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1 Laboratory of Developmental Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
2 Laboratory of Developmental Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA; Pediatric Cardiology, Children's National Medical Center, Washington, D.C., USA
3 Department of Anatomy and Cell Biology, Medical University of South Carolina, Charleston, SC, USA
4 The Jackson Laboratory, Bar Harbor, Maine, USA
* To whom correspondence should be addressed. E-mail: loc{at}nhlbi.nih.gov.
As part of a large scale noninvasive fetal ultrasound screen to recover ENU (ethylnitrosourea) induced mutations causing congenital heart defects in mice, we established a high throughput ultrasound scanning strategy for interrogating fetal mice in utero utilizing three orthogonal imaging planes defined by the fetus vertebral column and body axes, structures readily seen by ultrasound. This contrasts with the difficulty of acquiring clinical ultrasound imaging planes which are defined by the fetal heart. Using the three orthogonal imaging planes for 2D imaging together with color flow, spectral Doppler and M-mode imaging, all of the major elements of the heart can be evaluated. In this manner, 10,091 ENU mutagenized mouse fetuses were ultrasound scanned between embryonic day 12.5 to 19.5, with 324 fetuses found to die prenatally, and 425 exhibited cardiovascular defects. Further analysis by necropsy and histology showed heart defects that included conotruncal anomalies, obstructive lesions, shunt lesions, as well as other complex heart diseases. Ultrasound imaging also identified craniofacial/head defects, and body wall closure defects, which necropsy revealed as encephalocele, holoprosencephaly, omphalocele or gastroschisis. Genome scanning mapped one ENU induced mutation associated with persistence truncus arteriosus and holoprosencephaly to mouse chromosome 2, while another mutation associated with cardiac defects and omphalocele was mapped to mouse chromosome 17. These studies show the efficacy of this novel ultrasound scanning strategy for noninvasive ultrasound phenotyping to facilitate the recovery of ENU induced mutations causing congenital heart defects and other extracardiac anomalies.
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