Interrogating congenital heart defects with noninvasive fetal echocardiography in a mouse forward genetic screen
| Autor: | Youngsil Kim, Xiaoqin Liu, Li-yin Wong, Herbert C. Pratt, Ramiah Subramanian, Shane Anderton, Guozhen Chen, Laura G. Reinholdt, Cecilia W. Lo, William A. Devine, Judy Morgan, Ricardo Ramirez, Linda Leatherbury, Richard Francis, Kimimasa Tobita, Andrew J. Kim |
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| Rok vydání: | 2013 |
| Předmět: |
Heart Defects
Congenital Male Pathology medicine.medical_specialty Heredity Heart disease Ultrasound biomicroscopy Microscopy Acoustic Doppler echocardiography Ultrasonography Prenatal Article Hypoplastic left heart syndrome Pathogenesis Mice Fetal Heart medicine Animals Radiology Nuclear Medicine and imaging Genetic Predisposition to Disease Genetic Testing Genetic testing medicine.diagnostic_test business.industry Ultrasound medicine.disease Echocardiography Doppler Echocardiography Doppler Color High-Throughput Screening Assays Pedigree Mice Inbred C57BL Disease Models Animal Phenotype Ethylnitrosourea Mutation Female Cardiology and Cardiovascular Medicine business Fetal echocardiography |
| Zdroj: | Circulation. Cardiovascular imaging. 7(1) |
| ISSN: | 1942-0080 |
| Popis: | Background— Congenital heart disease (CHD) has a multifactorial pathogenesis, but a genetic contribution is indicated by heritability studies. To investigate the spectrum of CHD with a genetic pathogenesis, we conducted a forward genetic screen in inbred mice using fetal echocardiography to recover mutants with CHD. Mice are ideally suited for these studies given that they have the same four-chamber cardiac anatomy that is the substrate for CHD. Methods and Results— Ethylnitrosourea mutagenized mice were ultrasound-interrogated by fetal echocardiography using a clinical ultrasound system, and fetuses suspected to have cardiac abnormalities were further interrogated with an ultrahigh-frequency ultrasound biomicroscopy. Scanning of 46 270 fetuses revealed 1722 with cardiac anomalies, with 27.9% dying prenatally. Most of the structural heart defects can be diagnosed using ultrasound biomicroscopy but not with the clinical ultrasound system. Confirmation with analysis by necropsy and histopathology showed excellent diagnostic capability of ultrasound biomicroscopy for most CHDs. Ventricular septal defect was the most common CHD observed, whereas outflow tract and atrioventricular septal defects were the most prevalent complex CHD. Cardiac/visceral organ situs defects were observed at surprisingly high incidence. The rarest CHD found was hypoplastic left heart syndrome, a phenotype never seen in mice previously. Conclusions— We developed a high-throughput, 2-tier ultrasound phenotyping strategy for efficient recovery of even rare CHD phenotypes, including the first mouse models of hypoplastic left heart syndrome. Our findings support a genetic pathogenesis for a wide spectrum of CHDs and suggest that the disruption of left–right patterning may play an important role in CHD. |
| Databáze: | OpenAIRE |
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