Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a NovelNKX2-5Mutation and a Review of the Literature

Abstract

ObjectiveAtrial 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.ResultsWe 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.

Mutation of a common amino acid in NKX2.5 results in dilated cardiomyopathy in two large families

“…Mutations in this gene cause a phenotypically broad array of structural cardiac defects and arrhythmias with variable penetrance [13]. The most common of these include septal defects and conduction system disease, supported by a recent review of reported mutations [14–16]. While we observed these phenotypes among families 186 and 187, the index cases presented with dilated cardiomyopathy.…”

2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death

“…Experimental ischemia/reperfusion models demonstrate a cardioprotective effect of statins, and a large observational analysis observed this effect in humans (42,(56)(57)(58). This was explored further in HF in several secondary analyses of patients on statins in ICD prevention trials, including the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy), SCD-HeFT, AVID (Antiarrhythmics versus Implantable Defibrillators) (59), and DEFINITE (DEFibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation) trials that showed less SCD risk among the patients on statins (58,(60)(61)(62). However, this general effect in HF was not confirmed in 2 prospective RCTs of rosuvastatin in HF; the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) and GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure) (63,64).…”

“…The risk of SCD is highest among patients with moderate or severe complexity congenital heart disease, and accounts for approximately 25% of cardiac causes of death (5, 27, 28, 44-46, 55, 56). Patients with septal defects and a positive family history of septal defects, cardiomyopathy, or bundle-branch block/conduction defects may have the gene mutation NKX2.5, which portends an increased risk of early SCD; genetic testing and early consideration of ICD implantation if positive is warranted (57)(58)(59). Patients with repaired complex forms of congenital heart disease have undergone multiple intracardiac surgeries in the first few decades of life with resultant hypertrophy and risk for subendocardial ischemia as well as scar formation contributing to VT/VF.…”

Systems genetics analysis identify calcium signalling defects as novel cause of congenital heart disease

“…DNA samples were obtained from a cohort consisting of 90 individuals in 32 families. Index patients were screened for mutations in the NKX2-5 gene prior to WES [6]. Relatedness of family members was determined using the algorithm implemented in VCFtools.…”