Recurrent 2q13 deletion syndrome is associated with incompletely penetrant severe cardiac defects and craniofacial anomalies. We used an atypical, overlapping 1.34 Mb 2q13 deletion in a patient with pathogenically similar congenital heart defects (CHD) to narrow the putative critical region for CHD to 474 kb containing six genes. To determine which of these genes is responsible for severe cardiac and craniofacial defects noted in the patients with the deletions, we used zebrafish morpholino knockdown to test the function of each orthologue during zebrafish development. Morpholino-antisense-mediated depletion of fibulin-7B, a zebrafish orthologue of fibulin-7 (FBLN7), resulted in cardiac hypoplasia, deficient craniofacial cartilage deposition and impaired branchial arch development. TMEM87B depletion likewise resulted in cardiac hypoplasia but with preserved branchial arch development. Depletion of both fibulin-7B and TMEM87B resulted in more severe defects of cardiac development, suggesting that their concurrent loss may enhance the risk of a severe cardiac defect. We postulate that heterozygous loss of FBLN7 and TMEM87B account for some of the clinical features, including cardiac defects and craniofacial abnormalities associated with 2q13 deletion syndrome.
The pattern of chromosomal imbalances in patients with congenital cardiac defects suggests that many loci may be involved in normal heart development, some with very strong and direct effects and others with less direct effects. Chromosomal duplication/deletion mapping will provide an important roadmap for genome-wide sequencing and genetic mapping strategies to identify novel genes critical for heart development.
ObjectiveThe objective was to evaluate and improve accuracy of anticipatory counseling regarding neonatal intervention for prenatally diagnosed tetralogy of Fallot (TOF) by assessing new and previously published predictors of neonatal intervention.MethodsThis is a multi‐center, retrospective study from three centers of 112 fetal TOF patients undergoing third trimester fetal echocardiograms from 2004 to 2017. Additional cardiac defects requiring neonatal intervention were excluded. Fetal echocardiographic, clinical, and consultation data were compared between neonatal and late intervention. Optimal echocardiographic values were determined.ResultsTwenty‐six infants (23%) required neonatal intervention. Those infants had significantly different pulmonary valve (PV) z‐scores, PV:aortic valve (AoV) ratios, PV:AoV z‐score differences (absolute difference between z‐scores), and increased likelihood of abnormal ductal flow. Counseling during fetal echocardiogram regarding interventional timing was accurate for 50% needing neonatal intervention and 86% undergoing late intervention (P = .002). The best neonatal intervention predictors were PV:AoV ratio of <0.6 and counseling for neonatal intervention. PV:AoV z‐score difference ≥5 provided 89% negative predictive value for excluding patients from neonatal repair.ConclusionsThird trimester fetal echocardiograms can predict interventional timing. The best predictors of neonatal intervention are PV:AoV ratio <0.6, PV:AoV z‐score difference ≥5, and cardiologist counseling that neonatal intervention was likely.
In patients with repaired tetralogy of Fallot (rTOF), left-ventricular ejection fraction (LVEF) predicts adverse outcomes. Two-dimensional echocardiographic (2DE) methods of measuring LVEF require geometric assumptions and may be limited in this population due to altered ventricular geometry. This study evaluated the performance of the 5/6 area × length (AL) method in this population as well as which factors limit agreement with the results of cardiovascular magnetic resonance (CMR). In 20 patients with rTOF (28.5 ± 14.7 years old) and CMR and 2DE within 3 months, two investigators blinded to CMR measured LVEF from 2DE by the AL method, biplane Simpson's (BiS) method, and visual estimate. Two investigators blinded to 2DE measured LVEF from CMR by Simpson's and AL methods. The AL method on 2DE more closely approximated LVEF by CMR (r = 0.73, p = 0.0003) than BiS method (r = 0.53, p = 0.02). AL method was not limited by geometric assumptions, as AL method on CMR closely approximated Simpson's method on CMR (r = 0.90, p < 0.0001) despite median left-ventricular diastolic eccentricity index of 1.24. AL method on 2DE was primarily limited by short-axis area measurement rather than foreshortening of the ventricle. In conclusion, in adults with rTOF, AL method on 2DE moderately approximates LVEF by CMR, even in the context of altered left-ventricular geometry. Although the AL method may be the most appropriate 2DE method in this population, significant limitations remain for LVEF assessment by 2DE, and strategies to optimize image position and border detection are essential.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.