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

Liu, Xiaoqin, Francis, Richard, Kim, Andrew J., Ramirez, Ricardo, Chen, Guozhen, Subramanian, Ramiah, Anderton, Shane, Kim, Youngsil, Wong, Liyin, Morgan, Judy, Pratt, Herbert C., Reinholdt, Laura, Devine, William, Leatherbury, Linda, Tobita, Kimimasa, and Lo, Cecilia W. (2014) Interrogating congenital heart defects with noninvasive fetal echocardiography in a mouse forward genetic screen. Circulation: Cardiovascular Imaging, 7 (1). pp. 31-42.

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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.

Item ID: 60710
Item Type: Article (Research - C1)
ISSN: 1941-9651
Keywords: heart defects, congenital, microscopy, acoustic
Copyright Information: © 2013 American Heart Association, Inc.
Funders: National Institutes of Health (NIH)
Projects and Grants: NIH UO1HL098180
Date Deposited: 23 Oct 2019 12:36
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 30%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 40%
08 INFORMATION AND COMPUTING SCIENCES > 0801 Artificial Intelligence and Image Processing > 080109 Pattern Recognition and Data Mining @ 30%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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