1. Genetics of Cardiovascular System Disorders

2. Genetic Diseases Single gene disorders Chromosomal disorders
Mendelian
Nonmendelian
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
Non-Mendelian
UPD
Triple nucleotide repeat disorders
Mitochondrial

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 .
Echocardiography usually shows a dilated poorly contractile left ventricle, with accompanying dilatation of the right ventricle in some cases. 

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/
Caused by mutations of
FBN1 (fibrillin-1) gene – Microfibril glycoprotein in elastic and non elastic tissues
TGFR B 1-2 (Transforming growth factor beta 1-2) – 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’s Syndrome / Clinical Features
2. Eye: superior lens dislocation
(ectopia lentis)
3. Pulmonary: Spontaneous pneumothorax
4. Neurologic: Dural ectasia
5. 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
Untreated Marfan’s is a/w dissection: usually type 1 or type A. Often, there is family h/o dissection as well.
In patients under age of 40, approx 50% of those cases are related to Marfan’s dz (also in differential is cocaine)

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’s Syndrome 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,and may 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 glycosphingolipids in 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.)
Congenital Heart Diseases (CHD) present in 40-50%
Endocardial cushion defect – most common
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 – most common
Bicuspid aortic valve
Dilated aortic root

24. Microdeletion syndromes
Williams syndrome – 7q11.23
Elfin facies
Friendly behavior MR
Supravalvular
Aortic Stenosis
Pulmonary stenosis

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

27. Isolated Congenital Heart Defects
Prevalence: % of live births (8/1000).
Etiology: Unknown,multifactorial inheritance,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. Teratogenic Efects 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
Hennekam Lymphangietasia (AR)

30. Klippel-Trenaunay-Weber Syndrome