Genetics of Cardiovascular System Disorders. Genetic Diseases Single gene disorders Mendelian...
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Transcript of Genetics of Cardiovascular System Disorders. Genetic Diseases Single gene disorders Mendelian...
Genetics of Cardiovascular
System Disorders
Genetic Diseases
• Single gene 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
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. 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
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