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Cardiovascular System > Genetics of Inherited CV Disease > Flashcards

Genetics of Inherited CV Disease Flashcards

1
Q

What are the three basic inheritance patterns in CV diseases?

A

Autosomal dominant

Autosomal recessive

X-linked recessive

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2
Q

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

A

Autosomal dominant

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3
Q

What is reduced penetrance?

A

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

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4
Q

What is variable expressivity?

A

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

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5
Q

What is genetic heterogeneity?

A

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

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6
Q

What is pleiotropy?

A

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

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7
Q

What are the inherited CV diseases?

A
  • Arrhythmias
  • Cardiomyopathies
  • Aneurysm syndromes
  • Familial Hypercholesterolemia
  • Pulmonary Arterial Hypertension
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8
Q

Arrhythmias are usually due to gene mutations in ___ _______

A

ion channels

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9
Q

What are common findings associated with Arrhythmias?

A

Syncope

SCD (Sudden cardiac death)

SIDS (Sudden infant death syndrome)

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10
Q

At what age are patients affected with arrhythmias?

A

Any age

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11
Q

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

A

potassium

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12
Q

LQTS is associated with what life threatening complication?

A

Torsades de pointes (TdP)

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13
Q

Syncopal episodes of LQTS usually occur during ______ or ______ _______

A

exercise; high emotions

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14
Q

What are the congenital causes of LQTS?

A

Romano Ward syndrome (RWS)

Jervell and Lange-Nielson syndrome

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15
Q

What are some acquired causes of LQTS?

A
  • Primary myocardial problems (infarction/cardiomyopathy)
  • Electrolyte abnormalities
  • Autonomic influences
  • Drug effects
  • Hypothermia
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16
Q

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

A

males: >470
females: >480

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17
Q

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

A

males: 400-450
females: 400-470

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18
Q

What type of inheritance is shown by RWS?

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

A

Autosomal dominant; 50% (half)

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19
Q

How many genes are known to be associated with RWS?

A

13

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20
Q

What are the three most common genes associated with RWS?

A

KCNQ1

KCHN2 (HERG)

SCN5A

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21
Q

What events can trigger RWS in genetically susceptible individuals?

A
  • Exercise
  • Sudden emotion
  • Swimming
  • Postpartum
  • Sleep
22
Q

How is LQTS treated?

A
  • Avoidance of strenuous exercise (triggers)
  • Beta blockers
  • Pacemakers
  • Access to defibrillators
  • ICD
23
Q

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

A

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

24
Q

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

A

SIDS (sudden infant death syndrome); 15

25
Q

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

A

75%

26
Q

Why does a negative genetic test not rule out LQTS?

A

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

27
Q

Brugada syndrome presents as ______, _______ or ______

A

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

28
Q

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

A

SCN5A (alpha subunity of cardiac sodium channel)

29
Q

What is CPVT?

A

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
Q

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

A

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

31
Q

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

A

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
Q

What are the main proteins involved in cardiomyopathies?

A
  • Cytoskeletal proteins
  • Sarcomeres
  • Nuclear envelope proteins
  • Desmosomes
33
Q

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

A

Hypertrophic cardiomyopathy

34
Q

How do patients with HCM present clinically?

A
  • Typically includes chest pain, exertion related dyspnea or syncope
  • Majority of individuals remain asymptomatic
35
Q

HCM is a disease of the ______

A

sarcomere

36
Q

What is the inheritance pattern of HCM?

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

A

Autosomal dominant inheritance

  • MYH7: classic presentation
  • MYBPC3: later age of onset
  • TNNT2: mild or absent LVH; higher risk for arrhythmia
37
Q

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

A

Most likely HCM caused by multiple mutations

38
Q

Which cardiomyopathy is the primary indication for cardiac transplantation?

A

Dilated Cardiomyopathy

39
Q

Dilated cardiomyopathy usually occurs in what age group?

A

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

40
Q

What are the clinical features of DCM?

A

Congestive heart failure

Reduced cardiac output

Arrhythmias and/or conduction system disease

Thromboembolic disease

(Some patients may have muscle weakness or dystrophy)

41
Q

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

A

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

42
Q

What pattern of inheritance is associated with DCM?

What genes are often involved?

A

Most cases show autosomal dominant inheritance

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

43
Q

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?

A

LMNA (nuclear envelope gene)

Pleiotrophy

44
Q

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

A

ICD implantation

45
Q

Clinical screening for cardiomyopathy is recommended for….

A
  • 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
Q

How is Cardiomyopathy managed pharmacologically? Non-pharmacologically?

A

Pharm: ACE inhibitors and diuretics

  • Lifestyle modifications
  • Pacemakers, ICD
  • Surgical intervention (alcohol ablation)
  • Cardiac transplantation
47
Q

What are complications of Familial hypercholesterolemia?

A

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

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

48
Q

LDL and cholesterol levels in FH for…

Untreated adults?

Untreated children?

A

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

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

49
Q

What are the genes affected in FH?

A

LDLR (low density lipoprotein receptor)

APOB (apolipoprotein B)

PCSK9

50
Q

What two patterns of inheritance are associated with FH?

A

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

51
Q

What are the benefits of genetic testing for FH?

A
  • Risk factor modification before onset of disease
  • Pharmacotherapy : statins (HoFH not responsive)
  • Early screening and therapy for elevated cholesterol levels
52
Q

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

A

Prevents insurance discrimination based on genetic testing results

Cardiovascular System (35 decks)

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