Genetics of Cardiovascular

System Disorders

Genetic Diseases

• Single gene disorders • Chromosomal disorders• Multifactorial

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

Autosomal recessive

• Male/Female equally homozygous affected

• Parents are usually asymptomatic heterozygous carriers

• Consanguinity• Recurrence risk 1/4

Inborn Errors of Metabolism

See Medical Genetics Lecture in Committee V Coming Soon…

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 .

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

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

Marfan’s Syndrome / Clinical Features

1. 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

Marfan’s Syndrome / Clinical Features

2. Eye: superior lens dislocation (ectopia lentis) 3. Pulmonary: Spontaneous pneumothorax

4. Neurologic: Dural ectasia

5. Skin: Stretch marks

6. Cardiac:• Mitral valve prolapse • Aortic root dilation

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

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

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

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

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!!!

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

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.

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 !!!

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.

Cardiovascular System Disorders Associated with Chromosomal

DisordersCaused 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)

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 !!!

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

Microdeletion syndromesWilliams

syndrome – 7q11.23 Elfin faciesFriendly behavior MRSupravalvular Aortic StenosisPulmonary

stenosis

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,

Multifactorial

Isolated congenital heart diseases

Teratogenic effects Hypertension

Isolated Congenital Heart Defects

• Prevalence:0.5-0.8% 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%

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

Hereditary disorders of lymphatic and venous system

• Milroy Disease (hereditary lymphedema I ) • FLT4 gene mutation, Autosomal

dominant

• Hennekam Lymphangietasia (AR)• Klippel-Trenaunay- Weber

Syndrome• Macrocephaly-cutis marmorata-

telengiectasia- congenita telengiectatica-congenita