Genetics and CVD

Question 1

Congenital Heart Disease causes

Answer 1

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

Question 2

Down syndrome

Answer 2

Trisomy 21
95% maternal nondisjunction (mat age)
3% translocation
2% mosaic
15% atrio-ventricular septal defects
duodenal atresia

Question 3

% of newborns vs fetuses with chromosome abnormality and CHD

Answer 3

19% of fetuses with CHD have abnormal chromosomes
Associated with cystic hygroma on scan
Only 13% of newborns with CHD have abnormal chromosomes

Question 4

Turner

syndrome (45,X)

Answer 4

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

Question 5

Neck webbing

Answer 5

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

Question 6

Noonan

Syndrome

Answer 6

Pulmonary stenosis
Short stature
neck webbing
cryptorchidism (testes don't descend)
characteristic face
PTPN11 gene (chr 12)

Question 7

l Cardio-Facio-

Cutaneous (CFC) syndrome

Answer 7

l Noonan-like
l Plus:
l Ectodermal problems
l Develomental delay

Question 8

l Leopard syndrome

Answer 8

l Noonan-like
l Plus:
l Multiple lentigenes
l Deafness

Question 9

l Costello syndrome

Answer 9

l Noonan-like
l Plus
l thickened skin folds
l susceptible to warts
l cardiomyopathy
l Later cancer risk

Question 10

22q11 deletion syndrome

Answer 10

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

Question 11

digeorge + velocardiofacial syndromes = noonans

Answer 11

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

Question 12

Williams syndrome

Answer 12

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

Question 13

Teratogens

Answer 13

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

Question 14

VSD is associated with folate deficiency

Answer 14

Periconceptual multivitamin use and

nonsyndromic cardiac defects

Question 15

Genetic Cardiac Diseases

Answer 15

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

Question 16

Marfan Syndrome

Answer 16

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

Question 17

TGFb and fibrillin

Answer 17

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

Question 18

Optimal management of

Marfan

Answer 18

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

Question 19

Aortic Root Surgery for aneurysm in marfanss#

Answer 19

mechanical valve replacement lasts longer but need warfarin

valve sparing procedure may need reoperation but no warfarin

Question 20

Marfan - like syndromes

Answer 20

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

Question 21

Sudden Unexpected Death

Answer 21

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

Question 22

Genotype prediction

Answer 22

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

Question 23

Brugada syndrome

Answer 23

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

Question 24

ARVC

Answer 24

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

Question 25

Hypertrophic
Cardiomyopathy
Sarcomere disease alleles

Answer 25

Monoallelic
l MYH7 Beta cardiac myosin 30% 13% (7)
l MYBPC3 myosin binding protein 20% 19% (10)
l TNNT2 cardiac troponin T 20% 4% (2)
l TNNI3 cardiac troponin 5% 4% (2)
l Other genes 6% (3)
l Diallelic
l MYH7 2 mutations 4% (2)
l MYBPC3/TNNT2 2% (1)
Overall, Sarcomere genotyping 27/52 (52%) have a genetic abnormality

Question 26

Dilated Cardiomyopathy genes

Answer 26

l Genetic testing should include TTN, LMNA, MYH7, MYBPC3, TNNT2,
TNNI3, SCN5A, and perhaps other genes such as dystrophin

Question 27

Sanger sequencing

Answer 27

Sanger sequencing is a method of DNA sequencing based on the selective incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication.

Question 28

Inherited Cardiac Conditions how to tell

Answer 28

l Diagnosis in proband
l Cardiac phenotype
l Genetic testing
l Family history
l Assess relatives
l Cascade screening of relatives
l Prevention of avoidable
morbidity and mortality