19.04.12 Cardiac genetics

Question 1

What are the two main groups for cardiac groups?

Answer 1

1) Cardiomyopathies 2) Inherited cardiac arrhythmias

Question 2

What are cardiomyopathies?

Answer 2

• Disorders of cardiac muscle - Get measurable deterioration of cardiac muscle function - Due to various causes, such as inherited and sporadic pathogenic variants in muscle proteins, as well as external factors such as hypertension, ischemia, and inflammation - NOT caused by coronary artery disease, increased blood pressure/problems with heart’s valves - Phenotypic variation - can be asymptomatic to severe

Question 3

Name 5 main subtypes of cardiomyopathies

Answer 3

• Classification based on WHO guidelines according to phenotypic and clinical measurements 1) Dilated Cardiomyopathy (DCM) 2) Hypertrophic Cardiomyopathy (HCM) 3) Restricted cardiomyopathy (RCM) 4) Arrythmogenic Right Ventricular Cardiomyopathy (ARVC) 5) Left Ventricular Non-Compaction (LVNC)

Question 4

What are inherited cardiac arrhythmias?

Answer 4

• Disorders of heart’s electrical system resulting in tachycardia (fast), bradycardia (slow) or arrhythmia - Leading cause of sudden cardiac death (SCD)

Question 5

Name 4 main subtypes of inherited cardiac arrhythmias

Answer 5

1) Long QT Syndrome (LQT) 2) Brugada Syndrome (BS) 3) Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) 4) Short QT syndrome (SQT)

Question 6

DCM - What is the associated physiology and presentation?

Answer 6

• Increase in myocardial mass - Reduction in ventricular wall thickness - Globular shape to heart, diffuse endocardial thickening, decreased force of contraction - Most prevalent cardiomyopathy - Mainly adult onset - Range from asymptomatic, arrhythmia, reduced cardiac output, stroke, heart failure, SCD

Question 7

DCM - How is it diagnosed?

Answer 7

• Based on left ventricular enlargement and systolic dysfunction; cardiac MRI (CMR), echocardiogram (echo) - Idiopathic DCM - all acquired forms excluded - Familial DCM - ≥2 relatives with IDCM/SCD occurs at young age within family

Question 8

DCM - What are the common genetic causes?

Answer 8

• Can be AD, AR, X-linked and mitochondrial - Heterogeneous - >40 genes described - Titin (TTN) accounts for ~1/3 of inherited cases; huge gene, poorly characterized diagnostically - Variants in HCM genes have opposite effect in DCM e.g. MYH7 variants reduce motor function - MYH7 and LMNA each account for 5-8% of all Familial DCM cases

Question 9

HCM - What is the associated physiology and presentation?

Answer 9

• Typically asymmetric thickening of cardiac muscle, involving inter-ventricular septum (2/3 cases) - 25% of individuals have obstruction to outflow of blood from left ventricle at rest - 70% have obstruction provoked under certain conditions (dynamic outflow obstruction) - Symptoms include angina, palpitations, jerky pulse. - Range from asymptomatic, progressive heart failure to SCD (caused by ventricular fibrillation/tachycardia)

Question 10

HCM - How is it diagnosed?

Answer 10

• Unexplained hypertrophy of left ventricle (and occasionally right ventricle; CMR, echo) - Usually with predominant involvement of interventricular septum - Cardiomyocyte disarray and fibrosis on histology

Question 11

HCM - What are the common genetic causes?

Answer 11

• Typically AD with variable penetrance - Heterogenous - most variants in genes coding for sarcomeric proteins involved in contraction - 30% of HCM patients do not have sarcomere gene variants - 5-10% patients have multiple sarcomeric gene variants - dose-dependent severity

Question 12

RCM - What is the associated physiology and presentation?

Answer 12

• Ventricles become stiff (not necessarily thickened) - resist normal filling with blood - Common symptoms are fatigue, shortness of breath, oedema and abdominal enlargement, blood clots, arrhythmia and palpitations

Question 13

RCM - How is it diagnosed?

Answer 13

• Rhythmicity and contractility of heart may be normal - Blood flow reduced - backs up in circulatory system - RCM patients develop diastolic dysfunction and eventually heart failure; CMR, echo. - Can be a symptom of other conditions e.g. Churg-Strauss syndrome, cystinosis, lymphoma, Gaucher’s disease, hemochromatosis, Fabry’s disease

Question 14

RCM - What are the common genetic causes?

Answer 14

• Genes involved in HCM also involved in some cases of RCM (families with HCM can have RCM individuals)

Question 15

ARVC - What is the associated physiology and presentation?

Answer 15

• Progressive loss of cardiomyocytes (mainly in right ventricle) caused by massive/partial replacement of myocardium with fatty/fibro-fatty tissue; predisposes to electrical instability - Ventricular arrhythmias, heart palpitations, syncope, SCD - more common in adolescents and young adults; may be precipitated by exertion - Mean age of diagnosis = 31 years

Question 16

ARVC - How is it diagnosed?

Answer 16

• Detection of structural and rhythm abnormalities, family history - CMR, echo

Question 17

ARVC - What are the common genetic causes?

Answer 17

• 50% AD inheritance with incomplete penetrance. - Heterogeneous (>8 genes) - Include variants in genes involved in intercellular connections (e.g. desmoplakin (DSP)) and calcium homeostasis (e.g. RYR2) - can get compound heterozygosity (e.g. PKP2) and digenic variants e.g. PKP2 and DSG2

Question 18

LVNC - What is the associated physiology and presentation?

Answer 18

• Left ventricle appears spongy and “non-compacted” - Consists of meshwork of numerous muscle bands called trabeculations - Ranges from asymptomatic to heart insufficiency-related disorders e.g. fatigue, oedema in lower extremities, breathlessness, arrhythmia, increased risk of blood clots in heart

Question 19

LVNC - How is it diagnosed?

Answer 19

• Structural changes visible on CMR, ECG

Question 20

LVNC - What are the common genetic causes?

Answer 20

• AD, X-linked and mitochondrial inheritance - Heterogeneous - multigenic -each with small contribution e.g. TAZ, RYR2, LMNA and FKPB12

Question 21

LQTS - What is the associated physiology and presentation?

Answer 21

• Delay at end of each heartbeat - Heart takes longer than normal to repolarise - Delay visible on “Q-T” wave of ECG - Arrhythmogenic syncope, ventricular tachycardia, cardiac arrest and SCD - usually occur in conditions of either physical or emotional stress in otherwise healthy young individuals (mostly children and teenagers)

Question 22

LQTS - How is it diagnosed?

Answer 22

• ECG - resting ECG not 100% sensitive/specific for diagnosis - ~25% of patients with confirmed LQTS have normal range corrected QT (QTc) - Exercise-ECG tests/24–48 hour ECG monitoring may be required - Subdivided into types (based on genes in which variants occur - currently 15 types) - Types 1+2 = variants in K+ channels - Type 3= variants in Na+ channels - Types 1-3 account for ~75% of LQT cases - Romano-Ward syndrome = LQTS with purely cardiac phenotype, inherited in AD manner (LQTS types 1-3, 5, 6, and 9-15) - Jervell and Lange-Nielson syndrome (JLNS) = LQTS disorder caused by biallelic pathogenic KCNQ1/KCNE1 variants (AR) associated with profound sensorineural hearing loss

Question 23

LQTS - What are the common genetic causes?

Answer 23

• Genes associated with LQTS encode for potassium/sodium cardiac ion channels/interacting proteins - Pathogenic variants in these genes cause abnormal ion channel function: 1) loss of function in potassium channels 2) gain of function in sodium channel - Abnormal ion function results in prolongation of cardiac action potential and susceptibility of cardiac myocytes to early after depolarizations (EADs) which initiate ventricular arrhythmia, torsade de pointes (TdP) - AD and AR inheritance 1) AD: KCNQ1, KCNH2, and SCN5A pathogenic variants 2) AR: KCNQ1 and KCNE1 pathogenic variants

Question 24

Brugada syndrome - What is the associated physiology and presentation?

Answer 24

• Ventricular fibrillation caused by cardiac conduction abnormalities due to ST segment abnormalities on ECG
• Asymptomatic to SCD (mean age of SCD = 40yrs)
• Originally described in Southeast Asian populations where it is major cause of death

Question 25

Brugada syndrome - How is it diagnosed?

Answer 25

• Type 1 ECG (elevation of J wave ≥2 mm with negative T wave and ST segment that is coved type and gradually descending) in >1 right precordial lead (V1-V3) with/without administration of sodium channel blocker (i.e. flecainide, pilsicainide, ajmaline or procainamide)

Question 26

Brugada syndrome - What are the common genetic causes?

Answer 26

• AD inheritance >20 genes linked
• • E.g. SCN5A* (15-30% of cases) , GPD1L, CACNA1C , CACNB2, KCNE3 , SCN1B , SCN10A and HEY2
• • SCN5A* encodes α subunit of cardiac sodium channel
• Responsible for phase 0 of cardiac action potential
• Pathogenic variants in SCN5A decrease Na+ current availability either by lack of expression of mutated channel/accelerated inactivation of channel

Question 27

CPVT - What is the associated physiology and presentation?

Answer 27

• Inherited arrhythmogenic disease characterized by cardiac electrical instability exacerbated by acute activation of adrenergic nervous system
• Episodic syncope occurring during exercise/acute emotion in individuals without structural cardiac abnormalities; underlying cause is onset of fast ventricular tachycardia

Question 28

CPVT - How is it diagnosed?

Answer 28

• ECG during graded exercise (exercise stress test) allows ventricular arrhythmias to be reproducibly elicited in majority of affected individuals

Question 29

CPVT - What are the common genetic causes?

Answer 29

• AD and AR inheritance
  1) AD: RYR2 variants = 50-55% of cases
  2) AR: CASQ2 and TRDN

Question 30

ICC screening and treatment strategies

Answer 30

• Panel testing 25-72 genes
• Identify at risk individuals by cascade testing of family members using molecular genetic techniques
• Once definite pathogenic variant identified in index case, cascade testing of other family members can be performed using molecular genetics rather than clinical cardiology
• Individuals found to be mutation positive then followed up by cardiology
• Management is varied - includes drug treatments (e.g. beta blockers), risk management (e.g. stopping competitive sports, swimming, avoiding alarm clocks), corrective cardiac surgery and procedures, use of pacemakers and internal deliberators, LVAD, etc.
• ICCs are a leading cause of heart failure, and ultimately, heart transplant.