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Adding Genetics to the Cardiologist’s Toolbox
Matthew Taylor MD, PhD: [email protected] 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
