Sudden Cardiac Death: Use of Genetics in the diagnosis
Ramon Brugada MD PhD [email protected] “Genetic testing is expensive; the system can not afford it”
However, the real question is
can we, physicians, afford not doing it?
CORONARY ARTERY DISEASE CAUSES 80% OF SUDDEN CARDIAC DEATHS What do young people die from?
From the patient to the research laboratory
BRUGADA SYNDROME SHORT QT SCN5A SYNDROME KCNH2
HYPERTROPHIC LONG QT CARDIOMYOPATHY SYNDROME MYOSIN HEAVY CHAIN KCNQ1
DILATED CARDIOMYOPATHY MARFAN SYNDROME LAMIN A/C FIBRILLIN-1 Genetics of Sudden Cardiac Death Hypertrophic Cardiomyopathy
Assymetric hypertrophy of the left ventricle.
Most common cause of sudden cardiac death in the athlete.
Steve R. Ommen, and Bernard J. Gersh Eur Heart J 2009 Dilated Cardiomyopathy
Gene Symbol Gene Symbol
Cardiac α-actin ACTC Telethonin (T-cap) TCAP β-Myosin heavy chain MYH α-Sarcoglycan SGCA Cardiac troponin T TNNT2 β-Sarcoglycan SGCB α-Tropomyosin TPM1 δ-Sarcoglycan SGCD Titin TTN Dystrophin DMD Arrhythmogenic Right Ventricular Dysplasia
Right ventricular dilatation
Fibro adipose myocardial substitution
Sudden death often the first symptom
Sudden Cardiac Death: Electrical
Short QT syndrome Brugada syndrome
CPVT Long QT syndrome Long QT syndrome: Diagnosis Short QT syndrome: Diagnosis
Gollob MH et al. J Am Coll Cardiol 2011 Catecholaminergic polymorphic ventricular tachycardia Brugada Syndrome Diagnosis Genetic diseases associated with sudden cardiac death
CARDIOMYOPATHIES CHANNELOPATHIES Sudden Death: Monogenic diseases
Diseases associated with SCD
Channelopathies Cardiomyopathies 60% 30% 50%
50% 80% 60% 60% From the research laboratory to the patient
BRUGADA SYNDROME SHORT QT SCN5A SYNDROME KCNH2
HYPERTROPHIC CARDIOMYOPATHY LONG QT MYOSIN HEAVY CHAIN SYNDROME KCNQ1
DILATED CARDIOMYOPATHY MARFAN SYNDROME LAMIN A/C FIBRILLIN-1 Give an answer to the families
Research Translation Bringing research to the bedside
2007 -Consensus report on risk stratification in BrS 2008 -Consensus report on ion channelopathies 2009 -Compendium of scn5a gene mutations 2010 -Canadian recommendations on genetic testing 2011 -American and European recommendations Clinical Guidelines
Heart Rhythm 2011 Added value of genetics Recommendations on genetic testing
Disease Genetic Panel Patients Family Long QT Syndrome (LQTS) KCNQ1, KCNH2, SCN5A It is recommended It is recommended Catecholaminergic Polymorphic It is recommended RYR2, CASQ2 It is recommended Ventricular Tachycardia (CPVT) Brugada Syndrome (BrS) SCN5A Can be useful It is recommended
Short QT Syndrome (SQTS) KCNH2, KCNQ1, KCNJ2 May be considered It is recommended
Hypertrophic Cardiomyopathy MYH7, MYBPC3,TNNT2, TNNI3, It is recommended It is recommended (HCM) TPM1
Arrythmogenic right ventricular DSC2, DSG2, DSP, PKP2, It is recommended Can be useful cardiomyopathy (ARVC) TMEM43, JUP Dilated cardiomyopathy (DCM) LMNA, SCN5A It is recommended It is recommended It is recommended Left Ventricular MYH7, ACTC1, TNNT2, MYBPC3, Can be useful LBD3 noncompactation (LVnC)
Restrictive cardiomyopathy MYH7, ACTC1, TNNT2, TNNI3, May be considered It is recommended (RCM) It is recommended Clinically guided It is recommended Sudden Death Survival
Forensic Analysis in SCD. RYR2, KCNQ1, KCNH2, SCN5A It is recommended It is recommended Requirements for Clinical Genetic Testing
- State of the art laboratory - State of the Art technology - State of the Art technical procedures - State of the Art bioinformatics analyses - High quality diagnostic tools - Fast - Efficient - Reliable results
State of the Art technology
Variant name Gene Consequence cDNA 4_114213631_C/T ANK2 SYNONYMOUS_CODING 2390 CACNA 12_2558186_G/A 1C SYNONYMOUS_CODING 612 6_7577260_C/T DSP SYNONYMOUS_CODING 3203 15_48797307_A/G FBN1 SYNONYMOUS_CODING 2203 NON_SYNONYMOUS_CODIN 1_156106775_C/T LMNA G 1656 14_23874507_G/T MYH6 SYNONYMOUS_CODING 481 14_23899060_G/A MYH7 SYNONYMOUS_CODING 1140 NON_SYNONYMOUS_CODIN 3_38645420_T/C SCN5A G 1867 15_63351873_T/C TPM1 SYNONYMOUS_CODING 691 1_116311367_CA/- CASQ2 5PRIME_UTR 35-36 1_236926026_-/G ACTN2 3PRIME_UTR 2957-2958 1_237586384_T/C RYR2 SPLICE_SITE N/A 1_237996581_G/A RYR2 3PRIME_UTR 15856 CACNB 10_18439810_A/T 2 ESSENTIAL_SPLICE_SITE N/A 10_75879750_G/A VCL 3PRIME_UTR 5322 10_75879777_-/C VCL 3PRIME_UTR 5348-5349 10_88495504_C/G LDB3 3PRIME_UTR 4993 15_48779402_C/T FBN1 SPLICE_SITE N/A State of the Art bioinformatics Causal or Normal variant? State of the Art Research and Development The ion channel: the generator of the electrical activity
GENE EXPRESSION TRAFFIC TO MEMBRANE
GENETICS
POSTRANSLATIONAL MODIFICATIONS FUNCTIONAL ACTIVITY Requirements for Clinical Genetic Testing - State of the art laboratory - State of the Art technology - State of the Art technical procedures - State of the Art bioinformatics analyses - State of the Art Research and Development - High quality diagnostic tools - Fast - Efficient - Reliable results - Specialized support - Clinical support pre-genetic testing - Own pipeline pathogenicity algorithms - Support for genetic data interpretation - Support for clinical decision making
Interfamily variability
C1764G N588K
C1764A N588K Intrafamily variation Confirm a Genetic Diagnosis
MISSENSE MUTATION MYOSIN HEAVY CHAIN Reach a Diagnosis
54 years DELETION SYNCOPE DESMOPLAKINE Diagnosis based on the presence of a mutation Guide therapy and prevention Evaluation of borderline cases Complement clinical tests Identify non carriers Decisions on offspring
? Diagnosis in Unexplained sudden cardiac death One third of the unexplained deaths in the young are caused by a genetic cardiac disease Clinical cases Clinical cases
17 yo. SCD while exercising Clinical cases Clinical cases
Septum 16 mm Normal ECO Clinical cases
Septum 9 mm Septum 16 mm Septum 10 mm Septum 8 mm Clinical cases
Mutation MYH7
No Mutation MYH7
Septum 9 mm Septum 16 mm Septum 10 mm Septum 8 mm Clinical cases
8 yo SCD No ECG Clinical cases
40 years old SCD Clinical cases Clinical cases
45 years old Collapse in college QTc 460 Procainamide +
Clinical cases
44 years old asymptomatic QTc 480 Clinical cases
31 years old asymptomatic QTc 420
Sudden cardiac death in Canary Islands
- Family with more than 2000 members - 32 patients died suddenly at young age
Sudden cardiac death in Canary Islands
Basal ECG Isolated premature ventricular beats
Exercise progression Bidirectional ventricular arrhythmia SCD in the Canary islands Cardiac events in the family
p.G357S Clinical cases
TTN_p.Q18907X Epilepsy
23 yo Sudden cardiac death Hx of epilepsy for 20 years Sister with epilepsy Epilepsy
23 yo Sudden cardiac death Hx of epilepsy for 20 years Sister with epilepsy
Palpitations previous to epilepsy Associated with sudden loud noise Epilepsy
KCNH2_p.G604S Importance of segregation studies
? ?
LQS and Epilepsy epilepsy
SUDEP LQTS Importance of segregation studies
? ?
KCNE1 LQS and Epilepsy HTR2A epilepsy CDKL5 KCNQ1 CDKL5
SUDEP LQTS Deletion Exon 2 KCNQ1 KCNQ1 p.R98W (c.292C>T) KCNE1 KCNE1 p.PI206V (c.616A>G) HTR2A p.R914K (c.2714G>A) CDKL5 Importance of segregation studies
? ?
KCNE1 LQS and Epilepsy HTR2A epilepsy CDKL5 KCNQ1 CDKL5
SUDEP LQTS Deletion Exon 2 KCNQ1 KCNQ1 The deletion of exon 2 of KCNQ1 p.R98W (c.292C>T) KCNE1 KCNE1 gene could explain the LQTS and the p.PI206V (c.616A>G) HTR2A variant in CDKL5 gene could explain p.R914K (c.2714G>A) CDKL5 the epilepsy in this family Gencardio-SUDEP: Sudden Cardiac Death in Epilepsy Genetic predisposition to miocarditis? Benefits of using NGS Unexplained sudden cardiac death
10 years old Sudden Death Unexplained sudden cardiac death
Disease Genetic Panel Patients Family
Long QT Syndrome (LQTS) KCNQ1, KCNH2, SCN5A It is recommended It is recommended
Catecholaminergic Polymorphic It is recommended RYR2, CASQ2 It is recommended Ventricular Tachycardia (CPVT)
Brugada Syndrome (BrS) SCN5A Can be useful It is recommended
Short QT Syndrome (SQTS) KCNH2, KCNQ1, KCNJ2 May be considered It is recommended Hypertrophic Cardiomyopathy MYH7, MYBPC3,TNNT2, TNNI3, It is recommended It is recommended (HCM) TPM1
Arrythmogenic right ventricular DSC2, DSG2, DSP, PKP2, It is recommended Can be useful cardiomyopathy (ARVC) TMEM43, JUP
Dilated cardiomyopathy (DCM) LMNA, SCN5A It is recommended It is recommended
It is recommended Left Ventricular noncompactation MYH7, ACTC1, TNNT2, MYBPC3, LBD3 Can be useful (LVnC)
MYH7, ACTC1, TNNT2, TNNI3, May be considered It is recommended Restrictive cardiomyopathy (RCM)
It is recommended Clinically guided It is recommended Sudden Death Survival
Forensic Analysis in a Sudden Death RYR2, KCNQ1, KCNH2, It is recommended It is recommended Case SCN5A Unexplained sudden cardiac death
10 years old Sudden Death No mutation in SCN5A, RYR2, KCNQ1, KCNH2 Benefit of using NGS
10 years old Sudden Death Mutation GPD1-L Benefit of using NGS
Role of CNVs in Sudden Cardiac Death
Exon 6 Exon 7 Exon 8 Exon 9 Benefit of using NGS
FBN1 Dup exons 45-65
KCNH2_p.G903R GENETICS: A NEW DIAGNOSTIC TOOL “Doctor, if you had performed a genetic test would my brother still be alive?”
If you answer yes (or maybe) to that question, you are in trouble.
Thank you