Genetics of Inherited CV Disease Flashcards Preview

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Flashcards in Genetics of Inherited CV Disease Deck (52):
1

What are the three basic inheritance patterns in CV diseases?

Autosomal dominant

Autosomal recessive

X-linked recessive

2

If affected parents have a 50% chance of having an affected child, the inheritance pattern is...

Autosomal dominant

3

What is reduced penetrance?

Less than 100% of individuals with a certain genotype actually express signs or symptoms

4

What is variable expressivity?

The signs and symptoms of a genetic condition differ among affected individuals

5

What is genetic heterogeneity?

A genetic disorder can be caused by more than one mutation in an allele

6

What is pleiotropy?

Genetic variants in a particular allele can cause several signs or symptoms

7

What are the inherited CV diseases?

  • Arrhythmias
  • Cardiomyopathies
  • Aneurysm syndromes
  • Familial Hypercholesterolemia
  • Pulmonary Arterial Hypertension

8

Arrhythmias are usually due to gene mutations in ___ _______

ion channels

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9

What are common findings associated with Arrhythmias?

Syncope

SCD (Sudden cardiac death)

SIDS (Sudden infant death syndrome)

10

At what age are patients affected with arrhythmias?

Any age

11

Long QT syndrome (LQTS) is usually caused by mutations in  _______ channels

potassium

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12

LQTS is associated with what life threatening complication?

Torsades de pointes (TdP)

13

Syncopal episodes of LQTS usually occur during ______ or ______ _______

exercise; high emotions

14

What are the congenital causes of LQTS?

Romano Ward syndrome (RWS)

Jervell and Lange-Nielson syndrome

15

What are some acquired causes of LQTS?

  • Primary myocardial problems (infarction/cardiomyopathy)
  • Electrolyte abnormalities
  • Autonomic influences
  • Drug effects
  • Hypothermia

16

What QT intervals are indicative of positive certainty for RWS (68% of affected individuals) in males? females?

males: >470

females: >480

17

QT intervals which cause uncertainty of RWS diagnosis are between what two values for males and what two values for females?

males: 400-450

females: 400-470

18

What type of inheritance is shown by RWS?

___ of individuals with RWS mutation will not show symptoms (reduced penetrance)

Autosomal dominant; 50% (half)

19

How many genes are known to be associated with RWS?

13

20

What are the three most common genes associated with RWS?

KCNQ1

KCHN2 (HERG)

SCN5A

21

What events can trigger RWS in genetically susceptible individuals?

  • Exercise
  • Sudden emotion
  • Swimming
  • Postpartum
  • Sleep

22

How is LQTS treated?

  • Avoidance of strenuous exercise (triggers)
  • Beta blockers
  • Pacemakers
  • Access to defibrillators
  • ICD

23

What clinical defects are associated with Jervell and Lange-Nielson syndrome (JLNS)?

Congenital, proofound, bilateral sensorineural deafness and QT prolongation often > 500ms

24

Infants with JLNS have increased risk for _____ and > 50% of untreated children with JLNS die prior to age ___

SIDS (sudden infant death syndrome); 15

25

In genetic testing for RWS, what is the current detection rate?

75%

26

Why does a negative genetic test not rule out LQTS?

5-12% of patients with normal sequencing of the most common LQTS genes had large genomic rearrangements

27

Brugada syndrome presents as ______, _______ or ______

Syncope, SIDS, SUNDS (sudden unexpected nocturnal death syndrome)

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28

What genetic defect is most likely to be seen in Brugada syndrome?

SCN5A (alpha subunity of cardiac sodium channel)

29

What is CPVT?

Cathelominergic polymorphic ventricular tachycardia

  • Syncope caused by exercise or acute emotion in an individual without structural heart disease
  • Tachycardia that can degenerate into ventricular fibrillation and cause sudden death

30

For CPVT, gene mutations in ______ are inherited in an autosomal dominant manner while gene mutations in _____ are inherited in an autosomal recessive manner

RYR2 (Cardiac ryanodine receptor channel); CASQ2 (calsequestrin - calcium binding protein of the sarcoplasmic reticulum)

31

What is the difference between single gene analysis and gene panels?

Single gene analysis allows for coding exon sequencing to evaluate the mutation in one gene

Gene panels perform massive parallel sequencing of the coding exons within multiple genes

32

What are the main proteins involved in cardiomyopathies?

  • Cytoskeletal proteins
  • Sarcomeres
  • Nuclear envelope proteins
  • Desmosomes

33

Which cardiomyopathy is a major cause of sudden cardiac death (SCD) in the young and the most common cause of SCD in young athletes

Hypertrophic cardiomyopathy

34

How do patients with HCM present clinically?

  • Typically includes chest pain, exertion related dyspnea or syncope
  • Majority of individuals remain asymptomatic

 

35

HCM is a disease of the ______

sarcomere

36

What is the inheritance pattern of HCM?

What are the 3 most common gene mutations and how do they present?

Autosomal dominant inheritance

  • MYH7: classic presentation
  • MYBPC3: later age of onset
  • TNNT2: mild or absent LVH; higher risk for arrhythmia

37

Why are 6% of individuals with HCM more severely affected, showing earlier age of onset, more severe LVH and more frequent and rapid progression?

Most likely HCM caused by multiple mutations

38

Which cardiomyopathy is the primary indication for cardiac transplantation?

Dilated Cardiomyopathy

39

Dilated cardiomyopathy usually occurs in what age group?

Adult years (30s to 50s) - but varies widely

40

What are the clinical features of DCM?

Congestive heart failure

Reduced cardiac output

Arrhythmias and/or conduction system disease

Thromboembolic disease

(Some patients may have muscle weakness or dystrophy)

41

What would prompt genetic testing to rule out an idiopathic cause to DCM?

Two or more closely related family members that meet the criteria for idiopathic DCM (non-aquired type)

42

What pattern of inheritance is associated with DCM?

What genes are often involved?

Most cases show autosomal dominant inheritance

Genes involved in sarcomere, Z-disk, nuclear lamina, intermediate filaments, desmosomes, dystrophin...

43

What gene mutation is associated with DCM, muscular dystrophy, Hutchinson-Gilford progeria syndrome (Benjamin Button disease) and bracydactyly?

What is it called when a gene mutation has multiple manifestations?

LMNA (nuclear envelope gene)

Pleiotrophy

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44

If an LMNA mutation is detected, patients may benefit from a ___ _________ before EF<35%

ICD implantation

45

Clinical screening for cardiomyopathy is recommended for....

  • Asymptomatic first degree relatives
  • At-risk relatives who are know to carry the disease causing mutation
  • Asymptomatic at-risk first degree relatives when genetic testing has not been performed or has not identified a disease-causing mutation

46

How is Cardiomyopathy managed pharmacologically? Non-pharmacologically?

 Pharm: ACE inhibitors and diuretics

  • Lifestyle modifications
  • Pacemakers, ICD
  • Surgical intervention (alcohol ablation)
  • Cardiac transplantation

47

What are complications of Familial hypercholesterolemia?

Xanthomas: yellowish cholesterol rich material in tendons or other body parts

Atheromas: Accumulation of debris containing cholesterol in the artery walls (plaques)

48

LDL and cholesterol levels in FH for...

Untreated adults?

Untreated children?

Untreated adults: LDL-C> 190 or total cholesterol >310

Untreated children: LDL-C > 160 or total cholesterol > 230

49

What are the genes affected in FH?

LDLR (low density lipoprotein receptor)

APOB (apolipoprotein B)

PCSK9

50

What two patterns of inheritance are associated with FH?

Autosomal dominant (HeFH) and autosomal recessive (HoFH) inheritance

51

What are the benefits of genetic testing for FH?

  • Risk factor modification before onset of disease
  • Pharmacotherapy : statins (HoFH not responsive)
  • Early screening and therapy for elevated cholesterol levels

52

What did GINA (2008) do to affect genetic testing?

Prevents insurance discrimination based on genetic testing results