ROLE OF Genetics in cardiovascular system

1. Dr. MALLESWARA RAO (DM CARDIOLOGY)

3. CARDIOMYOPATHY
 HYPERTROPHIC CARDIOMYOPATHY (HCM)
 DILATED CARDIOMYOPATHY (DCM)
 RESTRICTIVE CARDIOMYOPATHY (RCM)
 ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY
(ARVC)
 INITIALLY THOUGHT AS IDIOPATHIC

4. HCM

5. Hypertrophic cardiomyopathy
 hallmark -unexplained left ventricular hypertrophy (LVH)
 prevalence - 1:500
 Diagnosis requires exclusion of secondary causes of LVH, such as
hypertension
 aortic stenosis
physiological hypertrophy, as seen in highly trained athletes.

6. HCM
 monogenic disorder -dominant trait
 mutations in genes that encode the protein components of the
cardiac sarcomere
 penetrance is incomplete and lowest at very young ages, which
often delays clinical diagnosis until adolescence or adulthood

7. 8 genes
 β-myosin heavy chain (MYH7)
 α-tropomyosin (TPM1)
 cardiac troponin T (TNNT2)
 cardiac myosin binding protein-C (MYBPC3)
 myosin regulatory light chain (MYL2)
 myosin essential light chain (MYL3)
 cardiac troponin I (TNNI3)
 cardiac α-actin (ACTC1)

9. MUTATIONS

10. CHALLENGES IN INTERPRETING GENETIC TESTING
 genetic heterogeneity (e.g., distinct genes that cause the same
disease)
 allelic variation (distinct mutations in the same gene)
 morphological phenotypes and disease severity-Background
genomic variation, lifestyle, and exposures are other contributory
factors.

12. Genotype-phenotype correlation
 modifying genetic, epigenetic, and environmental factors
 MYH7 - increased risk for sudden cardiac death
 MYBPC3 mutations- presents later in life, and displays less
morbidity and lower penetrance

13. Storage and metabolic cardiomyopathies
mimicking GCM -phenocopies
 cytoplasmic vacuoles that contain lipid (GLA mutations), lysosomal
remnants (LAMP2 mutations), and glycogen
(PRKAG2 and GAA mutations).

14. Gene-based diagnosis- appropriate management
 PRKAG2 cardiomyopathy –require monitoring due to the high
incidence of conduction defects.
 LAMP2 mutations -requires early heart transplantation.
 GLA mutations ( Fabry disease ) -early treatment with enzyme
replacement therapy .

15. Dilated Cardiomyopathy
 ventricular chamber enlargement and systolic dysfunction
 50% of non-ischemic DCM has no identifiable etiology - genetic
causes are increasingly identified.
 prevalence of unexplained DCM at 1:2,500

17. Dilated cardiomyopathy
 Genes involved in force generation, force transmission, sarcomere integrity,
cytoskeletal and nuclear architecture, electrolyte homeostasis, mitochondrial
function, and transcription
 most - AD
 few - AR, X-linked, and matrilineal inheritance.
 age-dependent penetrance,
 clinical expression may be delayed until after the fifth or sixth decade
 penetrance can be incomplete
 genetic heterogeneity
 low sensitivity for detection of pathogenic mutations.
 Next-generation sequencing -should substantially increase mutation detection

19. Role of Genetic Testing in cardiomyopathy
 Improve clinical management
 Eliminates ambiguities associated with phenotypic variation (i.e., mild
ventricular remodeling in a competitive athlete),
 Guide the use of emerging therapies that target the biophysical
consequences associated with mutations
 Cost-effective screening of first-degree family members and eliminates
healthcare expenditures for relatives without pathogenic mutations
 Family screening -important with children and adolescents who may not
yet have manifested clinical features of disease, but who may be at risk
for sudden death

20. Interpreting genetic testing
 identification of a definitively pathogenic mutation
 identification of a probable pathogenic mutation, but additional
evidence, such as familial cosegregation or confirmatory data in
unrelated affected patients, is necessary
 identification of a variant of unknown significance (VUS)
 specificity is low and overall accuracy is only ∼65% to 80% for
predicting pathogenicity

21. The genotype-positive phenotype-negative individual
 Genotype-positive phenotype-negative individuals -require
continued clinical screening
 Often these individuals are younger than the typical age at which
clinical disease is recognized
 complexities of managing these individuals
 Longitudinal study of genotype-positive phenotype-negative
individuals provides the unique opportunity to study the natural
history of disease, including phenotype conversion.

22. CARDIOMYOPATHY

23. CONGENITAL HEART DISEASE
 occurs in association with other anomalies (25 to 40%) or as
isolated problem
 Aneuploidy, or abnormal chromosomal -accounts for a significant
proportion of CHD
 55 genes -identified
 same heart defect phenotype show strong familial clustering, with
relative risks of recurrence of 3-fold to 80-fold in first-degree
relatives.

24. Chromosomal anomalies
 50% with Trisomy 21 have CHD
 80% of Trisomy 13
 Trisomy 18- nearly all will have CHD,
 One third of females with Turner -CHD.
 Klinefelter syndrome, or 47, XXY- 50% have CHD
 22q11.2 deletion (DiGeorge Syndrome)- dysmorphic facies
 7q11.23 deletion(Williams-Beuren Syndrome)

25.  conventional karyotype
 fluorescence in situ hybridization (FISH)

26. SINGLE GENE MUTATIONS

29. FETAL GENETICS
 Fetal cells are obtained from amniotic fluid or chorionic villus
biopsy.
 fetuses in whom CHD -genetic testing
 fetal echocardiography -indicated when a
chromosomalabnormality is diagnosed due to other reasons.

30. Familial Hypercholesterolemia
 1 in 500
 identification of pathogenic mutations in probands -utmost
importance in pediatric and adolescent family members, in which
the clinical criteria may not be well defined,
 LDLR, ApoB, PCSK9
 AD transmission

32. Phytosterolemia
 abnormal absorption of sterols, especially those of plant origin
 premature coronary atherosclerosis,
 hemolytic anemia and/or liver disease
 ABCG5 and ABCG8

34. Genes Associated with Triglyceride Metabolism Alterations
 APOA5 gene variants
 APOA5, APOC2, APOE
 LPL

35. Genes related with HDL-c levels
 APOA1 -familial hypoalphalipoproteinemia, AD
 ABCA1 gene-Tangier disease, AR.
 LCAT genes-fish-eye disease

36. Statin-induced myopathy
 1 to 10%
 CYP2D6, PPARA, SLC22A8 and SLCO1B1.

37. Heritable PAH (HPAH)
 (1) belong to a family known to have documented PAH in 2 or more
individuals; or
 (2) mutation in a gene known to strongly associate with PAH
 Many subjects with HPAH do not have a known family history.
 mutations in the bone morphogenic protein receptor type 2 (BMPR2) -AD
 reduced penetrance, variable expressivity, and female predominance -
genetic, genomic and other factors modify disease expression.
 EIF2AK4 -AR
 misclassified IPAH
 BMPR2 mutation PAH patients are diagnosed and die approximately 10
years earlier than PAH patients without mutation,unlikely to respond to
acute vasodilator testing

38. CHANNELOPATHIES

39. Sudden cardiac death
 ≈5% to 15% --No evidence of structural abnormalities at autopsy
 Initially considered idiopathic
 now known to have a genetic basis
 mutations in genes primarily encoding ion channels
 Heterogeneous -mutations in different genes.

41. LQTS-Long QT Syndrome
 Isolated or with extracardiac manifestations
 Jervell and Lange Nielsen syndrome- congenital deafness
 Andersen-Tawil syndrome- facial dysmorphisms and hypokalemic
periodic paralysis
 Timothy syndrome-syndactyly, developmental disorders/autism
spectrum disorders
 AD - Romano-Ward syndrome

43.  mutations in the first 3 genes identified in the early 1990s
(KCNQ1, KCNH2, and SCN5A) -80%–90% of patients.
 incomplete penetrance
 Genetic testing
guide the management of mutation
 risk stratification
 Each of these genetic variants has typical trigger for arrhythmic
events, and a variable respons to β-blockers

44. trigger response
LQT1 EXERCISE , SWIMMING BEST RESPONSE TO BETA BLOCKERS
LQT2 LOUD NOISE, SUDDEN
AWAKENING
PARTIAL RESPONSE TO BETA BLOCKERS
LQT3 SLEEP NO RESPONSE TO B BLOCKERS, a+ channel
blockers are useful

45. OTHER CHANELLOPATIES

46. BRUGADA SYNDROME
 Sudden cardiac death at rest, with fever, after meal
 Loss-of-function mutations of SCN5A >>CACNA1c and CACNB2
 no more than 30% -positive for a disease-causing mutations
 genetic testing cannot guide therapeutic decisions , limited for
family screening

47. Short-QT Syndrome
 Mutations in 6 genes –still account for only a few
 no single gene accounts for >5% of cases
 value of genetic testing – limited except for family screening

48. Catecholaminergic polymorphic ventricular tachycardia (CPVT)
 mutations of ryanodine receptor (RyR2) -AD
 calsequestrin (CASQ2)-AR
 genotyping -screening to family members
 protect mutation carriers with β-blockers

50. Pharmacogenomics
 study of genetic variations that influence individual’s response to
drugs.
 More personalized approaches.
 Fewer Side effects

54. Variation in response to Clopidogrel
 genetic variability in the Cytochrome P450- 2C19 gene (CYP2C19
gene)
 more than 33 alleles

55. PHARMACOGENETICS

56. Vitamin K antagonist
 Dosage is difficult to predict and frequent monitoring is necessary
because of wide inter-patient variability.

59. TAKE HOME MESSAGE
 Genetics become important tool to study and understand the
aetiology, pathogenesis, and development and family
screening of various cardiac gisease
 pharmacogenomics are expected to optimize therapy and
reduce toxicity through genetically guided individualized
therapy

60. THANK YOU