This document discusses various types of cardiomyopathy including hypertrophic cardiomyopathy, dilated cardiomyopathy, and restrictive cardiomyopathy. It describes the genetic causes and mutations involved in each type. For many cardiomyopathies, genetic testing can help with clinical management, guide family screening, and identify individuals who may develop disease later in life. The document also discusses genetic causes of congenital heart disease, channelopathies, and the role of pharmacogenomics in personalized treatment of cardiac conditions.

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