Genetics Flashcards
- Connective tissue disorder with mutation of fibrillin gene (FBN1)
- Dominant negative pathogenesis: mutant fibrillin 1 prevents formation of normal microfibrils & stimulates proteolysis of extracellular microfibrils
- Mitral valve prolapse
- Borderline and nonprogressive aortic enlargement -> aortic regurgitation and dilation, dissection of the ascending aorta
- Cardiovascular effects may manifest at any age
- Major cause of death: heart failure from valve regurgitation and aortic dissection & rupture
- Tx: beta blockers to decrease HR & force of contraction; prophylactic aortic root replacement in severe cases
- Pregnancy is risky
Marfan syndrome
Autosomal Dominant
- Deletion syndrome: 22q11
- Aplasia or hypoplasia of the parathyroid glands
- Present in infancy with congenital HD, hypocalcemia, immunodeficiency, facial dysmorphia (tubular nose, hypoplastic alae nasi, bulbous tip nose, low-set or dysplastic ears, myopathic facies)
- Loss of long arm of 1 copy of chromosome 22 seen on karyotype; 22q11 deletion by FISH
- Most common CV defects associated with 22q11 deletion: tetralogy of Fallot, interrupted aortic arch type B, truncus arteriosus, conoventricular VSDs, aortic arch abnormalities
DiGeorge/Velocardiofacial
autosomal dominant
- Microdeletion (detect by FISH): 7q11.23 deletion; most are de novo
- Infantile hypercalcemia, skeletal and renal anomalies, cognitive deficits, “social personality” and elfin facies
- Broad range of clinical presentations
- CV defects: supravalvular aortic stenosis, supravalvular pulmonary stenosis, peripheral pulmonary stenosis -> all from deletion of 1 copy of the elastin gene
- Pulmonary stenosis regresses with time but supravalvular aortic stenosis tends to progress
- Important to diagnose hypercalcemia/hypercalciuria because can cause renal failure is not treated
- see HTN in adults
Williams-Beuren
Autosomal Dominant
- Microdeletion (detect by FISH) in 3-7%: 20q12; mutation of JAG1 associated with the deletion (it’s for a Notch ligand protein)
- Bile duct paucity with cholestasis (liver disease), CV & skeletal anomalies
- CV defects (in >90%): peripheral pulmonary hypoplasia, tetralogy of Fallot, pulmonary valve stenosis, left-sided lesions and septal defects(ASD) in some, labile systolic HTN
- Ophthalmologic: anterior chamber defects, pigmentary retinal anomalies, posterior embryotoxon
- Orthopedic: butterfly vertebrae
- Heme: tendency to bleed
- Renal: structural, cysts, tubular acidosis
- Triangular facies, prominent forehead and chin,
Alagille syndrome
Autosomal dominant
**need to do genetic testing on family members
- Most are sporadic
- Mutation in TBX5 transcription factor (chromosome 12q24.1) -> loss of expression impairs development of heart and limb ->
- “heart hand syndrome” -> associated with CHD in patients with upper limb deformities
- Triphalangeal, hypoplastic or absent thumb (radial ray defects)
- CV: ASD or VSD, progressive AV conduction disease
Holt-Oram syndrome
Autosomal Dominant
- Heterogenous: PTP11 (encodes for SHP-2 which is involved in signaling for development of semilunar valves), SOS1, KRAS
- Short stature, facial dysmorphism, webbed neck, chest deformity, CV abnormalities
- CV defects: pulmonic stenosis & hypertrophic cardiomyopathy, secundum ASD, AV septal defect, mitral valve abnormalities, aortic coarctation, tetralogy of Fallot
- Cryptorchidism, bleeding diathesis, developmental delay
- LEOPARD syndrome is associated with NS: Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, Deafness (sensorineural)
Noonan syndrome
Autosomal dominant
(trisomy 21)
• Congenital heart disease in 1/3
• Ventricular dilation
Down syndrome
(45, X) • Sporadic • Delayed or absent sexual development • Webbed neck, low nuchal hair line • Broad chest • Edema of hands & feet • Renal anomalies • Sensorineural hearing loss • 50% have bicuspid aortic valve, so increased risk of aortic root dilation and dissection Coarctation of the aorta
Turner syndrome
most common cardiac malformation
bicuspid aortic valve
Type of Congenital Flow Lesions
- hypoplastic left heart syndrome
- coarctation of the aorta
- ASD secundum type
- pulmonary valve stenosis
- VSD
note: 25% have 22q11 deletion (as seen in velocardiofacial syndrome)
cardiac malformations associated with subtelomere chromosomal rearrangements
- aortic arch abnormalities
- VSD
- ASD
- mitral valve insufficiency
- concomitant pulmonary stenosis with VSD
Reasons to identify genetic pattern to CHD
- may involve other organ systems (30% of children with chromosome abnormalities have CHD)
- prognostic for clinical outcomes
- genetic reproductive risk in the family
- may identify other family members who need to have genetic testing
hyperlipoproteinemia-elevated levels of plasma lipids (cholesterol, triglycerides or both)
-mutation of LDL receptor or apoprotein B-100 (protein component of LDL)
-mutation of PCSK9 protease gene (gain of function missense mutation) ->LDL receptor degraded so uptake of cholesterol is prevented (protective from coronary heart disease -> African Americans)
-ARH adaptor protein mutation: impairs internalization of LDL:LDL receptor complex and therefore LDL clearance
-LDL receptor gene mutation
Premature heart disease from atheromas in both heterozygotes & homozygotes
Familial Hypercholesterolemia
Autosomal semi-dominant inheritance (gene dose is a factor)
causes adult-onset heart disease-gene mutations of structural proteins with specialized functions in contraction, force transmission or cell-to-cell communications
-inheritance risk for first degree relatives: 50%
-sarcomere mutations -> usually missense mutations (aa substitutions) that cause gain of function stimulus for remodeling
Over 300 mutations
Most are for beta-cardiac myosin heavy chain (MYH7) -> 40%
Cardiac myosin binding protein C (MYBPC3)
Cardiac Troponin T (TNNT2)
Autosomal Dominant
Hypertrophic cardiomyopathy
heterogeneous and panethnic-channelopathy
-loss of function mutations of KCNQ1, KCNH2, SCN5A (sodium channel), KCNE1, KCNE2
-decreased outward potassium current, prolonging the action potential and lowering the threshold for depolarization
-Long QT interval and T wave abnormalities
-symptom: syncope from cardiac arrhythmia
-tachyarrhythmia or torsades de pointes
KCN -> potassium channelopathies
SCN-> sodium channelopathy
Long QT syndrome
