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Project 3: Genotype and Clinical Outcome in Conotruncal Defects

Project 3: Genotype and Clinical Outcome in Conotruncal Defects. Elizabeth Goldmuntz. Facial dysmorphia Aplastic/hypoplastic thymus Aplastic/hypoplastic parathyroid Conotruncal cardiac defects Interrupted aortic arch (IAA) Truncus arteriosus (TA) Tetralogy of Fallot (TOF).

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Project 3: Genotype and Clinical Outcome in Conotruncal Defects

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  1. Project 3: Genotype and Clinical Outcome in Conotruncal Defects Elizabeth Goldmuntz

  2. Facial dysmorphia Aplastic/hypoplastic thymus Aplastic/hypoplastic parathyroid Conotruncal cardiac defects Interrupted aortic arch (IAA) Truncus arteriosus (TA) Tetralogy of Fallot (TOF) DiGeorge Syndrome

  3. Chromosome 22:The Commonly Deleted Region

  4. Cleft palate Learning disorders Congenital heart disease Tetralogy of Fallot Ventricular septal defect Right aortic arch Characteristic facies Velocardiofacial Syndrome

  5. Conotruncal cardiac defects Typical facial features Nasal voice Mild mental retardation Neonatal tetany Thymic aplasia or hypoplasia Conotruncal Anomaly Face Syndrome

  6. The 22q11 Deletion Syndrome:DiGeorge, Velocardiofacial, Conotruncal Anomaly Face Syndromes

  7. del (22) 22 The 22q11 Deletion Syndrome • Most common deletion syndrome • Estimated to occur in 1 in 4,000 livebirths • 6-10% familial cases (ie: child inherited deleted chromosome from parent and parent usually mildly affected) • The rest are de novo deletions

  8. CHD in the 22q11 Deletion Syndrome (McGinn et al., 1997; Ryan et al., 1997)

  9. Frequency of 22q11 Deletions in CHD

  10. Overall Goals • Decipher the genetic contribution to the etiology of conotruncal defects • Impact of genotype on clinical outcome

  11. Specific Aims • Investigate the role of NKX2.5 and its molecular partners in the etiology of conotruncal defects • Investigate whether subset of D-TGA and DORV share a common genetic etiology with heterotaxy syndrome • Impact of genotype on clinical outcome

  12. Impact of Genotype on Clinical Outcome • Aim 3: Analyze relationship between genotype and each of the following: • a. Cardiac anatomy • b. Operative outcome • c. Intermediate outcome • d. Intermediate cardiovascular status: cross sectional analysis

  13. 1° Cohort: Tetralogy of Fallot 22q11 deletion Trisomy 21 JAG1 mutation No identified syndrome/genetic alteration 2° Cohort: IAA or truncus: 22q11 deletion No identified syndrome/genetic alteration Study Subjects: Inclusion Criteria

  14. SubAim 3a: Genotype and Anatomy • Detailed reports for basic anatomy • Echo and/or cath to review for detailed measurements

  15. SubAim 3a: Genotype and Anatomy

  16. SubAim 3b: Genotype and Operative Course • Limited to those with surgery at CHOP • Retrospective chart review of operative admission • Prospective chart review of operative admission for new infants

  17. Control for anatomic subtypes Primary variables to examine: Total cardiopulmonary by pass time Deep hypothermic arrest time Length of ventilatory support # cardiac events # non cardiac events Total length of hospital stay Mortality SubAim 3b: Genotype and Operative Course

  18. SubAim 3c: Genotype and Intermediate Course • Retrospective chart review of existing CHOP and/or outside records • Control for anatomic subtype and possibly surgical approach

  19. Primary variables to examine: Mortality (deceased/living) Cardiac medications Arrhythmias requiring medications/pacemaker # of hospitalizations (cardiac) # of hospitalizations (non cardiac) # non cardiac subspecialists # of cardiac catheterizations # of repeat surgical intervention # of out-of-hospital cardiac events SubAim 3c: Genotype and Intermediate Course

  20. Inclusion Criteria TOF, IAA, truncus 8-18 yo Available records Known genetic status or agree to testing Exclusion Criteria Unrepaired CHD SubAim 3d: Cross Sectional Study

  21. Retrospective assessment of intermediate course and events (Aim 3c) Return to CHOP for complete cardiovascular assessment Protocol: Echocardiogram Exercise stress test (ECG) Cardiac MRI Child Health Questionnaire SubAim 3d: Cross Sectional Study

  22. SubAim 3d: Cross Sectional Study

  23. Study Sample Size

  24. Existing SCOR Ongoing recruitment to SCCOR Existing research databases: Alagille and VCFS centers Existing medical databases Source of Study Subjects

  25. Aim 3d: Progress to Date

  26. Aim 3d: Progress to Date

  27. Tests Performed to Date

  28. Statistical Considerations • Primary aim is to analyze the relationship between genotype and cardiac anatomy • Test the hypothesis using regression methods • Pulmonary artery size, pulmonary annular size (continuous) • Pulmonary valve anatomy, aortic arch anomaly (polychotomous) • MAPCAs (dichotomous) • Factors of interest • Genetic alterations (22q11, JAG1, trisomy 21, etc)

  29. Statistical Considerations • Examine the relationship between selected genotypes and peri-operative outcomes • Test hypotheses using regression methods • Circulatory arrest time, total bypass time, length of ventilatory support, total number of cardiac events, length of hospital stay, and mortality • Most are continuous and linear, except mortality which is survival-based • Factors of interest • Genotype and cardiac anatomy

  30. Statistical Considerations • Examine the relationship between selected genotypes and intermediate clinical course • Test hypothesis using regression methods • Mortality, use of cardiac medications, presence of arrhythmias, total number of hospitalizations, total number of cardiac catheterizations, presence of repeat surgical interventions, total number of out of hospital cardiac events • Most are continuous and linear, except mortality which is survival-based • Factors of interest • Genotype and cardiac anatomy

  31. Statistical Considerations • Examine the relationship between selected genotypes and intermediate cardiovascular status • Test hypothesis using regression methods • EKG values, echocardiographic values, MRI values, EST values, and CHQ score • Most are continuous and linear • Factors of interest • Genotype and cardiac anatomy

  32. Statistical Consideration • Each hypothesis builds upon analyses of prior hypotheses • Knowledge gained will influence the model building

  33. Database • Revision of previous case report forms: • Demographics • Birth/pregnancy/family history (Progeny) • Genetics examination • Extracardiac and Cardiac • Cytogenetics • Transfer of early SCCOR data into Clintrials platform • Develop new Case Report Forms for Operative and Cross Sectional Study • Daily and operative forms (3b) • Echo, EST, MRI, EP, Cath, medical history (3d), QOL

  34. Investigators: Betsy Goldmuntz, P.I. Ronn Tanel, EP Jack Rychik, Echo Mark Fogel, MRI Steve Paridon, EST Jack Rome, Cath Support Staff Clinical nurse specialist (Dee) Research specialist (Donnette) Data coordinator (Sharon Edman) Biostats core (Chuck and crew) Personnel for Aim 3

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