Genetics and CVD Flashcards
Congenital Heart Disease causes
Copy number variation (CNV) whole chromosome (trisomy, monosomy) -part of a chromosome (22q11 deletion, Williams)
Single nucleotide variation(SNV)
Mendelian disorders: (Noonan/CFC, Marfan, SVAS, Holt-Oram)
CNV (copy number variation) or SNV (single nucleotide variation)
-CHARGE
Uncertain
-VACTERL (vertebral, anal atresia, cardiac, tracheoesophageal fistula, renal/limb anomalies)
Multifactorial
-isolated CHD
Teratogens
-rubella, alcohol, anti-epileptic drugs, maternal diabetes mellitus
Down syndrome
Trisomy 21 95% maternal nondisjunction (mat age) 3% translocation 2% mosaic 15% atrio-ventricular septal defects duodenal atresia
% of newborns vs fetuses with chromosome abnormality and CHD
19% of fetuses with CHD have abnormal chromosomes
Associated with cystic hygroma on scan
Only 13% of newborns with CHD have abnormal chromosomes
Turner
syndrome (45,X)
l 30% mosaic, 5% 45,X/46XY l 1/3000 LB (20% of SAB) l coarctation of aorta l short stature l gonadal dysgenesis l puffy hands
Neck webbing
l Excess nuchal folds l An indicator of prenatal cardiac difficulties? l Turner syndrome l Noonan syndrome l CFC syndrome l Leopard syndrome l Costello syndrome
Noonan
Syndrome
Pulmonary stenosis Short stature neck webbing cryptorchidism (testes don't descend) characteristic face PTPN11 gene (chr 12)
l Cardio-Facio-
Cutaneous (CFC) syndrome
l Noonan-like
l Plus:
l Ectodermal problems
l Develomental delay
l Leopard syndrome
l Noonan-like
l Plus:
l Multiple lentigenes
l Deafness
l Costello syndrome
l Noonan-like l Plus l thickened skin folds l susceptible to warts l cardiomyopathy l Later cancer risk
22q11 deletion syndrome
l Cardiac malformation l Abnormal facies l Thymic hypoplasia l Cleft palate l Hypoparathyroidism l Psychiatric – 22% of adult 22q11 deletion patients have schizophrenia and (2%) schizophrenic patients had 22q11 deletion l Speech delay/palatal dysfunction common l Very variable disorder l Look for additional clinical features l If 2 or more features present – test l Low frequency (~1-2%) in unselected CHD l Only ~25% are familial
digeorge + velocardiofacial syndromes = noonans
DiGeorge Syndrome l Thymic hypoplasia l Hypoparathyroidism l Outflow tract cardiac malformation l Usually sporadic
Shprintzen Syndrome l Cleft palate/palatal insufficiency l Outflow tract cardiac malformation l Characteristic face l Autosomal dominant
Williams syndrome
l Aortic stenosis (supravalvar) l Hypercalcemia l 5th finger clinodactyly l characteristic face l cocktail party manner l Deletion of Elastin on chromosome 7 l Deletion of contiguous genes l LIM kinase
Teratogens
l Fetal alcohol syndrome l IUGR < 10th centile l Head < 10th centile l Face l ADHD l 3-5 units per week l Antiepileptic drugs l Rubella l Maternal Diabetes Mellitus
VSD is associated with folate deficiency
Periconceptual multivitamin use and
nonsyndromic cardiac defects
Genetic Cardiac Diseases
l Cardiovascular Connective Tissue Disease l Marfan l Loeys-Dietz l Ehlers Danlos l FTAA l Familial Arrhythmias l Long QT l Brugada l CPVT l ARVC
l Familial Cardiomyopathy
l HCM
l DCM
Marfan Syndrome
l Autosomal dominant l Multisystem l Connective tissue l Fibrillin 1 gene l chromosome 15q21 l TGFbR 2 (and TGFbR 1) l chromosome 3p22 (9q33) aortic root dilatation that gets more apparent with age plus tall stature, pectus carinatum (breast bone sticks out) Ectopia lentis and subluxation l Family history l Unequivocally affected relative l Fibrillin 1 l Mutation known to cause MFS
TGFb and fibrillin
TGFb and fibrillin are both secreted into the extracellular matrix and interact in vitro. Incorporation of fibrillin into microfibrils results in
proteolytic release of TGFb
TGFb signalling affects cell proliferation, differentiation
and apoptosis
Transgenic mice, deficient in Fibrillin have excess TGFb
signalling and Marfan features. TGFb antibodies, or the
TGFb antagonist Losartan rescue the Marfan phenotype
in Fibrillin deficient mice
Optimal management of
Marfan
At least annual clinical review l echocardiogram l b blockers l Angiotensin II Receptor Blockers l Prophyllactic aortic surgery if Sinus of Valsalva exceeds l 5.5 cm or 5% growth per year (2 mm in adults) l Monitor aortic root frequently in pregnancy if diameter exceeds 4cm
Aortic Root Surgery for aneurysm in marfanss#
mechanical valve replacement lasts longer but need warfarin
valve sparing procedure may need reoperation but no warfarin
Marfan - like syndromes
l Loeys-Dietz Syndrome l Arterial dissection, tortuosity, bifid uvula/cleft palate, hypertelorism, skin and skeletal findings l TGFBR1/2, SMAD3, TGFB2,TGFB3 l Familial Thoracic Aortic Aneurysms l 29 gene TAAD gene panel l TGFBR2, MYH11, ACTA2, SMAD3, COL3A1 l BAV/FTAA l bicuspid aortic valve/familial thoracic aortic aneurysm l NOTCH1 l MASS phenotype l myopia, mitral valve prolapse, mild aortic dilatation (<2sd), striae, minor skeletal involvement l fibrillinopathy
Sudden Unexpected Death
l Between 1 year and 40 years l 1-5/100,000 patient years l 29-35% show no post mortem cause l Assumed to be arrhythmic l 1st degree relative studies: l 40-53% identifiable inherited heart disease l Mayo Clinic Molecular Autopsy series: l 35% had ion channelopathy l Majority of these are Long QT
Genotype prediction
Exercise,
particularly
swimming-Normal/
broad T wave pattern-KCNQ1 mutation
Noise/arousal
e.g telephone
ring, alarm clock-Notched T qave pattern,KCNH2
Sleep/
bradycardia
Biphasic SCN5A
Brugada syndrome
l SCD or VF/VT and l Type 1Brugada ECG l Other features: l prolonged PR interval l enlarged LV/poor LV function l more common in young men especially of far Eastern origin l Ajmaline challenge l SCN5A loss of function l ~8 other genes are rare causes l Management l Avoid fever, excess alcohol, overeating (>vagal effects) ICD
ARVC
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare type of cardiomyopathy. It occurs if the muscle tissue in the right ventricle dies and is replaced with scar tissue. This disrupts the heart's electrical signals and causes arrhythmias. Symptoms include palpitations and fainting after physical activity. 2010 Task Force Criteria l Echo/MRI (RV dyskinesia) l ECG – epsilon waves, T wave inversion l SAECG – late potentials l Effort induced VT (LBBB) l Histology – fatty infiltration of RV l Family history / pathogenic gene variant
