1. Genetics and Biomarkers in Congenital Heart Disease SSA Conference, November 9, 2010 Allen D. Everett, MD Associate Professor, Pediatric Cardiology Helen B. Taussig Children’s Congenital Heart Center

2. Translating Congenital Heart Disease for the Non-Cardiologist This is a difficult task but I hope to better than this translation:

3. Genetics of Congenital Heart Disease

4. Syndromic-Congenital heart disease associated with other defects such as brain, liver, etc. Uncommon, and tend to be single gene defects –Noonan’s (CHD, hematologic, neurologic) PTPN11 –Alagille’s (CHD, liver disease) JAG1 –Holt-Oram (CHD, skeletal defects) TBX5

5. Genetics of Congenital Heart Disease Non-syndromic-Congenital heart disease alone. Sporadic and common. –Incidence of gene mutations is low. In Hypoplastic left heart syndrome, the incidence of mutations in NKX2.5, NOTCH1, HAND1 and GJA1 is 2%. Therefore occurrence is related to multifactoral inheritance of a multitude of susceptibility genes (unknown) with low penetrance mutations (being discovered) superimposed on unfavorable environmental conditions (unknown). June 20, 20155

6. Chromosomal deletions –22q11: Tetralogy of Fallot, Interrupted aortic arch and Tricuspid atresia. –Other less common are 9q34, 1q21.1, 16p11.2 and 17p11.2. –The use of genomic array technologies for routine genetic screening is identifying an increasing number of chromosome microdeletions in children with CHD. June 20, 20156 Genetics of Congenital Heart Disease

7. June 20, 20157 Genetics of Congenital Heart Disease MW Wessels and PJ Willems. Clin. Genetics, 2010 78:103

8. Biomarkers in Congenital Heart Disease Biomarker (HUPO): Used to indicate or measure a biological process (for instance, levels of a specific protein in blood or spinal fluid, genetic mutations, or brain abnormalities observed in a PET scan or other imaging test). Detecting biomarkers specific to a disease can aid in the identification, diagnosis, and treatment of affected individuals and people who may be at risk but do not yet exhibit symptoms. June 20, 20158

9. Biomarkers in Congenital Heart Disease Classic example is measurement of specific heart muscle proteins (troponin I) released into the circulation after a myocardial infarction. The heart also secretes hormones into the circulation when the workload of the heart is excessive. –Brain naturetic peptide (BNP) June 20, 20159

10. Biomarkers in Congenital Heart Disease BNP –Shown to be a significant diagnostic measure of heart failure in adults –In patients with pulmonary hypertension, a significant predictor of sudden death –In children with CHD a potential indicator of poor heart function and recovery after heart surgery –In the non-surgical setting the levels are so high in children with CHD that they have little value. –May be useful in detecting transplant rejection. June 20, 201510

11. Biomarkers in Congenital Heart Disease Brain Injury Biomarkers –36-60% of neonates having surgery for CHD will have evidence of new brain injury on MRI –Peri-operative brain injury is the most significant morbidity of CHD repair. The average Psychomotor Development Index score after CHD repair is 85, with normal 100. –Identification of circulating brain specific proteins released with injury (similar to what happens with a myocardial infarction) will help improve and standardize perioperative care to reduce brain injury. June 20, 201511

12. Translating Congenital Heart Disease for the Non-Cardiologist I hope my translation came out better than this: