Interrogating congenital heart defects with noninvasive fetal echocardiography in a mouse forward genetic screen

Xiaoqin Liu, Richard Francis, Andrew J. Kim, Ricardo Ramirez, Guozhen Chen, Ramiah Subramanian, Shane Anderton, Youngsil Kim, Liyin Wong, Judy Morgan, Herbert C. Pratt, Laura Reinholdt, William Devine, Linda Leatherbury, Kimimasa Tobita, Cecilia W. Lo

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)31-42
Number of pages12
JournalCirculation: Cardiovascular Imaging
Issue number1
StatePublished - Jan 2014

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine


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