Case Report: A Novel NKX2-5 Mutation in a Family With Congenital Heart Defects, Left Ventricular Non-compaction, Conduction Disease, and Sudden Cardiac Death

Abstract

The NKX2-5 gene encodes for a transcription factor crucial for cardiac cell differentiation and proliferation. It was the first gene associated with congenital heart disease (CHD) in humans and has been linked to conduction disorders or cardiomyopathies. However, an overlapping phenotype is not frequent in the literature. We describe a family with a novel missense mutation in the NKX2-5 gene (p.Gln181Pro) with numerous antecedents with atrial septal defect (ASD), left ventricular non-compaction (LVNC), conduction disease, and sudden cardiac death (SCD).

NKX2-5 genetic mutation in a young woman with an atrial septal defect presenting with complete heart block: ICD or bradycardia pacemaker?

“…The NKX2-5 gene, located on chromosome 5, plays an important role in cardiac development and maintenance of the normal function of the AV node and myocardium throughout adult life 3–5. Previous literature has suggested that a large proportion of NKX2-5 mutations originate from Europe (24.1%) 6…”

“…NKX2-5 mutations have also been reported in patients with dilated cardiomyopathy and left ventricular non-compaction (LVNC) 3 10 11. Yamada et al 11 identified a novel heterozygous NKX2-5 variant (NM_004387.1: c.255_256delCT, p.Phe86fs) in a girl in early adolescence with previous ASD repair, who presented with exertional syncope and was found to have AV block and LVNC on echocardiography.…”

“…Yamada et al 11 identified a novel heterozygous NKX2-5 variant (NM_004387.1: c.255_256delCT, p.Phe86fs) in a girl in early adolescence with previous ASD repair, who presented with exertional syncope and was found to have AV block and LVNC on echocardiography. Morlanes-Gracia et al described a family with a novel missense mutation (p.Gln181Pro) who suffered from AV block, LVNC, paroxysmal AF and non-sustained VT 3. A family member who had non-sustained VT detected on their implanted PPM subsequently had their device upgraded to an ICD.…”

“…The signature phenotype in NKX2-5 mutations is a triad of atrial septal defect (ASD) with AV conduction disturbance and an increased risk of sudden cardiac death (SCD) 2 3. A high index of suspicion of NKX2-5 mutation is imperative in individuals with familial CHD and complete AV block, and genetic testing and prompt family screening are recommended.…”

A young boy with ventricular arrhythmias and thyroid dysgenesis: two genes are not enough?

“…Several inactivating mutations in the NKX2-5 gene, primarily located within the homeodomain, have been described in patients with a spectrum of congenital heart diseases (CHD), the most frequent ones being atrial or ventricular septal defects and tetralogy of Fallot (2). In addition, NKX2-5 pathogenic variants have been reported in adult patients with heart conduction defects such as atrial fibrillation (3) and, more recently, with sudden cardiac death from ventricular arrhythmia (4)(5)(6).…”