction disorders [52]. More recently, Wenckebach periodicity, ventricular non-compaction and sudden death have been added to the spectrum of clinical manifestations associated with NKX2.5 mutations [53,54], and experimental studies have confirmed that NKX2.5 regulates the proliferation of atrial working and conduction myocardium in coordination with Notch pathway [55 && ].…”

Associations between Two Genetic Variants in NKX2-5 and Risk of Congenital Heart Disease in Chinese Population: A Meta-Analysis

“…After review of the titles and abstracts, 10 articles were excluded. Seven publications were further excluded after review of the full texts because of the following reasons: the cases in the study by Ouyang et al suffered from coronary artery disease (CAD) and rheumatic heart disease (RHD) [38]; two studies carried out in non-Chinese populations, plus one of which extracted DNA from formalin fixed tissue samples [26], [39]; no complete allele data obtained in other four studies [18], [40], [41], [42]. Finally, 7 studies containing 1243 cases and 1139 controls were relevant to 63A>G and 4 studies containing 748 cases and 630 controls were relevant to 606G>C. Of these studies, 3 studies just explored a single type of CHD [28], [29], [33], whereas multiple types of CHD were involved in the other studies [27], [30], [31], [32].…”

“…Synonymous variants are gradually acknowledged to alter protein expression, conformation and function through mechanisms of affecting splicing accuracy, translation fidelity, mRNA structure and protein folding [49]. It has reported that the 63A>G variant weakened the transactivation activity of NKX2.5 by approximately 20% [38]. Furthermore, the RESCUE ESE, a program for validation of exonic splicing enhancers, demonstrated that 63A>G could repeal an exonic splice site starting 4 base pairs upstream of the variant [50], exerting an influence on translational kinetics.…”