Genetics of Cardiovascular System Disorders

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

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

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 1-2) – works through apoptosis cell cycle regulation and prevents incorporation of fibrillin into tissues

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

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

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)

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 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)

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

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