presentazione standard di powerpoint · phenotype gene tests available yield of positive results...
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![Page 1: Presentazione standard di PowerPoint · Phenotype Gene Tests Available Yield of Positive Results Hypertrophic (HCM) MYH7, MYBPC7, TNNT2, TNNI3, TPMI, ACTC, MYL2, MYL3 MYH7, MYBPC3](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22143447b07630856cfc1c/html5/thumbnails/1.jpg)
Cardiomyopathies
Prevalenza: 1/500 – 1/4000
Storia Naturale• variabile• SCC, aritmia, MI, trapianto
Genetica• Forme “Familiare” 20 – 50% • AD, AR, XL, matrilineare• Penetranza correlata all’età
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DCM HCM ARVD MYOC.
N° of pts1184 304 127 117
Mean age (years) 45±15 46±19 37±16 38±16
Males (%) 70 64 69 70
Follow-up (months) 125±83 79±90 139±115 97±67
Years of enrolment 1978-2016 1983-2016 1976-2016 1981-2016
N° Follow-up (approx.)
> 7500 > 1000 700 500
HEART MUSCLE DISEASE REGISTRY OF TRIESTE (UPDATE – 12/2016)
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Arbustini et al.J Am Coll Cardiol 2014;64:304–18
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Elliot et al. European Heart Journal (2008) 29, 270–276
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Hershberger, R. E. et al., Nat. Rev. Cardiol. 2013;10:531–547
The Cardiomyopathies Phenome
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Cardiomyopathies and genetic complexityMutations within the same gene may cause different phenotypes
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DCM genes (n 152; solo varianti P o LP)
TTN; 27
LMNA/c; 7
DES; 4
DMD; 5
FLMNc; 8
OBSL-1; 1DSP; 7
PKP2; 1
DSC2; 1
DSG2; 1
MYBPC3; 7
MYH6; 10
MYH7; 3
ACTC; 1TNNT; 1
RYR2; 1
SCN5a; 6
RMB20; 2
LAMA4; 2
No gene VP; 63
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Phenotype Gene Tests Available Yield of Positive Results
Hypertrophic (HCM)
MYH7, MYBPC7, TNNT2, TNNI3, TPMI, ACTC, MYL2, MYL3
MYH7, MYBPC3 = 60-80% of mutations, TNNT2 = 10-20%. Genetic cause identifiable in 35-45% overall. If family history is positive, 60-65%
Dilated (DCM) LMNA,MYH7, TNNT2, SCN5A, DES, MYBPC3, TNNI3, TPMI, ACTC, PLN, LDB3, TAZ
LMNA = 5.5%, MYH7 = 4.2%, TNNT2 = 2.9%. All data from research cohorts
ARVD/C DSP, PKP2, DSG2, DSC2 DSP = 6-16%, PKP2 = 11-43%, DSG2 = 12-40%
LVNC Uncertain Uncertain
Restrictive Uncertain Uncertain
SPECIFIC GENES AVAILABLE FOR SCREENING BASED
ON CARDIAC PHENOTYPE
Genetic evaluation of cardiomyopathy: HFSA 2010 comprehensive heart failure practice guideline. J Card Fail 2010 Jun;16(6):e180-94.
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Genetic determinants of dilated cardiomyopathy
FDC frequency in DCM
2
7
20
35
4850
0
10
20
30
40
50
60
Fuster et
al, 1981
Mestroni et
al, 1990
Michaels et
al, 1992
Gruenig et
al, 1998
Baig et al,
1998
Gregori,
Mestroni et
al, 2002
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Pedigree
Symptoms
Physicalexam
ECG
Laboratory
Echo
Autosomal dominantAutosomal recessiveX-linkedMatrilinear
, .
Deafness Muscle pains/weakness Paraesthesia
Muscle weaknessPostural hypotensionRash , Ocular
Preexcitationa-v BlockPseudo-infarct pattern
Creatinine kinase , Creatinine/Proteinuria FerritinLactate
Signs of infiltrative/storage diseasesLVNCPresence/distribution of dyskinesiasRV abn
“Red flags approach”
Eur Heart J 2012, Rapezzi et al
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I
II
III
aVR
aVL
aVF
V1 V4
V6V3
V2 V5
A
A 17-year-old asymptomatic man. The father: unexplained left ventricular hypertrophy and received a PM at age 35 for SSS.
DB C
E
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DCM with initial symptomatology characterized by✓ supraventricular arrhythmias,✓ atrioventricular conduction delay✓ and elevated creatine kinase levels. LMNA gene mutation should be considered highly likely.
Patients with DCM and peculiar phenotype characterized by an arrhythmogenic trait
✓supraventricular arrhythmias✓atrial fibrillation✓sick sinus syndrome
SCN5A gene mutations (approximately 2% of patients with DCM)
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CMPD “sindromica”
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JACC 2011;57:2160-8.
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Results:LMNA carriers with MVA: 18%
11 cardiopulmonary resuscitation
25 appropriate ICD treatment
12 SD
4 independent Risk Factors,
cumulative risk:
nonsustained ventricular tachycardia
LVEF < 45%
Male gender
Truncating mutations
Rijsingen et al., J Am Coll Cardiol 2012;59:493–500
LMNA mutations in Dilated Cardiomyopathy
Study design:
multicenter cohort of 269 LMNA mutation carriers
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231
FLNC splicingexon skipping
het het
hethet
DSP non syn Rs200250096
het
Cav3 non syn Rs116840776
het
FAM#225:DCM – Sudden death
DCM; ICD
DCM; FEVsin 45%+ SD “d”
DCM; FEVsin 35%;ICD ”a”
DCM; FEVsin 50%”b”
DCM; FEVsin 48%
DCM; FEVsin 30%+ SD
DCM + SD
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Am Heart Assoc. 2015 Oct 16;4(10):e002149.
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Begay, Sinagra, Mestroni at al
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Ortiz-Genga et al. J Am Coll Cardiol 2016;68:2440–51
Major Cardiovascular Events
In families with truncating FLNC mutations, freedom from sudden death, appropriate defibrillator shock, heart failure death, or heart transplantation in all clinically or genetically affected subjects (A) and discriminated by sex (B) decreased as subjects aged.
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freedom from composite endpoint (HTx and death from cardiac causes)
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Watkins H. NEJM 2011;364:1643-56.
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Genetica CMP
• A chi? forme accertatamentefamiliari per guidare loscreening/idoneità; casi controversimolto selezionati;
• Quando? Nei maggiorenni; casiminorenni molto selezionati;
• Per quale uso? Stratificazioneprognostica; in casi selezionati perorientare la tp con device