clinicians viewpoint of channelopathies: integrating science into … · 2016-10-25 · s-wave in...
TRANSCRIPT
![Page 1: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/1.jpg)
Clinicians Viewpoint of Channelopathies: Integrating Science into Practice
Andras Bratincsak, MD, PhD Kapi’olani Medical Specialists, Hawai’i Pacific Health
9th Annual International SADS Foundation Conference, September 30th, 2016
![Page 2: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/2.jpg)
Disclosure
No financial relationship relevant to this presentation.
![Page 3: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/3.jpg)
Phenotype to genotype
The aim of genetic studies 20-30 years ago was to connect an existing disease phenotype to a genotype.
![Page 4: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/4.jpg)
Explosion of discoveries
Finding genes that underlie complex traits. Glazier et al, 2002, Science.
![Page 5: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/5.jpg)
Genome available to anyone
Whole exome sequencing and whole genome sequencing is available to the public. What do we do with the information? Who is going to interpret it?
![Page 6: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/6.jpg)
What is in my genes?
![Page 7: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/7.jpg)
Gattaca - 1997
![Page 8: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/8.jpg)
Genetic printout
![Page 9: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/9.jpg)
Clinicians viewpoint
= parental perspective What does this mean to my patient? What is the risk of arrhythmia? How can I best treat it/prevent it?
![Page 10: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/10.jpg)
Mendelian 1-to-1
What the genes code is visible 100% penetrance 100% predictability
Versuche uber Pflanzen-Hybriden. Mendel, 1865.
![Page 11: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/11.jpg)
Variable phenotype
The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. Vincent et al, 1992, New Engl J Med.
![Page 12: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/12.jpg)
Variable penetrance
![Page 13: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/13.jpg)
Variable penetrance
![Page 14: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/14.jpg)
Gene to function
![Page 15: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/15.jpg)
Phenotypic plasticity
Everyone is different (1-to-0) 0% predictability Individualized medicine
![Page 16: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/16.jpg)
Example 1 - LQTS
Genotype: KCNH2 mutation E637K, non-conservative AA change in the pore-loop of IKr (rapid inward rectifying K)
![Page 17: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/17.jpg)
Example 1 - LQTS
![Page 18: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/18.jpg)
Example 1 - LQTS
The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. Vincent et al, 1992, New Engl J Med.
Predictors of cardiac events
Relative risk p-value
First cardiac event in childhood (<7 y)
4.34 (2.35-8.03) <0.001
QTc > 500 msec 2.01 (1.16-3.51) 0.01
LQT2 vs LQT1 LQT3 vs LQT1
2.81 (1.5-5.27) 4 (2.45-8.03)
0.001 <0.001
![Page 19: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/19.jpg)
Example 1 - LQTS
Genetic testing for long QT syndrome. Kapa et al, 2009, Circulation.
![Page 20: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/20.jpg)
Example 1 - LQTS
Consistent with LQT2 Appropriate risk stratification based on the type and location of mutation Therapy guided by mutation
![Page 21: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/21.jpg)
Example 2 - LQTS
Genotype: KCNQ1 mutation R594Q, semi-conservative AA change in the IKs (slow inward rectifying K) causing loss of function
QTc: 427 msec
QTc: 462 msec
![Page 22: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/22.jpg)
Example 2 - LQTS
The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. Vincent et al, 1992, New Engl J Med.
![Page 23: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/23.jpg)
Example 2 - LQTS
Low penetrance in the long-QT syndrome: clinical impact. Priori et al, 1999, Circulation
![Page 24: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/24.jpg)
Example 2 - LQTS
Risk stratification in the long-QT syndrome. Priori et al, 2003, New Engl J Med.
![Page 25: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/25.jpg)
Example 2 - LQTS
Variable phenotype, not always consistent with LQT1 Risk stratification may be useful based on LQT type, gender, and QTc length Therapy is standard, but not tailored to phenotype
![Page 26: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/26.jpg)
Example 3 - BrS
Genotype: SCN5A heterozygous mutation E1053K, non-conservative AA change in Na channel, c/w BrS1
![Page 27: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/27.jpg)
Example 3 - BrS
Genotyping helps in diagnosis, but up to 40% of BrS may be genotype negative. Genotyping does not influence risk stratification and therapy due to heterogeneity of symptoms and phenotype. Insights: Spontaneous type 1 ECG carries arrhythmia risk Brugada type 1 ECG pattern during fever suggests higher arrhythmia risk compared to drug-elicited BrS S-wave in lead I – marker for SCD in BrS
Prognostic significance of fever-induced Brugada syndrome. Mizusawa et al, 2016, Heart Rhythm.
A new electrocardiographic marker of sudden death in Brugada syndrome. Calo et al, 2016, J Am Coll Cardiol.
Risk stratification in Brugada syndrome. Priori et al, 2012, J Am Coll Cardiol.
![Page 28: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/28.jpg)
Example 3 - BrS
Consistent with BrS, not always Risk stratification based on phenotype Therapy is not guided by genotype
![Page 29: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/29.jpg)
Example 4 – CPVT (VUS)
Genotype: RyR3 deletion S443Y fsX20 causing frame shift and truncation of the ryanodine receptor – VUS
Genotype: RyR3 mutation K2723R resulting in a conservative AA change – VUS
![Page 30: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/30.jpg)
Example 4 - CPVT
CPVT guidelines: Genetic diagnosis is important, genes involved: RYR2, CALM1, CASQ, TRDN. Exercise stress testing: bidirectional or polymorphic VT Primary prevention and secondary prevention guided by genotyping and observed arrhythmias, SCA
![Page 31: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/31.jpg)
Example 4 - CPVT
VUS for CPVT Documented VT/VF triggered by exercise vs. PVCs Therapy based on phenotype
![Page 32: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/32.jpg)
Example 5 – Na channel
Genotype: SCN5A mutation R814W, non-conservative AA change in the voltage-sensing domain of the Nav1.5 channel
![Page 33: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/33.jpg)
Example 5 – Na channel
SCN5A mutations have been associated with DCM, BrS, LQT3, SIDS, CCD, AF. Even a single mutation (E1784K) has been associated with different phenotypes: LQT3 and BrS. R814W is a mutation in the voltage sensor domain, and has been documented in association with DCM, AF and VT, likely due to anomalous currents (window current, gating pore current).
Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. Olson et al, 2005, JAMA.
Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents.. Moreau et al, 2015, Front Pharmacol.
The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 lon g QT syndrome. Makita et al, 2008, J Clin Invest.
Long QT syndrome, from genetics to management. Schwartz et al, 2012, Circ Arrhythm Electrophysiol.
![Page 34: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/34.jpg)
Example 5 – Na channel
Not clear, phenotype c/w DCM, not c/w BrS, LQT3, AVB Not clear, FH is important Therapy based on phenotype, if phenotype is unclear…? SCA prevention
![Page 35: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/35.jpg)
Phenotypic plasticity
![Page 36: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/36.jpg)
From gene to protein
![Page 37: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/37.jpg)
EPIGENETICS
Modifying factors influencing expressivity, penetrance and the variable phenotype: • Genomic imprinting • Transcription enhancers and silencers • Single nucleotide polymorphism in the UTRs • Alternative splicing • Methylation • Post-translational modifications • Protein folding, trafficking, turnover • Ethnicity • Environmental factors
![Page 38: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/38.jpg)
Genomic imprinting
Human KVLQT1 gene shows tissue-specific imprinting. Lee et al, 1997, Nat Gen.
KCNQ1 gene encoding the KvLQT1 potassium channel
![Page 39: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/39.jpg)
Genomic imprinting
Variable biallelic expression in the cardiomyocyte
Human KVLQT1 gene shows tissue-specific imprinting. Lee et al, 1997, Nat Gen.
![Page 40: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/40.jpg)
RNA modulation
5’UTR 3’UTR exon intron exon intron
Enhancers / silencers long non-coding RNA micro RNA
![Page 41: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/41.jpg)
RNA modulation
5’UTR 3’UTR exon intron exon intron
![Page 42: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/42.jpg)
RNA modulation
![Page 43: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/43.jpg)
SNPs
Single nucleotide polymorphisms in non-coding regions
Genetic modifiers for the Long-QT syndrome. Crotti et al, 2016, Circ Cardiovasc Gen.
![Page 44: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/44.jpg)
SNPs
Variants in the 3’ UTR of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity. Amin et al, 2011, Eur Heart J.
![Page 45: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/45.jpg)
SNPs
Variants in the 3’ UTR of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity. Amin et al, 2011, Eur Heart J.
![Page 46: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/46.jpg)
Alternative splicing
![Page 47: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/47.jpg)
Alternative splicing
SCN5A exon 6 can be expressed in splice variants Canonical exon 6 – common adult variant Fetal exon 6A – a fetal splice variant with 7 AA altered in the voltage-sensing domain of the NaV1.5 channel with slower activation and inactivation and greater currents LQT3 severity has been associated with higher ratio of exon 6A in fetuses and infants Muscular dystrophy 1 patients can develop AF, CCD, VT – found to have exon 6A splice variants without mutation SIDS, VT, SUDS without genetic mutation?
![Page 48: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/48.jpg)
Ethnicity
Common sodium channel promoter haplotype in Asian subjects underlies variability in cardiac conduction. Bezzina et al, 2006.
![Page 49: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/49.jpg)
Epistasis
Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk. Mann et al, 2012, J Am Coll Cardiol..
![Page 50: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/50.jpg)
Post-translation modification Hydrophobic groups for membrane localization[edit] myristoylation, attachment of myristate, a C14 saturated acid palmitoylation, attachment of palmitate, a C16 saturated acid isoprenylation or prenylation, the addition of an isoprenoid group (e.g. farnesol and geranylgeraniol) farnesylation geranylgeranylation glypiation, glycosylphosphatidylinositol (GPI) anchor formation via an amide bond to C-terminal tail Cofactors for enhanced enzymatic activity[edit] lipoylation, attachment of a lipoate (C8) functional group flavin moiety (FMN or FAD) may be covalently attached heme C attachment via thioether bonds with cysteins phosphopantetheinylation, the addition of a 4'-phosphopantetheinyl moiety from coenzyme A, as in fatty acid, retinylidene Schiff base formation Modifications of translation factors[edit] diphthamide formation (on a histidine found in eEF2) ethanolamine phosphoglycerol attachment (on glutamate found in eEF1α)[9] hypusine formation (on conserved lysine of eIF5A (eukaryotic) and aIF5A (archaeal)) Smaller chemical groups[edit] acylation, e.g. O-acylation (esters), N-acylation (amides), S-acylation (thioesters) acetylation, the addition of an acetyl group, either at the N-terminus [10] of the protein or at lysine residues.[11] See also histone acetylation.[12][13] The reverse is called deacetylation. formylation alkylation, the addition of an alkyl group, e.g. methyl, ethyl methylation the addition of a methyl group, usually at lysine or arginine residues. The reverse is called demethylation. amide bond formation amidation at C-terminus amino acid addition
arginylation, a tRNA-mediation addition polyglutamylation, covalent linkage of glutamic acid residues to the N-terminus of tubulin and some other proteins.[14] (See tubulin polyglutamylase) polyglycylation, covalent linkage of one to more than 40 glycine residues to the tubulin C-terminal tail
butyrylation gamma-carboxylation dependent on Vitamin K[15] glycosylation, the addition of a glycosyl group to either arginine, asparagine, cysteine, hydroxylysine, serine, threonine, tyrosine,. polysialylation, addition of polysialic acid, PSA, to NCAM malonylation hydroxylation iodination (e.g. of thyroglobulin) nucleotide addition such as ADP-ribosylation oxidation phosphate ester (O-linked) or phosphoramidate (N-linked) formation phosphorylation, the addition of a phosphate group, usually to serine, threonine, and tyrosine (O-linked), or histidine (N-linked) adenylylation, the addition of an adenylyl moiety, usually to tyrosine (O-linked), or histidine and lysine (N-linked) propionylation pyroglutamate formation S-glutathionylation S-nitrosylation S-sulfenylation (aka S-sulphenylation), reversible covalent attachment of hydroxide to the thiol group of cysteine residues[16] succinylation addition of a succinyl group to lysine sulfation, the addition of a sulfate group to a tyrosine. Non-enzymatic additions in vivo[edit] glycation, the addition of a sugar molecule to a protein without the controlling action of an enzyme. carbamylation the addition of Isocyanic acid to an N-terminus of either lysine, histidine, taurine, arginine, or cysteine.[17] carbonylation the addition of carbon monoxide to other organic/inorganic compounds. Non-enzymatic additions in vitro[edit] biotinylation, acylation of conserved lysine residues with a biotin appendage pegylation
More than 200 PTM discovered: Phosphorylation Hydroxylation Carboxylation Palmitoylation Glycosylation Glycation Ubiquitination SUMOylation Neddylation
![Page 51: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/51.jpg)
Post-transcriptional modification
Glycosylation alters the voltage dependent gating of Nav1.5 channels. Glycosylation of IKs regulatory subunit encoded by KCNE1 at threonine-7 is essential for trafficking and membrane localization. S-nitrosylation of ryanodine receptor leads to progressive activation and increased Ca release. MOG1 enhances Nav1.5 channel trafficking and membrane localization.
Identifying potential functional impact of mutations and polymorphism. Jagu et al, 2013, Front Physiol.
![Page 52: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/52.jpg)
“Cellular” environment
Gender: male or female in long QT syndrome Hormones: estrogen Fever: enzyme kinetics, Brugada syndrome Drugs: drug induced long QT syndrome or BrS Glucose: TS Oxidative stress / NO availability
![Page 53: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/53.jpg)
Clinician viewpoint
Is somewhat different from the viewpoint of the policymakers: Policymakers – create guidelines based on established associations, scientific evidence and trends. Clinicians – deal with families 1-on-1 integrating science into practice, and making up for the gaps of science using judgment and individualized medicine.
![Page 54: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/54.jpg)
Back to Gattaca
Ideally I would love to tell a patient that Based on your mutation in gene X, the surrounding SNPs, the predicted genomic imprinting, alternative splicing during different time-points in your life, and additonal factors due to ehtnicity and gender: your ECG will look like A, your risk of SIDS is B%, risk of arrhythmia and SCA in teenage years is C%, and by age 40 rises to D%. Therefore I suggest strict q3h feeding until age 1 year, immidiate attention and medication of fever or vomiting/diarrhea, starting medication Y at age 2 weeks, adding medication Z and receiving an ICD by age 10.
![Page 55: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/55.jpg)
Genotype-phenotype
HRS/EHRA expert consensus statement. Ackerman et al, 2011, Europace.
![Page 56: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/56.jpg)
Phenotype-phenotype
Channelopathy Prognosis (SCA) Therapy
LQTS +++ (symptoms, scoring, QTc, TWA, TdP)
+ (symptoms, TdP)
SQTS +/- -
BrS ++ (symptoms, ECG) -
CPVT ++ (symptoms, EST) +
ARVC ++ (symptoms, scoring, MRI, ECG, Holter)
+
![Page 57: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/57.jpg)
Future trends
Laboratory studies replicating and confirming suspected phenotype-genotype correlations. Studies conducted in strictly stratified patient sub-groups analyzing genotype, SNPs, RNAs and clinical data (symptoms, ECG, Holter, ICD recording). Scoring algorithms for BrS, CPVT and SQTS integrating genotype and phenotype data. Potential therapeutic targets in transcription modifiers and post-translational modification.
![Page 58: Clinicians Viewpoint of Channelopathies: Integrating Science into … · 2016-10-25 · S-wave in lead I – marker for SCD in BrS . Prognostic significance of fever -induced BrugadaA](https://reader034.vdocuments.mx/reader034/viewer/2022050500/5f92c9e107180c0f753f9146/html5/thumbnails/58.jpg)
Thank you!