inherited cardiac coditiosn in clinical genetics Flashcards
cardiovascular geentics?
Vascular * Anomalies
* Functional
Structural * Developmental
* Cardiomyopathies
* Valvular
Functional * Arrhythmias
* Conduction abnormalities
inherited cardiovascular conditons?
Chromosomal
Aneuploidies- Downs, Edwards, Turner etc.
Microdeletion- 22qdel; Williams etc.
Mendelian
Familial cardiomyopathies- HCM, DCM, ARVC
Familial arrhythmias- LQTS, BRS, CPVT etc.
Inherited skeletal muscle- DMD/BMD; LGMD, Emery-Dreiffus, myotonic dystrophy etc.
Mitochondrial- Barth; DCM
Multi-factorial/Polygenic- congenital heart; CAD, hypertension etc.
examples of inherited cardiovascular disease?
Congenital heart disease (isolated/ syndrome) - most common
Marfan syndrome
Familial hypercholestrolaemia
Inherited cardiomyopathies
Inherited arrhythmias
Coronary heart disease
Hypertension
developmental heart abnormalities - congenital heart disease?
Septal defects- VSD; ASD; AVSD
Valvular defects- TS, PS, AS, Bicuspid…
Ventricle size- Hypoplastic left heart; ventricular non-compaction..
Blood vessels- Abnormal aortic arch; transposition of great vessels, anomalous pulmonary venous drainage….
Complex- Tetralogy of Fallot; Eisenmenger’s complex
tetrology of fallot?
left hypoplastic heart
Hypoplastic left heart syndrome (HLHS), is a rare congenital heart defect in which the left ventricle of the heart is severely underdeveloped.
transposition of great arteries?
Transposition of the great vessels (TGV) is a group of congenital heart defects (CHDs) involving an abnormal spatial arrangement of any of the primary blood vessels: superior and/or inferior venae cavae (SVC, IVC), pulmonary artery, pulmonary veins, and aorta. CHDs involving only the primary arteries (pulmonary artery and aorta) belong to a sub-group called transposition of the great arteries (TGA).
causes of abnormal aortic arch
Supravalular aortic stenosis
- Williams syndrome
- Microdeletion 7q
- Elastin gene
Coarcation of Aorta
- Turner syndrome
- Systemic hypertension
- Other features
- 45X; 46X, abnormal X
genetic managment of conditions?
Family history- familial; autosomal dominant
Isolated- low recurrence risk; fetal echocardiography
Complex/ dysmorphic- cytogenetic/ FISH/ array CGH
Multi-system- syndromal; specific gene
anuploidy syndomes with major cardio anomalies?
down
edwards
patau
turner
deletios and conditons
most common deletion syndrome?
22q deletion syndrome
Common microdeletion syndrome
High risk for congenital heart ~80%
Most outflow tract abnormalities- TOF
Dysmorphic appearance
Developmental delay
Increased risk for infections- T cell
Hypocalcemic seizures- absent/hypoplastic parathyroid
Increased risk for psychosis/ schizophrenia
locus specific probe for deleted 22
tuple 1 (shows normal) and control (shows deleted)
most common inherited arteripathes?
marfan syndrome
chest going in and out?
pectus excavatum - in
pectus carinatum - out
ghent diagnostic nosology skeletal?
ghent diagnostic nosology occular?
ghent diagnostic nosology cardio?
ghent diagnostic nosology pulmonary?
ghent diagnostic nosology skin?
ghent diagnostic nosology dura?
ghent diagnostic nosology genetic?
ghent diagnoses?
marfans
marfans criteria, crdiology?
Major Criteria
Dilation/Dissection of ascending Aorta
Minor Criteria
Mitral valve prolapse with or without MR, dilation of PA without other cause, calcification of mitral annulus <40yrs of age, dilation or dissection of the descending thoracic or abdominal aorta below age of 50yrs
Two most common features are mitral valve prolapse [MVP] and dilation of the ascending aorta
Up to 80% of MFS show echocardiographic signs of MVP. Occurs early in disease process and involves stretching of the chordae and remodelling of the valve leaflets. Annulus may dilate and calcification can ensue
Incidence of MVP increases with age. F>M
¼ MVP progress to MR
SVT/VT more common in MFS
? Primary cardiomyopathic process in MFS
asessing aortic root dilatation?
Transthoracic echocardiography used for assessment of aortic root
Enlargement can occur from in utero to adulthood
Early onset correlates with greater risk of dissection/AR
Diameter naturally increases with growth, therefore must be corrected for body surface area and age
Dilation can, but rarely proceeds beyond innominate artery. However desending thoracic and AAA can occur
Aortic measurements made at:
Sinuses of Valsalva, the supraaortic ridge and proximal aorta
Dilation often begins at SoV and progresses distally
aotic dissection?
other features of marfans?
Spontaneous Pneumothorax
Cor pulmonale following chest wall deformity
Poor muscular development
Lack of adipose tissue
Varicose veins
Degenerative arthritis
Uterine prolapse
ADHD
Body image
genetic of marfan syndrome?
AD, Chromosome 15q. Penetrance 100%. 3p locus in French family.
Missense and nonsense mutations described
25% new mutation (gonadal mosaicism described)
Paternal age effect (39yrs vs 26yrs)
Several hundred mutations known. Most private
Probable dominant negative mechanism, but some evidence for haploinsufficiency
Genotype-phenotype correlation limited to neonatal MFS
management of marfans?
Life expectancy in MFS has increased greatly in last 30yrs
Life expectancy is primarily determined by the extent and severity of cardiovascular involvement
Improvement has followed improved surgical and medical management in conjunction with improved surveillance
However social, lifestyle e.g. sports, employment and insurance issues are also important
inherited cardiomyopathies?
Hypertrophic [HCM]
Dilated [DCM]
Restrictive [RCM]
Arrhythmogenic right ventricular
cardiomyopathy [ARVC]
Left ventricular non-compaction
[LVNC]
Skeletal myopathies [DMD; DM…]
Other forms [Danon, WPW.]
hypertrophic cardiomyopathy?
Hypertrophy
Hypercontractility
Diastolic dysfunction
Fibrosis and disarray
~15 genes/ >200 mutations
Sarcomeric/cytoskeletal proteins
No unifying “sarcomeric” hypothesis of pathogenesis
Clinical studies suggest 50% familial
Penetrance is incomplete and age dependant
Molecular analysis shows
>90% of cases are familial - AD
15 disease genes
>100 known mutations
many “private” mutations
disease genes encode sarcomeric or cytoskeletal proteins
proteins part of both thick and thin filaments
management of HCM?
Clinical history- clinical examination
12 lead ECG
Risk stratification: 24 hour tape, exercise tolerance test, echocardiogram
60% low risk
30% mod risk
10% high risk
dilated crdiomyopathy?
1/5000-10000, idiopathic
30% “genetic”
AD, XL(dystrophin), AR
Penetrance age related
>15 disease loci sarcomeric protein genes
lamin A/C
cytoskeletal proteins
dystrophin, taffazin (Barth’s)
EYA4
phosphlamban
Linked loci
arrythmogenic right ventricular cardiomyopathy?
1/5000
Myocyte necrosis
apoptosis with fibrofatty replacement
RV +/- LV (76%)
AD
AR (Naxos disease)
clinical features?
Variability of age of onset, penetrance and clinical features
Ventricular/supraventricular arrhythmia
SCD 2.5%/year, CCF in late disease
ERVC genetis?
10 disease loci
6 known genes- most common 4 genes:
- plakophilin 2
- plakoglobin (Naxos)
- desmoplakin
- demsoglein
? Diverse pathophysiolog
arv screening?
inherited cardiac rhythm disease?
Familial Arrhythmic Syndromes
- Long QT [Romano-Ward syndrome
- Long QT with deafness [Jervel-Lange-Nielson]
- Short QT
- Brugada [SCN5A and others]
- Catecholaminergic polymorphic VT [CPVT]
- Familial Conduction disease e.g. Fam BBB
- Atrial Fibrillation
- Wolfe-Parkinson-White syndrome
- Familial Junctional Tachycardia
inherited long ST syndrome… ei
romano-ward syndrome
Autosomal dominant (mostly) or autosomal recessive (with deafness) Many different “channelopathies” cause prolonged ventricular repolarisation
genetics of long QT syndrome?
10 loci (LQT1-10) most genes now cloned AR variant (Jervell and Lange-Nielsen) results from mutations at LQT1 or LQT5. Parents heterozygous! Most genes encode K+ channels, except LQT3 (SCN5A) Mutation of KCNQ1(LQT1) or KCNE1(LQT5) disrupt slow inward K+ current (Iks). Mutations of HERG(LQT2) or KCNE2 (LQT6) disrupt the rapidly activating delayed rectifier K+ channel, IKr
MUTATIONS IN HERG GENE (LQT2) AND KCNE2 (LQT6) RESULT IN Ikr BLOCKADE RESULTING IN POTASSIUM ION EFFLUX BLOCK TOWARDS THE END OF VENTRICULAR ACTION POTENTIAL
signs?
Variable
50% have first cardiac event before 12yrs
90% by age 40yrs
SCD risk factors: deafness, QT length, previous history of syncope, female sex, documented TdP or VF, young age at first event and what gene is affected.
Age and Sex: females more often symptomatic, in males risk of cardiac event decreases after puberty with a natural decline in QTc
Pregnancy: increased risk in post-partum period.
PROLONGED QT MAY LEAD TO FATAL TORSADES DE POINTES AND VENTRICULAR FIBRILLATION- THE MOST COMMON SEQUENCE OF EVENTS IN SUDDEN CARDIAC DEATH
long qt syndrome?
signs if asymptomatic?
ECG: (QTc=QT/RR)
LQT = QTc>440-460
But 40% of LQT1/2 carriers have QTc 410-470. Overlap with normal
QTc>460 provides positive predictive accuracy of 96% in women and 91% in men
With QTc in this range, phenotypic studies become imprecise and molecular genetic analysis may be of increased utility.
Other Features: QT dispersion, T wave structure (biphasic?, alternans?), bradycardia with exersise, sinus pauses.
Symptomatic individuals require treatment including lifestyle and drug advice (avoid those that increase LQT)
Avoid competitive sports
Care around electrolyte losses e.g. diarrhoea
Beta-blockade decreases mortality from 50% to 5% in probands and affected family members.
Permanent pacemakers (esp with SCN5A) have been advocated.
If “breakthrough” events ICD has been shown to prevent death in LQT in conjunction with beta-blockers.
how to treat long qt syndrome?
Na+ blockers (e.g. mexilitine) for LQT3?
Modification of K+ in LQT1/2 e.g. oral K+ therapy, nicorandil
? Avoid beta-blockers for LQT3, pacemaker?
LQT1 avoid competitive exersise
LQT1 avoid diving and swimming
LQT2 remove sources of loud noise e.g. alarm clocks
brugada syndrome?
Not uncommon ? Prevalence unknown
Common among Oriental peoples
May only present with unexplained death
Genetic and clinical heterogeneity
Autosomal dominant inheritance
Mainly a sodium ion channelopathy (SCN5A)
Typical and atypical ECG changes
Unmasking by azmeline/flecainide challenge
No drug treatment- ICD only choice!
ecg changes?
Short PR
RBBB
ST elevation V1-V3
