Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature

Abstract

Objective: Atrial septal defect (ASD) is the second most common congenital heart defect (CHD) and is observed in families as an autosomal dominant trait as well as in nonfamilial CHD. Mutations in the NKX2-5 gene, located on chromosome 5, are associated with ASD, often combined with conduction disturbances, cardiomyopathies, complex CHD, and sudden cardiac death as well. Here, we show that NKX2-5 mutations primarily occur in ASD patients with conduction disturbances and heritable ASD. Furthermore, these families are at increased risk of sudden cardiac death.

Results: We screened 39 probands with familial CHD for mutations in NKX2-5 and discovered a novel mutation in one family (2.5%) with ASD and atrioventricular block. A review of the literature revealed 59 different NKX2-5 mutations in 202 patients. Mutations were significantly more common in familial cases compared to nonfamilial cases (P = 7.1 × 10(-9) ). The majority of patients (74%) had ASD with conduction disturbance. Nineteen patients (15%) of 120 with familial ASD and conduction disturbance died from sudden cardiac death of which nine (8%) were confirmed mutation carriers, and 10 were possible carriers.

Conclusions: NKX2-5 mutations mainly occur in familial CHD, the signature phenotype is ASD with conduction disturbances and mutation carriers are at increased risk of sudden cardiac death. We suggest that familial ASD patients should be screened for NKX2-5 mutations and, if they are mutation carriers, implantation of an implantable cardioverter-defibrillator should be considered in these patients.

Keywords: Congenital Atrioventricular Block; Congenital Heart Disease; Familial ASD; NKX2-5; Sudden Cardiac Death.

Figure 1

(A) Pedigree of Danish family with six affected individuals. I:2 (37 years old) had surgical closure of a secundum atrial septal defect (ASD2). ECG showed 1. degree atrioventricular block. II:2 (6 years old) had surgical closure of an ASD2. Twenty‐year‐old male had two episodes of dyspnea, retrosternal pain, and vertigo. ECG showed junctional rhythm with a heart rate of 49 beats per minute (bpm). ASD. II:3 (5 years old) had surgical closure of an ASD2. II:5 (6 years old) had surgical closure of an ASD2 with intermittent 1. and 2. Degree atrioventricular block, Wenckeback type, postoperatively. III:1 (8 months old) had complex CHD [double outlet right ventricle, fallot type (DORV‐TOF), coarctation of aorta (CoA), persistent left superior vena cava (PLSVC), and ASD]. She died from respiratory failure. III:2 had an insignificant muscular ventricular septal defect (VSD) and a small ASD2 at birth. III:4 was a healthy carrier of the mutation, but an echocardiogram had never been done by wish of the parents. (+/−) Indicates presence/absence of mutation, respectively. AVB, atrioventricular block. (B) Section of the nucleotide sequence of NKX2‐5 gene located on chromosome 5 (5q34). Top, normal individual. Bottom, affected individual. The deletion of a single nucleotide at position 112 causes a frameshift, resulting in a truncated protein and a premature stop codon.

Figure 2

The majority of patients with a confirmed mutation in NKX2‐5 has ASD with CD/A. ASD, atrial septal defect; TOF, tetralogy of Fallot; VSD, ventricular septal defect; HLHS, hypoplastic left heart syndrome; CM, cardiomyopathy (left ventricular noncompaction, dilated cardiomyopathy, left ventricle hypertrophy); SCD, sudden cardiac death (sudden death in otherwise healthy individual before age 50); Other: Interrupted aortic arch = 1; truncus arteriosus = 1; levo‐transposition of the great arteries = 1; coarctation of aorta = 2; double outlet right ventricle = 1; tricuspid valve anomaly (atresia, Ebstein) = 4; anomalous pulmonary venous return = 1; heterotaxy = 1.