Genetics of Cardiovascular System Disorders

1. Genetics of Cardiovascular System Disorders

2. Genetic Diseases • Single gene disorders • Chromosomal disorders • Multifactorial

3. Cardiovascular System Disorders Associated with Single-gene Disorders • Mendelian • Autosomal Recessive- Inborn errors of metabolism • Autosomal Dominant – Marfan’s Syndrome, Noonan Syndrome, Long QT Syndrome, Dilated Cardiomyopathy • X-linked- Duchenne/Becker Muscular Dystrophy, Fabry Disease, Dilated Cardiomyopathy

4. Autosomal recessive • Male/Female equally homozygous affected • Parents are usually asymptomatic heterozygous carriers • Consanguinity • Recurrence risk 1/4

5. Inborn Errors of Metabolism See Medical Genetics Lecture in Committee V Coming Soon…

6. Dilated Cardiomyopathy • Dilated Cardiomyopathy (DCM) has a genetic basis in a proportion (~25%) of cases with mutations found in more than 10 genes encoding cytoskeleton proteins leading to dilatation of the left ventricle predominantly .

7. Autosomal Dominant • Male/Female equally heterozygous affected • Phenotype usually appears in every generation • Recurrence risk for any child of affected parents is ½ • Isolated cases are mostly due to de-novo mutation

8. Marfan’s Syndrome • Autosomal dominant inherited connective tissue disorder • Incidence 1/3000-5000 • Caused by mutations of • FBN1 (fibrillin-1) gene – Microfibril glycoprotein in elastic and non elastic tissues • TGFR B 1-2 (Transforming growth factor beta 1-1) – works through apoptosis cell cycle regulation and prevents incorporation of fibrillin into tissues

9. Marfan’s Syndrome / Clinical Features • Musculoskeletal: • Tall stature (dolichostenomelia) • Long digits (arachnodactyly) • Thumb sign (distal phalanx protrudes beyond border of clenched fist) • Wrist sign (thumb and fifth digit overlap when around the wrist) • Sternal deformity • Scoliosis > 20 degrees • Joint hypermobility • Arm span exceeding height (ratio >1.05) • Reduced elbow

11. Marfan’sSyndrome / Clinical Features 2. Eye: superior lens dislocation (ectopialentis) 3. Pulmonary: Spontaneous pneumothorax 4. Neurologic: Dural ectasia 5. Skin: Stretch marks 6. Cardiac: • Mitral valve prolapse • Aortic root dilation

12. Marfan’s Syndrome Cardiovascular System • Aortic root disease (MAJOR CRITERION)  aneurysms, AR, dissection • In 50% children • In up to 80% of adults • May lead to neurovascular complications • AR murmur: decrescendo, diastolic • Mitral valve prolapse (minor criterion) • In 60-80% patients; most common valve disorder • Worsens with time, complicated by rupture • MVP murmur: ejection click, holosystolic • Arrhythmias

13. Diagnosis • Clinical diagnosis: the Ghent criteria • physical exam: 6 organ systems involved • family history • genetic testing • If (+) family history, additionally you need: • Involvement of 2 organ systems including 1 major criterion • If (–) family history, additionally you need: • Major criterion from 2 systems and involvement of a 3rd system

14. Summary • Marfan’sSyndrome is relatively common • If you have a patient < 40 with evidence of aortic root changes, think MFS • No cure, only cardiovascular management • Annual echo • Beta blockers • Counseling on physical activity

15. Noonan Syndrome • Autosomal dominant dysmorphic syndrome caused by heterozygous mutation in the PTPN11(protein-phosphate nonreceptor type11) gene • incidence of 1 in 1,000 to 2,500 live births

16. Noonan Syndrome / Clinical Features Dysmorphic features; hypertelorism, a downward eyeslant, and low-set posteriorly rotated ears short stature, a short neck with webbing or redundancy of skin, epicanthic folds, • deafness, • motor delay, • bleeding diathesis. Cardiac defects • Hypertrophic obstructive cardiomyopathy • Atrial septal defects • Ventricular septal defects • Pulmonic stenosis!!!

17. X-linked recessive • Heterozygous females are carriers, heterozygous males are affected • Isolated cases are mostly due to de-novo mutations • Recurrence risk for any sons of carrier mother is ½

18. Duchenne/Becker Muscular Dystrophies • X-linked recessive progressive muscular dystrophy caused by mutation on dystrophin gene. • DMD lethal form • BMD mild form • Dystrophin gene encodes an important protein of dystroglycan complex of the muscle membrane.

19. DMD/BMD • Progressive muscle weakness • Symptoms usually appear at age 3-4 for DMD, for BMD later • Cardiomyopathy is common • About 5 to 10% of female carriers of this X-linked disorder show muscle weakness,andmay develop dilated cardiomyopathy !!!

20. Fabry Disease • An X-linked inborn error of glycosphingolipid catabolism caused by mutations in the gene encoding alpha-galactosidase A • deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. • This defect leads to accumulation of glycosphingolipidsin the plasma and cellular lysosomes of vessels, nerves, tissues, and organs throughout the body . • The disorder is a systemic disease, manifest as progressive renal failure, cardiac disease (left ventricule hypertrophy), cerebrovascular disease, small-fiber peripheral neuropathy, and skin lesions.

21. Cardiovascular System Disorders Associated with Chromosomal Disorders Caused by structural or numerical changes of chromosomes Chromosome mutations; Structural Deletions, duplcations, insertions, translocations Genome mutations; Numerical Aneuploidies: triploidy (3n) tetraploidy (4n) Monosomy (2n-1), trisomy (2n+1), tetrasomy(2n+2)

22. Down Syndrome • 47,XX,+21 or 47,XY,+21 TRISOMY 21 • Most common chromosomal disorder (1/700) and the common cause of mental retardation • Typical facial feature (flat face, down slanting palpebral fissures, broad nasal root, micrognatia,etc.) • CongenitalHeartDiseases (CHD) present in 40-50% • Endocardial cushion defect – mostcommon • Atrial septal defect with cleft mitral valve • Pulmonary Hypertention!!!

23. Turner Syndrome • 45,X MONOSOMY X • 1/2500 females lacks an X chromosome • Short stature and amenorrhea is evaluated • 20-50% cardiovascular abnormalities • Aortic coarctation – mostcommon • Bicuspid aortic valve • Dilated aortic root

24. Microdeletion syndromes • Williams syndrome – 7q11.23 • Elfin facies • Friendlybehavior • MR • Supravalvular Aortic Stenosis • Pulmonarystenosis

25. Microdeletion syndromes • DiGeorge syndrome – 22q11 • conotruncal anomalies • tertrology of fallot (TOF) !!! • VSD • hypoplasia or agenesis of the thymus and parathyroid gland resulting in frequent infections and hypocalcemia,

26. Multifactorial Isolated congenital heart diseases Teratogenic effects Hypertension

27. Isolated Congenital Heart Defects • Prevalence:0.5-0.8% of live births (8/1000). • Etiology:Unknown,multifactorialinheritance,genetic factors implicated. • 3% have a single gene defect,13% have associated chromosomal abnormalities. • 2-4% are associated with environmental or maternal conditions & teratogenic influences. Recurrence risk of isolated CHD • with one affected child 2-5% • two affected children 10-15%

28. TeratogenicEfects • Alcohol- 50% CHD: VSD, ASD • Most common teratogen?? to which fetal embryo and fetus are exposed-first trimester (Fetal Alcohol Syndrome) • Warfarin- 10% CHD: PDA, PS, intracranial hemorrhage • Rubella- 50% of fetuses become infected with rubella virus when mother is infected during first trimester. PDA and ASD, PS

29. Hereditary disorders of lymphatic and venous system • Milroy Disease (hereditary lymphedema I ) • FLT4 gene mutation, Autosomal dominant • HennekamLymphangietasia(AR) • Klippel-Trenaunay- Weber Syndrome • Macrocephaly-cutis marmorata- telengiectasia- congenitatelengiectatica-congenita