Unexplained Sudden Cardiac Death in Saudi Arabia presentation2011/008005.pdf · Klinische Genetica...
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Unexplained Sudden Cardiac Death in Saudi Arabia
Transcript of Unexplained Sudden Cardiac Death in Saudi Arabia presentation2011/008005.pdf · Klinische Genetica...
Klinische Genetica
Unexplained Sudden Cardiac Death in Saudi Arabia
Klinische Genetica
Klinische Genetica
Sudden Unexplained DeathBoy: 1 yearGirl: 1 and ½ yearGirl: 16 yearBoy: 26 yearBoy: 16 year
Klinische Genetica
Family A:
VI:1: Sudden Death at 10 yrs, drowningVI:2: Sudden death at 5 yrs.VI:4: 3yrs, Aborted Sudden Cardiac ArrestVI:5: Sudden death at 12 yrs
Family B:
II:1: Sudden Death at 2 yrs with ConvulsionII:4: 14 yrs, Aborted Sudden Cardiac Arrest
I:1 I:2
II:1 II:2 II:3
III:1
II:4
III:2 III:3 III:4 III:5 III:6
IV:1 IV:2
V:1
V:2
V:3
V:4
VI:1 VI:2 VI:3 VI:4 VI:5
Family A
Family A and B: Referred by Dr. Tarek Momenah, PSCC
Family B
I:1 I:2
II:2II:1 II:3 II:4 II:5 II:6
Klinische Genetica
DSG2
DSG2
DSC2
DSC2PKP2
PKP2 JUP
JUP
DSPDSP
Heart at the Cellular Level
P
Q
T
R
S
Function of the Heart
Sino-atrial nodeAtrio-ventricular node
Left atrium
Right atrium
Right Ventricle Left Ventricle
Klinische Genetica
Heart at the Cellular Level: Ion Channels
Klinische Genetica
• Long QT Syndrome• Brugada Syndrome• Catecholamine-induced PMVT/VF• Short QT Syndrome• Isolated Cardiac Conduction Disorders • Familial Atrial Fibrillation• Sinus Node Disease, Atrial Standstill• Arrhythmogenic Right Ventricular Dysplasia/
Cardiomypathy
Cardiac Arrhythmia Syndromes
Klinische Genetica
Family A:
VI:1: Sudden Death at 10 yrs, drowningVI:2: Sudden death at 5 yrs.VI:4: 3yrs, Aborted Sudden Cardiac ArrestVI:5: Sudden death at 12 yrs
Family B:
II:1: Sudden Death at 2 yrs with ConvulsionII:4: 14 yrs, Aborted Sudden Cardiac Arrest
I:1 I:2
II:1 II:2 II:3
III:1
II:4
III:2 III:3 III:4 III:5 III:6
IV:1 IV:2
V:1
V:2
V:3
V:4
VI:1 VI:2 VI:3 VI:4 VI:5
Family A
Family A and B: Referred by Dr. Tarek Momenah, PSCC
Family B
I:1 I:2
II:2II:1 II:3 II:4 II:5 II:6
Klinische Genetica
Clinical Phenotypes
Triggering Factor
Family History
ECG Phenotypes
Investigation of Familial Cardiac Arrhythmia Syndromes
Klinische Genetica
Father
Mother
Child with History of Unconsciousness
ECG of Family Members with History of Sudden Unexplained Death
HealthySon
Klinische Genetica
Father
Mother
HealthySon Child with History of Unconsciousness
ECG of Family Members with History of Sudden Unexplained Death
Klinische Genetica
GTCTAGCAGCTTCCT
Patients
T>A (homozygous) Exon 2
GTCT T GCAGCTTCCT
Heterozygous carriers
T>A (heterozygous) Exon 2
DNA Analysis: KCNQ1 Gene
Klinische Genetica
E1a E1b E2 E3 E4 E5 E15
-5 T>A intron 1
DNA Analysis: KCNQ1 Gene
Klinische Genetica
1 1g gc c2 31 21 1
Family B
I:1 I:2
II:2II:1 II:3 II:4 II:5 II:6
I:1
I:2
II:1 II:2 II:3
III:1
II:4
III:2
III:3
III:4
III:5
III:6
IV:1
IV:2
V:1 V:2 V:3
V:4
VI:1
VI:2
VI:3
VI:4
VI:5
D11S4046(KCNQ1) Exon 13(KCNQ1) Exon 16D11S1338D11S902
D11S4046(KCNQ1) Exon 13(KCNQ1) Exon 16D11S1338D11S902
2 1a gc c3 13 2
2 1a gc t3 13 1
1 1g gc t1 12 1
3 1a gc t2 11 1
Family A
Arrhythmia Causing Founder Mutation in Assir
Klinische Genetica
N.H
Courtesy of Dr. Safar Al-Shahrani, Khamis Mashayt Military Hospital
N. H
Arrhythmia Causing Founder Mutation in Assir
Klinische Genetica
c.387 -5T>A in KCNQ1 gene is an Ancestral Founder Mutation in Assir Region of Saudi Arabia: Responsible for Cardiac Arrhythmia
Quite significant number of people from Assir region Carry this mutation.
Klinische Genetica
Disease (Arrhythmia)
Gene Mutation
Aberrant Protein Structure/Function
Pathology
Klinische Genetica
Mutation affects the Conduction Property of the Heart
Klinische Genetica
Klinische Genetica
ECG-PatientECG from the Patient
Klinische Genetica
ECG-FatherECG from the Father
Klinische Genetica
ECG-MotherECG from the Mother
Klinische Genetica
ECG from the Brother
Klinische Genetica
ECG-SisterECG from the Sister
Klinische Genetica
AAGGGGAGACTCTGCTGACACCC AAGGGGAGACTGCTGACACCC
AAGGGGAGACT………………… AAGGGGAGACT…………………
Control Patient
Father Mother
Genetic Analysis
Klinische Genetica
AAGGGGAGACTCTGCTGACACCC AAGGGGAGACTGCTGACACCC
AAGGGGAGACT………………… AAGGGGAGACT…………………
Control Patient
Father Mother
Genetic Analysis
Klinische Genetica
c.1486_1487delCT in KCNQ1 gene is MOST LIKELY an Ancestral Founder Mutation in
Al Baha region of Saudi Arabia: Responsible for Cardiac Arrhythmia
Klinische Genetica
Disease Transmission from Both Parents
Klinische Genetica
What About Madinah
Klinische Genetica
Patient from Madinah
2 yr old girl: Arrhythmia & Deaf
Klinische Genetica
Patient from Madinah
Father: NO symptom
Klinische Genetica
Patient from Madinah
Mother with occasional palpitation
Klinische Genetica
Patient from Madinah
Klinische Genetica
Patient from Madinah
TGGGCCTCATCTTCTCCTCGTAC TGGGCCTC…………………………
TGTGGTGGTGATGAGCCCAC TGTGGTGGTGATGAGCCCAC
Control Patient
Control Patient
Klinische Genetica
Disease Transmission: De Novo Origin
Klinische Genetica
Sudden Unexplained DeathBoy: 1 yearGirl: 1 and ½ yearGirl: 16 yearBoy: 26 yearBoy: 16 year
Klinische Genetica
ECG of the 6 yr old girl
QTc= 453 ms
Klinische Genetica
1168-TCCACCTGGAAGATCTACATC390- S T W K I Y I
1168-TCCACCTGGAATATCTACATC390- S T W N I Y I
Screening of the KCNQ1 Gene
Klinische Genetica
1168-TCCACCTGGAAGATCTACATC390- S T W K I Y I
1168-TCCACCTGGAATATCTACATC390- S T W N I Y I
Heterozygous G>T Homozygous G>T
Screening of the KCNQ1 Gene
Klinische Genetica
Neonatal Arrhythmia
Klinische Genetica
miscarriage,8th week
Mis-carriage,10th week
Still birth, 29th week
I:1 I:2
II:1 II:2 II:3 II:4 II:5 II:6 II:7
320 314155 14385 71336 332
320 320151 15585 85
334 336
320 320155 15585 85
332 336
320 320155 15585 85336 336
D7S661D7S636D7S798D7S2465
D7S661D7S636D7S798D7S2465
Patient from Assir
22nd week: bradycardia23-24th week:bradycardia/tachyarrhythmiastill birth: 29th week
22nd week: bradycardia24th week:bradycardia/tachyarrhythmia
Klinische Genetica
ECG: First day
Klinische Genetica
Father
MotherBrother
ECG: Father, Mother, Brother
Klinische Genetica
New Family from Assir
Klinische Genetica
ECG of the Neonate
Klinische Genetica
Screening the KCNH2 Gene
Klinische Genetica
c.3208 C>T in KCNH2 gene is an Ancestral Founder Mutation in Assir Region of Saudi Arabia: Responsible for Cardiac Arrhythmia
Klinische Genetica
Klinische Genetica
Conclusions from the Study
►Role of Genetics is Crucial in Cardiac Arrhythmia and/orSudden Cardiac Death.
► We have identified several ancestral founder mutations inSaudi Arabia, which are NOT UNCOMMON.
► Timely identification of the Genetic Aetiology will lead toproper preventive and as well curative measures.
► Genetic Investigation should always be considered in patientmanagement.
Klinische Genetica
Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders
King Abdulaziz University, Medical School, JeddahTel: 0264020000 Ext# 21053 or 20115Fax: 0264020000 Ext # 20115 or 20519
E. mail: [email protected]
Clinical Genetic Investigation of Arrhythmia
Klinische Genetica
Acknowledgments
▶Dr. Tarek Momenah, PSCC, Riyadh
▶Prof. Dr. Arthur Wilde, Amsterdam University
▶Dr. Saleh Al-Ghamdi, PSCC, Riyadh
▶Dr. Jumana Al-Aama, PACER-HD, Jeddah
▶Dr. Safar Al-Shahrani, Khamis Mashayt Military Hospital
▶Ms. Khalda Nasser, Ms. Alaa Qarawi, PACER-HD, Jeddah.
▶King Abdulaziz City for Science & Technology
Klinische Genetica
Merci beaucoup
Klinische Genetica
Cellular Localization
Control Patients
Klinische Genetica
Electrical Property of the Mutant KCNQ1
Klinische Genetica
Disease Transmission from One Parent
Klinische Genetica
Disease Transmission: De Novo Origin
Klinische Genetica
Conclusions from the Study
• c.387 -5 T>A (KCNQ1) is a LQT, type 1 causing Founder mutation in Saudi Arabia.
• Biallelic/Homozygous carriers are highly susceptible to Fatal Arrhythmias and Sudden Death (but no Deafness).
• Monoallelic carriers for this mutation are unlikely to suffer from LQT1 mediated arrhythmia.
• Cascade screening is strongly recommended in this community for this mutation as β–blockers could effectively protect the carriers from unexpected sudden deaths.
Klinische Genetica
Family-C: Homozygosity Mapping
Klinische Genetica
Family-D
