Genetics and cardiovascular disease Flashcards
What is copy number variation example?
Whole chromosome (trisomy, monosomy) part of a chromosome (22q11 deletion, Williams)
What is a single nucleotide variation example?
Mendelian disorders
What is a CNV or SNV example?
CHARGE association
What is a multifactorial example of congenital heart disease?
Isolated CHD
VACTERL association
What are teratogens examples of congenital heart disease?
Rubella
Alcohol
Anti-epileptic drugs
Maternal diabetes mellitus
What is down syndrome?
Trisomy 21
95% maternal non- disjunction (mat age)
3% translocation
2% mosaic
What are the heart linkage to down syndrome?
15% atrio-ventricular septal defects
Duodenal atresia
19% of fetuses with CHD have what?
Abnormal chromosomes
13% of newborns with CHD have what?
Abnormal chromosomes
What is Turner syndrome?
30% mosaic
5% 45,X/46XY
1/3000 LB (20% of SAB)
What is Turner sydrome features?
Coarctation of aorta
Short stature
Gonadal dysgenesis
Puffy hands
What is neck webbing?
Excess nuchal folds An indicator of prenatal cardiac difficulties
What are examples of syndromes that have neck webbing?
Turner syndrome
Noonan syndrome
CFC syndrome
Leopard syndrome
Costello syndrome
What are the presenting features with noonan syndrome?
Pulmonary stenosis
Short stature
Neck webbing
Cryptorchidism- one or both of the testes fail to descend from the abdomen into the scrotum
Characteristic face PTPN11 gene (chr 12)
What are features of cardio-facio cutaneous?
Noonan-like Plus: Ectodermal problems
Develomental delay
What are features of leopard syndrome?
Noonan-like
Plus: Multiple lentigenes
Deafness
What are features of costello syndrome?
Noonan-like
Plus thickened skin folds susceptible to warts cardiomyopathy
Later cancer risk
What is 22q11 deletion syndrome features?
Cardiac malformation
Abnormal facies
Thymic hypoplasia
Cleft palate
Hypoparathyroidism
22 q11 deletion
Renal
Psychiatric
What is DiGeorge syndrome?
Thymic hypoplasia
Hypoparathyroidism
Outflow tract cardiac malformation
Usually sporadic
What is shprintzen syndrome?
Cleft palate/palatal insufficiency
Outflow tract cardiac malformation
Characteristic face
Autosomal dominant
What does 22q11 deletion syndrome encompass?
DiGeorge and Velocardiofacial (Shprintzen) syndromes
What are LCR regions?
Low copy number repeats
Predispose to deletion and translocation (e.g. t11;22)
What are features of Williams syndrome?
Aortic stenosis (supravalvar)
Hypercalcemia
5th finger clinodactyly
Characteristic face
Cocktail party manner
Deletion of Elastin on chromosome 7
Deletion of contiguous genes
LIM kinase
What are examples teratogens?
Fetal alcohol syndrome
IUGR < 10th centile
Head < 10th centile
Face
ADHD
3-5 units per week
Antiepileptic drugs
Rubella
Maternal Diabetes Mellitus
What is VSD associated with?
Folate deficiency
Periconceptual multivitamin use and nonsyndromic cardiac defects
MTHFR and CHD
Affected prenatal series 677CT or TT
What are genetic cardiac diseases?
Cardiovascular Connective Tissue Disease
Marfan
Loeys-Dietz
Ehlers Danlos
Familial Arrhythmias
Long QT
Brugada
CPVT
ARVC
Familial Cardiomyopathy
HCM
DCM
What is Loeys-dietz syndrome?
Loeys-Dietz syndrome is primarily characterized by aortic aneurysms (weakened outpouchings of the aorta, the main artery in the body) in children
What is brugada syndrome?
Genetic disorder in which the electrical activity within the heart is abnormal.
It increases the risk of abnormal heart rhythms and sudden cardiac death.
Those affected may have episodes of passing out
What is a Catecholaminergic polymorphic ventricular tachycardia (CPVT)?
Condition characterized by an abnormal heart rhythm (arrhythmia).
As the heart rate increases in response to physical activity or emotional stress, it can trigger an abnormally fast and irregular heartbeat called ventricular tachycardia
What is ARVC-Arrhythmogenic right ventricular cardiomyopathy?
Type of cardiomyopathy that affects the ventricles (lower pumping chambers) of the heart and causes arrhythmias (abnormal heart rhythms).
It affects the right ventricle, and often also affects the left ventricle
What is Marfan syndrome?
Autosomal dominant
Multisystem
Connective tissue
Fibrillin 1 gene
Chromosome 15q21
TGFbetaR 2 (and TGFbetaR 1)
chromosome 3p22 (9q33)
How do you diagnose marfan?
Is it Marfan?
What follow-up?
Prophyllactic treatment?
How many positive findings do you need for a diagnosis of Marfan?
2
What is involved in the diagnosis of marfan?
Cardiovascular system
Aortic dilatation/dissection
Eyes
Ectopia lentis
Systemic Score ≥ 7
Skeletal
Skin
Respiratory
Mitral valve prolapse
Myopia
Family history
Unequivocally affected relative
Fibrillin 1
Mutation known to cause MFS
What do TGFbeta and fibrillin do?
Secreted into the extra- cellular matrix and interact in vitro Incorporation of fibrillin into microfibrils results in proteolytic release of TGFbeta
TGFbeta signalling affects cell proliferation, differentiation and apoptosis
Transgenic mice, deficient in Fibrillin have excess TGFbeta signalling and Marfan features
TGFbeta antibodies, or the TGFbeta antagonist Losartan rescue the Marfan phenotype in Fibrillin deficient mice
What is in the optimal management of Marfan
At least annual clinical review
Echocardiogram
Beta blockers
Angiotensin II Receptor Blockers
Prophyllactic aortic surgery if Sinus of Valsalva exceeds 5.5 cm or 5% growth per year (2 mm in adults)
Monitor aortic root frequently in pregnancy if diameter exceeds 4cm
Why is a mechanical valve good and bad?
Lasts longer but requires warfarin
Why is a valve sparing procedure good and bad?
May need re-operation
No warfarin
What are some marfan like syndromes?
Loeys-Dietz Syndrome
Arterial dissection, tortuosity, bifid uvula/cleft palate, hypertelorism, skin and skeletal findings
Familial Thoracic Aortic Aneurysms
11q, 5q BAV/FTAA
MASS phenotype
Myopia, mitral valve prolapse, mild aortic dilatation (<2sd), striae, minor skeletal involvement
What is sudden unexpected death?
Between 1 year and 40 years
1-5/100,000 patient years
29-35% show no post mortem cause: Assumed to be arrhythmic
1st degree relative studies: 40-53% identifiable inherited heart disease
Mayo Clinic Molecular Autopsy series: 35% had ion channelopathy Majority of these are Long QT
What is romano-ward syndrome?
Syncope, “seizure”, sudden death
Emotion, exercise, drugs
ECG shows prolonged QTc interval
Repolarisation anomalies (T/U waves)
Paroxysmal Polymorphic VT (Torsade de Pointes)
What is jervell lange-neilsen?
As above + congenital sensorineural deafness
What are some long QT syndromes?
Romano-ward syndrome
Jervell lange-neilsen
What does the mutation KCNQ1 show on a T-wave pattern on 12 lead ECG and what are the precipitants of arrhythmia?
Normal/broad Exercise, particularly swimming
What does the mutation KCNH2 show on a T-wave pattern on 12 lead ECG and what are the precipitants of arrhythmia?
Notched Noise/arousal e.g telephone ring, alarm clock
What does the mutation SCN5A show on a T-wave pattern on 12 lead ECG and what are the precipitants of arrhythmia?
Biphasic Sleep/bradycardia
What is brugada syndrome?
SCD or VF/VT and Type 1 Brugada ECG
Other features: Prolonged PR interval
Enlarged LV/poor LV function
More common in young men especially of far Eastern origin
Ajmaline challenge
SCN5A loss of function
~11 other genes are rare causes
Waht is the management of brugada sydnrome?
Avoid fever, excess alcohol, overeating (-vagal effects)
ICD
What is AVC?
Arrhythmogenic ventricular cardiomyopathy
What does AVC show?
Echo/MRI (RV dyskinesia)
ECG – epsilon waves, T wave inversion
SAECG – late potentials
VT (LBBB)
Histology – fatty infiltration of RV
Family history / pathogenic gene variant
What is hypertrophic cardiomyopathy?
Prevalence 1/500
Presentation very variable
Sudden death more common if diagnosed < 14 years, or symptomatic
Mortality 5.9% per year diagnosed clinically in childhood
What are modifiers of hypertrophic cardiomyopathy?
Lifestyle – e.g. sports
Other genes – e.g. ACE polymorphism
What is dilated cardiomyopathy?
Echocardiographic features of dilated cardiomyopathy
When should mitochondral disorder be considered?
Diabetes, deafness, retinitis pigmentosa, skeletal muscle disease, growth retardation or cognitive disorder.
What is the family history of dilated cardiomyopathy?
Family history of cardiomyopathy or sudden cardiac death compatible with cardiomyopathy should be evident.
What is genetic testing of dilated cardiomyopathy?
Genetic testing may include Titin, LMNA, SCN5A, dystrophin and the sarcomere genes
What is Genetic Cardiology Cardiac Genetics
Diagnosis in proband: Cardiac phenotype and Genetic testing
Family history
Assess relatives
Cascade screening of relatives
Prevention of avoidable morbidity and mortality
