What channelopathies present so early, and why? Or why is there an - - PowerPoint PPT Presentation

James C. Perry MD Electrophysiology Adult Congenital Heart Program

UC San Diego/Rady Children’s Hospital San Diego, California

What channelopathies present so early, and why?

Or … why is there an age-dependent presentation for channelopathy diseases?

Spoiler Alert!

I cannot answer these questions

Disclosures

• I have no formal genetics training or do lab-based genetic

science

• I was not clinically trained in the current era of genomics –

thanks to Mark Keating et al, I’ve had to relearn and try to keep up

• BUT!!! I’m old enough to see a big picture and ask questions
• Best outcome – this topic prompts some discussion
• Science. 1991 May 3;252(5006):704-6.

Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M

Start of the Big Picture from the clinic: The first discussion of “what’s channelopathy”…

I draw pictures

• “OK, I get it. But

why doesn’t the bad stuff happen ALL THE TIME?”

• “And why am I

fine with it, but my child was not?”

Parent response: after the first discussion of channelopathy…

Meds Pacemaker ICD Restrictions

The basic question: Why aren’t these channelopathy mutations LETHAL, from BIRTH (or earlier), ALL of the time?

Crude first hint?: Age-Dependent Clinical Disease Presentation

One of the more common issues we deal with: WPW and SVT We also don’t know why this happens early, then later.

Another age dependent change: Hemoglobin…

Circulation Journal Vol.80, March 2016

LQT “events”: LQT Type vs Age

?

Boczek et al. Circ CV Genetics 2016

Early age LQT: Genotype negative, phenotype positive NOW - Calmodulin mutations cause LQTS

Circulation Journal Vol.80, March 2016

Age dependent “Events”: LQT 1 and 2 Gender vs Age

LQT1 LQT2

Age-dependent “Events”: LQT 1 Gender, QTc, Mutation Location vs Age

Age-dependent “Events”: LQT 2 Gender, Mutation Location vs Age

Circulation Journal Vol.80, March 2016

Summary: Genotype, age onset

Role of “Founder” mutations vs Non-Founder mutations (small population, less genetic variability) Same mutation, but shorter QT, less syncope, other inherited genetic Founder factors?

Fetal

Fetal AVB Heterotaxy**

5 mo

Pre-op EKG DORV

14 mo

WES for FTT Ebstein, VSD**

7 yrs

Stress EKG ASD, hypo arch

8 yrs

Syncope, TdP IAA, DiGeorge

13 yrs

Syncope, TdP PO TOF

DOL 1

EKG: Long ST PS, hypo RV*

4 yrs

Pre-op EKG PDA LQT2 LQT1 LQT1 LQT1 LQT1 LQT1 (+LQT2 VUS) LQT2 LQT2 LQT2

arrhythmia EKG with CHD care incidental * Known positive family history; ** Positive cascade screening after LQTS diagnosis

EKG: Long ST Tri atresia

Ebrahim et al (submitted 2016)

LQT1 LQT2 LQT3 CALM TS BrS CPVT SVT Prenatal/NB 1 5 8 12 18 30 40+

Same mutation Not the same “disease”

(from the patient’s perspective)

“So, what about my child?”

“Probability of event” is not very patient-specific…

Incomplete Penetrance & Variable Expressivity

• Penetrance – same mutation, do you manifest the disease
• Expressivity – how severe are your clinical aspects of the disease
• Incomplete penetrance is the general rule in channelopathies

– “LQTS without a long QT”, – “what on Earth is Brugada Syndrome this week?”

• Is there any evidence for age-dependent variability in penetrance

and expressivity?

– Longitudinal changes in individual QTc by age – Severity of events by age (faint vs TdP)

Are there age-dependent (“dynamic”) regulators of gene expression that affect channelopathies?

Where to look?

• ther controls of gene expression
• SNPs, which allele?
• “second hit”; SNP or additional pathogenic

mutation

• Other common variants (e.g. NOS1AP and

QT interval)

• Environmental factors: epigenetics, ANS
• Cardiac anatomy, Embryology
• What of these other factors may be age-

dependent?

“Two hits” Common variants that affect QT

2013

Based on clinical LQT data, Penetrance and Expressity change with Age therefore - Static vs Dynamic Genomics

• Webster. Can J Cardiol 2013

1 - DNA methylation – generally decreases gene transcription 2 - Histone acetylation – generally increases gene transcription 3 - Long non-coding RNAs – can decrease or increase transcription

Epigenetic (dynamic) modifiers of gene expression

Dynamic DNA Code

1- DNA methylation: “aging”

• More a cell divides, the more opportunities for DNA methylation
• One-way process, Stem cell to differentiated cell
• Methyl groups added to DNA, 2 of 4 nucleotides can be methylated

Cytosine and adenine (prokaryotes) In humans, at locations where cytosine followed by guanine (CpG)

• Generally suppresses endogenous retroviral genes that are acquired over time
• If in gene promoter region, DNA methylation decreases gene transcription
• Generally, DNA methylation decreases with age
• (“Horvath’s epigenetic clock”)
• Between 5-10 years of age, environmental exposures change methylation

Dynamic DNA Code Genomic imprinting

• 2 copies of almost all genes, one from each parent
• ne gene out, other compensates
• Small number of genes, one copy ON one copy OFF –

“imprinting”

• In utero exposure to malnutrition – long term risks of CV, DM,
• besity, cancers
• Not known if this affects pertinent CV-related genes in an age-

dependent fashion

Li, Cell 2006

2 - Histones Age-dependent regulation: change of fetal to adult hemoglobin via chromatin looping due to histone acetylation

3 - Long non-coding RNAs

• Long noncoding RNAs (lncRNAs) are ≥200 nt long, abundant class
• f RNAs that are transcribed in complex patterns from both

intergenic and intronic regions of mammalian genome

• Age-dependent expression of lnc RNAs found in brain development

and aging

• MicroRNAs have been implicated in virtually all areas of

mammalian homeostatic gene regulation, to lower the expression of a shared target mRNA.

• Disruption of miRNA function has been causally linked to a variety
• f cardiovascular diseases (CVDs) that rise with advancing age.

Dynamic DNA Expression Exogenous triggers – clinical arrhythmias Heat/fever Stress Hypoxia Electrolyte abnormalities

Sakaguchi et al. J CV EP 2008

Different triggers by age:

Young – adrenergic Older - secondary

Different triggers by age and LQT subtype

Exogenous triggers

Autonomic nervous system versus age

• HR decreases with age
• PR prolongs with age
• Respiratory sinus arrhythmia starts around age 5-

10 years

• Atrial and ventricular ectopy in newborns then not

again until 7-8 years

• Changes in HF (parasymp) and LF (symp/para) in

spectral HR analysis with age and disease states

Triggers Ectopy Fever Stress Hypoxia Embryology STATIC Patient with channelopathy Autonomic changes Postural changes Epigenetics DNA methylation Histone acetylation lnc RNAs SNPs Physiology Pt AGE DYNAMIC Cumulative effect Regulation of gene expression

Why now??? Cumulative Developmental Arrhythmogenesis

SUBSTRATE TRIGGERS “environment” “modifiers” ANS anatomy & physiology embryology

AGE

genetic susceptibility

X X X X X X X X X X X X X X X X X X X X X X X X X X

Threshold for an EVENT

ectopy

“programmed cellular changes” response to dilation, HR, ERP

epigenetics, microbiome?

“ON/OFF”

Patient and age-specific therapies?

• If there’s risk, there’s “no risk” too –

– No therapy and no restrictions for long stretches of time, by specific pt age?

• Intervene by age depending on:

– Specific mutation – Age-dependent Epigenetic modification – Target the modifier: methylation, acetylation, purposeful environmental manipulation – If late age brings about lower risk, then induce a more “mature” gene expression?

We have seemingly isolated facts about “risk”

• QT type

– LQT 1>2>3 – LQT1: Male>Female risk at all ages – LQT2: Female risk increases at puberty – CALM – under 1 year old presentation (f/u?)

• QT duration: >500 always more risk
• Mutation: C-loop/pore > non
• Triggers

– LQT1: exercise – LQT2: emotion/noise – LQT3: rest/sleep – Older pt: 2° factors: low K+, AVB, drugs

Sounds like time for a “big data” opportunity

• Genomic Medicine Consortium:

– Sanford Children's – Children's Hospital Los Angeles – Rady Children's Hospital, San Diego – Children's Hospital Colorado – Children's Hospitals and Clinics of Minnesota – Banner Children's Tucson

• Need individual longitudinal data
• Public access
• Focus efforts on age-dependent epigenetics, microbiome (HMP)?
• Build a test algorithm: current age, gender, mutation, epigenetic

factors, age at presentation of prior untreated subjects, environmental exposures

we have a lot to learn…