Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease. A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located. Three different NKX2-5 mutations were identified. Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding. These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life.

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BACKGROUND Aortic dissection (AoD) is a serious complication of thoracic aortic aneurysm (TAA). Relative risk for AoD in relation to TAA etiology, incidence, and pattern after prophylactic TAA surgery are poorly understood. OBJECTIVES This study sought to determine the incidence, pattern, and relative risk for AoD among patients with genetically associated TAA. METHODS The population included adult GenTAC participants without AoD at baseline. Standardized core laboratory tests classified TAA etiology and measured aortic size. Follow-up was performed for AoD. RESULTS Bicuspid aortic valve (BAV) (39%) and Marfan syndrome (MFS) (22%) were the leading diagnoses in the studied GenTAC participants (n = 1,991). AoD occurred in 1.6% over 3.6 ± 2.0 years; 61% of AoD occurred in patients with MFS. Cumulative AoD incidence was 6-fold higher among patients with MFS (4.5%) versus others (0.7%; p < 0.001). MFS event rates were similarly elevated versus those in patients with BAV (0.3%; p < 0.001). AoD originated in the distal arch or descending aorta in 71%; 52% of affected patients, including 68% with MFS, had previously undergone aortic grafting. In patients with proximal aortic surgery, distal aortic size (descending thoracic, abdominal aorta) was larger among patients with AoD versus those without AoD (both p < 0.05), whereas the ascending aorta size was similar. Conversely, in patients without previous surgery, aortic root size was greater in patients with subsequent AoD (p < 0.05), whereas distal aortic segments were of similar size. MFS (odds ratio: 7.42; 95% confidence interval: 3.43 to 16.82; p < 0.001) and maximal aortic size (1.86 per cm; 95% confidence interval: 1.26 to 2.67; p = 0.001) were independently associated with AoD. Only 4 of 31 (13%) patients with AoD had pre-dissection images that fulfilled size criteria for prophylactic TAA surgery at a subsequent AoD site. CONCLUSIONS Among patients with genetically associated TAA, MFS augments risk for AoD even after TAA grafting. Although increased aortic size is a risk factor for subsequent AoD, events typically occur below established thresholds for prophylactic TAA repair.

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Background The associations of age and sex with phenotypic features of Marfan syndrome have not been systematically examined in a large cohort of both children and adults. Methods and Results We evaluated 789 Marfan patients enrolled in the NHLBI GenTAC Registry (53% male; mean age 31 [range: 1–86 years]). Females aged≥15 and males aged≥16 years were considered adults based on average age of skeletal maturity. Adults (n=606) were more likely than children (n=183) likely to have spontaneous pneumothorax, scoliosis, and striae, but were comparable in revised Ghent systemic score, ectopia lentis, and most phenotypic features, including prevalence of aortic root dilatation. Prophylactic aortic root replacement and mitral valve surgery were rare during childhood vs. adulthood (2 vs. 35% and 1 vs. 9%, respectively, both p<0.0001). Adult males were more likely than females to have aortic root dilatation (92 vs. 84%), aortic regurgitation (55 vs. 36%) and to have undergone prophylactic aortic root replacement (47 vs. 24%), all p<0.001. Prevalence of prior aortic dissection tended to be higher in males than females (25 vs. 18%, p=0.06); 44% of dissections were type B. Type B dissection was strongly associated with previous prophylactic aortic root replacement. Conclusions Pulmonary, skeletal and aortic complications, but not other phenotypic features, are more prevalent in adults than children in Marfan syndrome. Aortic aneurysms and prophylactic aortic surgery are more common in men. Aortic dissection, commonly type B, occurs in an appreciable proportion of Marfan patients, especially in men and following previous prophylactic aortic root replacement.

Background Heterozygous human NKX2-5 homeodomain (DNA binding domain) missense mutations are highly penetrant for varied congenital heart defects, including progressive atrioventricular block (AVB) requiring pacemaker implantation. We recently replicated this genetic defect in a murine knock-in model, in which we demonstrated highly penetrant, pleiotropic cardiac anomalies. In this study, we examined postnatal AV conduction in the knock-in mice. Methods and Results A murine knock-in model (Arg52Gly, Nkx2-5+/R52G) in a 129/Sv background was analyzed by histopathology, surface and telemetry ECG, and in vivo electrophysiology studies (EPS), comparing with control Nkx2-5+/+ mice at diverse postnatal stages, ranging from postnatal day 1 (P1) to 17 months. PR-prolongation (1st degree AVB) was present at 4 weeks, 7 months, and 17 months of age but not at P1 in the mutant mice. Advanced AVB was also occasionally demonstrated in the mutant mice. EPS showed that AV nodal function, and right ventricular effective refractory period, were impaired in the mutant mice, while sinus nodal function was not affected. AV nodal size was significantly smaller in the mutant mice compared to their controls at 4 weeks of age, corresponding to the presence of PR-prolongation, but not P1, suggesting, at least in part, that the conduction abnormalities are the result of a morphologically atrophic AV node. Conclusions The highly penetrant and progressive AVB phenotype seen in human heterozygous missense mutations in NKX2-5 homeodomain was replicated in mice by knocking-in a comparable missense mutation.

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