Atrial Septal Defect 7 With Or Without Atrioventricular Conduction Defects

A number sign (#) is used with this entry because of evidence that atrial septal defect of the secundum type, with or without atrioventricular conduction defects, is caused by heterozygous mutation in the NKX2-5 gene (600584) on chromosome 5q35.

For a discussion of genetic heterogeneity of atrial septal defect, see ASD1 (108800).

Clinical Features

Amarasingham and Fleming (1967) and Kahler et al. (1966) reported a total of 3 families with this combination. Because of the rarity of conduction defects with atrial septal defects of the secundum type, this may be a specific mendelizing form of atrial septal defect. Bizarro et al. (1970) referred to the form of atrial septal defect as fossa ovalis type (a synonym for secundum type). They demonstrated male-to-male transmission. The family of Weil and Allenstein (1961) probably represented an example of this syndrome. The occurrence of other forms of congenital heart disease in this syndrome was suggested by the family reported by Pease et al. (1976). Bosi et al. (1992) suggested that a prolonged PR interval can be the only manifestation of the gene in this condition. The finding of a prolonged PR interval in healthy first-degree relatives of patients with ASD secundum can be useful in genetic counseling.

Schott et al. (1998) studied 4 multigenerational families segregating autosomal dominant ASD with atrioventricular conduction defect, one of which (family MXP) was originally reported by Pease et al. (1976) and later restudied by Basson et al. (1995). Of 33 affected individuals, 27 had secundum ASDs; all underwent surgical repair except for 1 individual whose defect spontaneously closed. Other structural heart defects were identified in 8 affected individuals; these included ventricular septal defect (see VSD3; 614432), tetralogy of Fallot (TOF; see 187500), subvalvular aortic stenosis, left ventricular hypertrophy, pulmonary atresia, and redundant mitral valve leaflets with fenestrations. Electrocardiograms demonstrated atrioventricular conduction defects in all individuals with congenital heart defects and in 1 individual with normal cardiac structures. Invasive electrophysiologic studies performed in 3 individuals localized the prolonged conduction to the atrioventricular node; electrophysiologic properties of other conduction system components were normal. Pacemakers had been implanted in 14 affected individuals.

Mapping

In a large 5-generation family segregating autosomal dominant ASD with atrioventricular conduction defects (family MXP), originally reported by Pease et al. (1976), Schott et al. (1998) performed genomewide linkage analysis and obtained a lod score of 3.91 (theta = 0) at locus D5S1456. A common disease haplotype was identified in family MXP and another 5-generation family with ASD and AV conduction defects (family MBF), suggesting that there was a founding mutation in a distant unknown ancestor of both kindreds. Analyses of flanking loci on chromosome 5q35 indicated that no recombination events had occurred in either family MBX or MBF at loci within 12 cM of D5S1456 or D5S211.

Molecular Genetics

In 4 multigenerational families with autosomal dominant atrial septal defect and atrioventricular conduction defects, one of which was originally reported by Pease et al. (1976), Schott et al. (1998) analyzed the candidate gene NKX2-5 and identified 3 different heterozygous mutations that segregated with disease in the 4 families (600584.0001-600584.0003, respectively).

McElhinney et al. (2003) analyzed the NKX2-5 gene in 474 patients with congenital heart defects and identified heterozygous mutations in 3 (4%) of 71 patients with secundum ASD, 2 of whom had no atrioventricular conduction defects (600584.0018 and 600584.0019, respectively).

In a male patient with ASD secundum and AV block that progressed to Wenckebach-type second-degree heart block, Hirayama-Yamada et al. (2005) identified a T178M mutation in the NKX2E gene (600584.0001). The patient later developed sick sinus syndrome and required permanent pacemaker implantation. His mother had the same mutation and ASD with atrial fibrillation; her elder sister had ASD secundum with AV block and sick sinus syndrome requiring permanent pacemaker implantation, and a nephew had ASD with AV block. The patient's 2 sibs had arrhythmias but no cardiac malformations.

In 2 multiplex families with ASD and atrioventricular conduction defects, Watanabe et al. (2002) identified frameshift mutations in the NKX2E gene. In 1 family (see 600584.0009), surgical closure of the atrial septal defect had been performed in 4 of the genotype-positive members, in 3 of whom sinus venosus ASD had been identified. In addition, 1 of these 4 had a double orifice mitral valve and underwent mitral valve replacement at the time of ASD surgery. ECG evidence of AV block was confirmed in 4 patients; in 2 patients, this manifested as Mobitz type I second-degree block and was associated with atrial fibrillation. In 1 patient, atrial fibrillation was first noted 28 years after ASD surgery, and in another patient atrial fibrillation, first noted at age 46 years, was the sole manifestation of cardiac disease. Additionally, 1 member of the family heterozygous for the mutation was found to have polysplenia and a midline, symmetric liver by CT scan; malrotation was diagnosed by a barium x-ray study that showed the ascending colon and cecum were shifted to the midline and forward with the small intestine on the left. In 3 members of the other family (see 600584.0010), surgical closure of a secundum ASD had been performed; all 3 had ECG evidence of first- or second-degree AV block. In 1 member of the family, first-degree AV block was the only manifestation of heart disease.

Hirayama-Yamada et al. (2005) reported that 4 sibs from a family with ASD and AV conduction defects had the same deletion mutation (600584.0012) in the NKX2E gene. The proband was diagnosed with ASD secundum and first-degree AV block that progressed to second-degree block; in 2 of her sibs, AV block also progressed to second degree, although 1 of those sibs had no cardiac malformation. Their father had heart disease of unknown type. In a female patient with a combination secundum- and cribriform-type ASD at age 7 who later developed AV block that ultimately required pacemaker implantation, Hirayama-Yamada et al. (2005) identified a missense mutation in the NKX2E gene (600584.0013). The patient's deceased paternal grandmother died of an unknown type of heart disease and a cousin had an ASD; her father died of subarachnoid hemorrhage at age 63.

Gutierrez-Roelens et al. (2006) screened the NKX2E gene in 4 sporadic patients and 3 index cases of families with ASD and/or conduction defects and identified a nonsense mutation (600584.0014) in affected members of a 3-generation family; no mutations were found in the other 2 probands or 4 sporadic patients. One apparent asymptomatic carrier was found to have first-degree AV block on Holter monitoring. The conduction defect in this family was at the AV node, manifesting as first-degree block and evolving toward second-degree block; 3 patients also had atrial fibrillation, and 1 had unexplained ventricular tachycardia seen on Holter monitoring. Gutierrez-Roelens et al. (2006) suggested that atrial fibrillation and syncope may be part of the phenotype.