Adding Genetics to the Cardiologist’s Toolbox

Adding Genetics to the Cardiologist’s Toolbox

Matthew Taylor MD, PhD: matthew.taylor@cuanschutz.eduAdult Medical Genetics Program / Colorado Center for Personalized Medicine,

Division of Cardiology / Department of Medicinehttp://dx.doi.org/10.1172/JCI62862

26th Annual San Diego Heart Failure Symposium| September 2020

Normal Dilated CardiomyopathyGenetics Abnormal Genetics

Roadmap

• Advances in the field of genetics

• Broad impact on Cardiology

• Specific impact on Heart Failure

The Human Genome Project: 1990 – 2003

Strategy and early mapping

H. Influenzae sequenced

c. Elegans sequenced

Full-scale human sequencing begins

GWAS Diagram Browser http://ebi.ac.uk

Past: Before Human Genome Project (1990-2003)

Present: After Human Genome Project (Post-Genomic Era 2003-2020)

Future: Projected Medical Genomics Field (2020 - )

M Taylor

~3-4,000 genetic disorders

Phenotype description >> Biologic understanding

Very few genetic tests (most single gene)

<5 genetic therapies for genetic diseases

Genetic testing expensive & inaccessible

Genetic testing of minimal relevance to non-

geneticists

Molecular basis genetic disorders ~unknown

~>6,000 genetic disorders

Molecular basis genetic disorders ~known

Phenotype description = Biological understanding

1000 genetic tests(expanding panels)

Genetic testing expensive but increasingly accessible

Genetic testing of relevance to many

cliniciansFew dozen genetic therapies (100s in

pipeline)

It’s ~all genetic + environment

Maturation ofStem cell therapy

RNA IGene Therapy

CAR-T (for non-cancer also)Genome Editing

Pre-symptomatic ‘cures’

Biological understanding >> Phenotype description

Genome TestingAddition of: transcriptomics,

proteomics, metabolomics, and methylomics

Genome Democratization àavailable to all persons and not limited by race, socioeconomic

status, resources, etc.

GWAS in common diseases à PRS

Disease model accelerates (animals, cell lines, stem cells). HT drug screens

Biological understanding improves treatment. Genotype à phenotype

Testing AdvancesDiagnostics (Diagnostic Exome)Risk Assessment / PrognosticsPrenatal (Preimplantation GT)

Discovery (Secondary Findings Exome)Pharmacogenetics

Infectious Disease (HIV, HepC, CoV-2Wellness (Screening Exome)Direct-to-Consumer Testing

Successes: RNA-based therapies, small molecules, CAR-T cells, gene therapies

à Growing relevance of ethical, cultural, societal, and equitability of resource issues à

Past: Before Human Genome Project (1990-2003)

Present: After Human Genome Project (Post-Genomic Era 2003-2020)

Future: Projected Medical Genomics Field (2020 - )

M Taylor

~3-4,000 genetic disorders

Phenotype description >> Biologic understanding

Very few genetic tests (most single gene)

<5 genetic therapies for genetic diseases

Genetic testing expensive & inaccessible

Genetic testing of minimal relevance to non-

geneticists

Molecular basis genetic disorders ~unknown

~>6,000 genetic disorders

Molecular basis genetic disorders ~known

Phenotype description = Biological understanding

1000 genetic tests(expanding panels)

Genetic testing expensive but increasingly accessible

Few dozen genetic therapies (100s in

pipeline)

Genetic testing of relevance to many

clinicians

It’s ~all genetic + environment

Maturation ofStem cell therapy

RNA IGene Therapy

CAR-T (for non-cancer also)Genome Editing

Pre-symptomatic ‘cures’

Biological understanding >> Phenotype description

Genome TestingAddition of: transcriptomics,

proteomics, metabolomics, and methylomics

Genome Democratization àavailable to all persons and not limited by race, socioeconomic

status, resources, etc.

GWAS in common diseases à PRS

Disease model accelerates (animals, cell lines, stem cells). HT drug screens

Biological understanding improves treatment. Genotype à phenotype

Testing AdvancesDiagnostics (Diagnostic Exome)

Risk Assessment / PrognosticsPrenatal (Preimplantation GT)

Discovery (Secondary Findings Exome)Pharmacogenetics

Infectious Disease (HIV, HepC, CoV-2Wellness (Screening Exome)Direct-to-Consumer Testing

Successes: RNA-based therapies, small molecules, CAR-T cells, gene therapies

à Growing relevance of ethical, cultural, societal, and equitability of resource issues à

Progress in Genetic Testing: Last ~30 Years

Rare Genetic Diseases

Clinical Gestalt

Diagnoses

Gene Discovery

Mono-Genetic Testing

Oligo-Genetic Testing

Panel-Genetic Testing

Genomic Testing

‘Not’ Genetic Rare Mono-Genetic Complex Genetic Pharmacogenetic

Human Genome Project

Cost per human genome

‘Next Generation’ DNA Sequencing

The ‘Next’ Next-Generation Sequencers

Roadmap

• Advances in the field of genetics– Genetic underpinnings of most diseases identified

and beginning to be understood– Diagnostics (genetic testing) permeating medicine– On the cusp of using genotype to guide

management• Broad impact on Cardiology

• Specific impact on Heart Failure

Cardiomyopathies

Dilated (40-50%)

Hypertrophic (50%)

ARVC (20%)

LVNC (?)

10-90%+ genetic

Arrhythmias

Long QT (QTc prolonged)

Short QT (QTc shortened)

Brugada (ECG pattern)

CPVT (normal ECG)

20-80+% genetic

Sudden Death

Too-young-to-die events

Pediatric (arrhythmias)

Adult (> cardiomyopathies)

Unknown (frequently)

1-10% genetic

Flav

ors

Gen

etic

s

Marfan / Aortopathies

Marfan

Loeys Dietz

Familial Thoracic Aortic Aneurysm

Spontaneous dissections

5-95% Genetic

Congenital Heart Disease

Trisomy 21

22q

Noonan

Holt Oram

Syndromes are mostly genetic

Others

Lipid disorders

Pulmonary HTN / HHT

HTN Disorders

Multifactorial

Neuromuscular

Variable

Caus

esFi

ndin

gs

Circ Genom Precis Med. 2019;12:e000054.

Roadmap

• Advances in the field of genetics

• Broad impact on Cardiology– Growing number of cardiovascular conditions have a

diagnosable genetic etiology– Genetic diagnosis enables: diagnosis, family member

screening >> prognosis and management considerations >> targeted therapies >>> potential cures

• Specific impact on Heart Failure

55 y/o man with NYHA class IV HF

• ~5-10 years of: – hypertrophic (non-obstructive) cardiomyopathy– IVSd: 20mm, LVPWd 16mm, EF: 33%– atrial fibrillation and progressive symptoms

• Family history: – brother died suddenly at age 50

• Transplant evaluation: – included cath and endomyocardial biopsies à

Diagnosis of Fabry Cardiomyopathy• Novel, mutation directed, therapy applied

– Within 3 months, NYHA class IV, off transplant list– Novel therapy FDA approved 2018

N Engl J Med. 2001 Jul 5;345(1):25-32.

36 year old man with Dilated Cardiomyopathy

• 12-year history of non-exertional chest pain à– echocardiogram = MVP

• Developed shortness of breath à– echocardiogram= Dilated cardiomyopathy & ejection

fraction of 43%• Family History– Paternal uncle d. 57 with enlarged heart (alcohol user)– Paternal grandfather d. 38 of a ‘heart attack’

• A Pathogenic variant, c.514C>T (p.Gln172*), was identified in BAG3.– The BAG3 gene is associated with autosomal dominant dilated cardiomyopathy (DCM) (MedGen

UID: 462643), myofibrillar myopathy 6 (MFM6) (MedGen UID: 414119) and Charcot-Marie-Tooth disease type 2 (PMID:28754666)

• A Pathogenic variant, c.1807delG (p.Val603Trpfs*84), was identified in JUP.– The JUP gene is associated with autosomal dominant arrhythmogenic right ventricular

cardiomyopathy(ARVC) (MedGen UID: 409749) and autosomal recessive Naxos disease (MedGenUID: 321991).

• A Variant of Uncertain Significance, c.10266G>C (p.Gln3422His), was identified in RYR2.– The RYR2 gene is associated with autosomal dominant catecholaminergic polymorphic ventricular

tachycardia (CPVT) (MedGen UID: 351513), arrhythmogenic right ventricular cardiomyopathy (ARVC) (MedGen UID: 318748) and left ventricular noncompaction (LVNC) (PMID: 24394973).

• A Pathogenic variant, c.514C>T (p.Gln172*), was identified in BAG3.– The BAG3 gene is associated with autosomal dominant dilated cardiomyopathy (DCM) (MedGen

UID: 462643), myofibrillar myopathy 6 (MFM6) (MedGen UID: 414119) and Charcot-Marie-Tooth disease type 2 (PMID:28754666)

• A Pathogenic variant, c.1807delG (p.Val603Trpfs*84), was identified in JUP.– The JUP gene is associated with autosomal dominant arrhythmogenic right ventricular

cardiomyopathy(ARVC) (MedGen UID: 409749) and autosomal recessive Naxos disease (MedGenUID: 321991).

• A Variant of Uncertain Significance, c.10266G>C (p.Gln3422His), was identified in RYR2.– The RYR2 gene is associated with autosomal dominant catecholaminergic polymorphic ventricular

tachycardia (CPVT) (MedGen UID: 351513), arrhythmogenic right ventricular cardiomyopathy (ARVC) (MedGen UID: 318748) and left ventricular noncompaction (LVNC) (PMID: 24394973).

• A Pathogenic variant, c.514C>T (p.Gln172*), was identified in BAG3.– The BAG3 gene is associated with autosomal dominant dilated cardiomyopathy (DCM) (MedGen

UID: 462643), myofibrillar myopathy 6 (MFM6) (MedGen UID: 414119) and Charcot-Marie-Tooth disease type 2 (PMID:28754666)

• A Pathogenic variant, c.1807delG (p.Val603Trpfs*84), was identified in JUP.– The JUP gene is associated with autosomal dominant arrhythmogenic right ventricular

cardiomyopathy(ARVC) (MedGen UID: 409749) and autosomal recessive Naxos disease (MedGenUID: 321991).

• A Variant of Uncertain Significance, c.10266G>C (p.Gln3422His), was identified in RYR2.– The RYR2 gene is associated with autosomal dominant catecholaminergic polymorphic ventricular

tachycardia (CPVT) (MedGen UID: 351513), arrhythmogenic right ventricular cardiomyopathy (ARVC) (MedGen UID: 318748) and left ventricular noncompaction (LVNC) (PMID: 24394973).

Anatomy of a Mutation (Variant)

c.20A>T (p.Glu7Val) pathogenic

HBB gene mutation

Location in Coding DNA

DNA Nucleotide change

Location in protein

Protein Amino Acid changeGene

Symbol

pathogenic

Variant (mutation) Interpretation

Pa thogenec i t yBenign Likely Benign

Variant of Uncertain

Significance

Likely Pathogenic Pathogenic

Genet Med. 2015 May;17(5):405-24.

Considerations: Population frequencies, Computational predictions, Biological data, Segregation, de novo variants, Published literature

Looking Ahead

Heart Rhythm, Vol 16, No 11, November 2019

Looking Ahead

European Heart Journal (2019) 40, 19–33

Looking Ahead to Precision Medicine

J A C C V OL . 7 4 , N O . 2 3 , 2 0 1 9

Thank you for your attention

matthew.taylor@cuanschutz.edu