Genetic Cardiac Disease Flashcards
Connective tissue diseases
- Marfan
- Loeys-Dietz
- Ehlers Danlos
- FTAA
Familial Arrhythmias syndromes
- Long QT
- Brugada
- CPVT
- ARVC
Familial Cardiomyopathy syndromes
- HCM
- DCM
Features of Marfan syndrome
- Autosomal dominant
- Multisystem
- Connective tissue
- Fibrillin 1 gene
- Chromosome 15q21
- TGFbetaR 2 (and TGFbetaR1)
- Chromosome 3p22 (9q33)
Physical features of Marfan syndrome aged 13
- Tall stature/pectus carinatum/ arachnodactyly
- Lens subluxation
- Mild aortic root dilatation
Physical features of Marfan syndrome aged 5
- Tall stature/pectus carinatum/ arachnodactyly
- Aortic root at upper limit of normal
- Father died aortic aneurysm
Findings of Ghent 2010 for diagnosis of marfan
Cardiovascular system
- Aortic dilatation/dissection
Eyes
- Ectopia lentis
Systemic score >7
- Skeletal
- Skin
- Respiratory
- Dural ectasia
- Mitral valve prolapse
- Myopia
Family history
- Unequivocally affected relative
Fibrillin 1
- Mutation known to cause MFS
Features of Marfan in childhood (features are age varying)
- Tall stature
- Pes plenus
- Pectus
- Scoliosis
- Face/palate
- Myopia
- Ectopia lentis
- Aortic
- Striae (stretch marks)
Mechanism of TGFb and fibrillin in Marfan in transgenic mice
- TGFb and fibrillin are both secreted into the extra-cellular 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 methods of Marfan
At least annual clinical review
- Echocardiogram
- Beta blockers
- Angiotensin II receptor blockers
- Prophyllactic aortic surgery if sinus of valsalva exceeds: 5.5cm or 5% growth per year (2mm in adults)
- Monitor aortic root frequently in pregnancy if diameter exceeds 4cm
What are Marfan - like syndromes?
- Loeys-Dietz syndrome
- Familial thoracic aortic aneurysms
- BAV/FTAA
- MASS phenotype
Features of Loeys-Dietz syndrome
- Arterial dissection, tortuosity, bifid uvula/cleft palate, hypertelorism, skin and skeletal findings
- TGFBR1/2, SMAD3, TGFB2, TGFB3
Features of Familial thoracic aortic aneurysms
- 29 gene TAAD gene panel
- TGFBR2, MYH11, ACTA2, SMAD3, COL3A1
Features of BAV/FTAA
- Bicuspid aortic valve/familial thoracic aortic aneurysm
- NOTCH1
Features of MASS phenotype
- Myopia, mitral valve prolapse, mild aortic dilatation (<2sd), striae, minor skeletal involvement
- Fibrillinopathy
What are long QT syndromes?
- Romano-Ward syndrome
- Jarvell Lange-Neilsen
Features of 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 Bazett’s formula?
QTc = QT/ Sqaure root of RR
Features of Jarvell Lange-Neilson syndrome
Same as Romano-Ward syndrome but + congenital sensorineural deafness
Know genotype predictions: precipitants of arrthymia and mutations associated with them
and Patterns on ECGs
Which conditions should be excluded from dilated cardiomyopathy?
- Ischaemic heart disease (angiography)
- Hypertension
- Skeletal muscle disease (neurology/genetics evaluation, CPK)
- Alcohol abuse (history and biochemical evidence, but 9% have TTN mutation)
- Exposure to cardiotoxic drugs (history)
- Haemochromatosis (ferritin/genotyping)
In dilated cardiomyopathy, when should mitochondrial disease be considered?
If there is:
- Diabetes
- Deafness
- Retinitis pigmentosa - Skeletal muscle disease
- Growth retardation
- Cognitive disorder
Testing techniques in genomics
- Whole genome sequencing
- Whole exome sequencing
- Software filtering
Diagnosis methods of Inherited Cardiac Conditions
- Diagnosis in proband: cardiac phenotype, genetic testing
- Family history
- Assess relatives
- Cascade screening of relatives
- Prevention of avoidable morbidity and mortality
