8:00 AM - 9:00 AM
Pediatric Grand Rounds (CME) : Insights into the Genetic Landscape of Congenital Heart Disease from Mouse Forward Genetics
Cecilia Lo, PhD - University of Pittsburgh
A systems genetics approach with large scale mouse forward genetics was used to investigate the genetic landscape of congenital heart disease (CHD). From screening 100,000 mice, over 300 mutant mouse lines with a wide spectrum of CHD were recovered, including the first mouse models of hypoplastic left heart syndrome (HLHS).
A systems genetics approach with large scale mouse forward genetics was used to investigate the genetic landscape of congenital heart disease (CHD). Mice were chemically mutagenized, then bred and screened for CHD. Cardiovascular phenotyping was conducted with noninvasive fetal echocardiography and offspring with CHD were further analyzed by exome sequencing analysis to recover the CHD causing mutations. From screening 100,000 mice, over 300 mutant mouse lines with a wide spectrum of CHD were recovered, including the first mouse models of hypoplastic left heart syndrome (HLHS). Whole exome sequencing analysis of 200 mutant lines yielded 153 pathogenic CHD causing mutations. Statistical modeling suggests the screen is at 30% saturation, with an estimate of 270 genes contributing to a Mendelian model of CHD. Interestingly while most CHD lesions can be modeled by Mendelian genetics, HLHS appears to be mediated by more complex genetics. More recent studies with a new screen focused on dominant mutations show an important role for suppressor mutations in determining the penetrance of CHD phenotypes, findings that more closely model the often variable penetrance and sporadic nature of CHD. Together these studies yield new insights into the genetic landscape of CHD.
Education goals for this session:
- Experimental design of a mouse forward genetic screen
- Mouse fetal ultrasound diagnosis of congenital heart defects
- Biological processes and pathways that contribute to the pathogenesis of congenital heart defects
- The genetic architecture of congenital heart disease
Cecilia Lo, PhD
Professor and Chair
F. Sargent Cheever Chair
Department of Developmental Biology,
University of Pittsburgh
The Stanford University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
The Stanford University School of Medicine designates this live activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Cultural and Linguistic Competency
California Assembly Bill 1195 requires continuing medical education activities with patient care components to include curriculum in the subjects of cultural and linguistic competency. The planners and speakers of this CME activity have been encouraged to address cultural issues relevant to their topic area. The Stanford University School of Medicine Multicultural Health Portal also contains many useful cultural and linguistic competency tools including culture guides, language access information and pertinent state and federal laws. You are encouraged to visit the portal: http://lane.stanford.edu/portals/cultural.html