title: Interrogating congenital heart defects with noninvasive fetal echocardiography in a mouse forward genetic screen.
abstract: 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.
  
  
  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.
authors: Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA.
authors: Xiaoqin
authors: X
authors: Liu
authors: Richard
authors: R
authors: Francis
authors: Andrew J
authors: AJ
authors: Kim
authors: Ricardo
authors: R
authors: Ramirez
authors: Guozhen
authors: G
authors: Chen
authors: Ramiah
authors: R
authors: Subramanian
authors: Shane
authors: S
authors: Anderton
authors: Youngsil
authors: Y
authors: Kim
authors: Liyin
authors: L
authors: Wong
authors: Judy
authors: J
authors: Morgan
authors: Herbert C
authors: HC
authors: Pratt
authors: Laura
authors: L
authors: Reinholdt
authors: William
authors: W
authors: Devine
authors: Linda
authors: L
authors: Leatherbury
authors: Kimimasa
authors: K
authors: Tobita
authors: Cecilia W
authors: CW
authors: Lo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D018618:Echocardiography, Doppler, Color; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D005318:Fetal Heart / Q000002:abnormalities / Q000000981:diagnostic imaging*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging* / Q000196:embryology / Q000235:genetics*; D040941:Heredity; D057166:High-Throughput Screening Assays; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D033401:Microscopy, Acoustic; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016216:Ultrasonography, Prenatal / Q000379:methods*
chemical_list: D005038:Ethylnitrosourea
keywords: heart defects, congenital; microscopy, acoustic