high risk of cardiac events in hypertrophic cardiomyopathy

High risk of cardiac events in hypertrophic cardiomyopathy patients with double/compound heterozygosity

Serio A, Pasotti M, Gambarin F, Pilotto A, Serafini E, Diegoli M, Grasso M, Tagliani M, Disabella E, Arbustini E

Centre for Inherited Cardiovascular Diseases

IRCCS Fondazione Policlinico San Matteo, Pavia

Italy

A. Serio -Centre for Inherited Cardiovascular Diseases IRCCS Fondazione Policlinico San Matteo, Pavia

Background

• Hypertrophic Cardiomyopathy (HCM) is caused by mutations of genes coding:– sarcomeric proteins (sarcomeric HCM)

– non sarcomeric proteins (non-sarcomeric HCM)

with considerable genetic heterogeneity and variability in phenotypic

expression.

• Major complications are sudden cardiac death (SCD) and evolution through left ventricular dilatation and dysfunction.


Marian AJ et al. J Mol Cell Cardiol 2001Seidman CE et al. Basic Res Cardiol 1998

Maron BJ. JAMA 2002

Background

• Most HCM are autosomal dominant, associated with a single heterozygous mutation of one disease gene. A minority is associated with double or combined heterozygosity.

• When all known disease genes are systematically screened in consecutive patients, a minority of cases show double/triple or compound heterozygosity.

• The prevalence of these latter cases is still provisional.• Phenocopies (drug toxicity such as chloroquine) may clinically

mimic HCM.


Kwon JB et al. J Clin Reumatol 2010Keating RJ et al. J Am Soc Echocardiogr 2005

Arbustini E et al. Heart 1998Girolami F et al. J Am Coll Cardiol 2010

Background Compound or double heterozygosity

• First implication: genetic screening should systematicallyinclude at least major disease genes

• Second implication: in the families reported by Richard et al.the age of onset, the degree of hypertrophy or the prognosisare related to the number of mutations.

• Compound or double heterozygosity (5%, 4/80 pts) wasassociated with more severe clinical phenotype (more severehypertrophy, more frequent sudden death)

→ CMGCV: genetic diagnosis in families without co-segregationby age is provided as non-conclusive


Richard et al. Eurogene Heart Failure Project. Circulation 2003

Ingles et al, Seidman, J Med Genet 2005

Purpose

• We aimed at determining the prevalence of double or compound heterozygosity in a consecutive series of genotyped families with HCM and analyzing their outcome during a mean follow-up of 87±65 months


Methods

• Population: 495 mutated patients

– 188 unrelated probands

– 307 relatives

(December 2009)

• HCM diagnosis:

– done according to the WHO criteria


Methods

Clinical and instrumental evaluation: • physical examination• ECG• Echocardiography• Holter ECG monitoring• biochemical testing: sCPK, lactic acid, Troponin• neuromyological examination• coronary angiography• electrophysiology study, right catheterization• endomyocardial biopsy (when clinically indicated)


for probands and relatives

Methods

Genetic testing:– genetic testing was performed after counselling and

written informed consent.

– MYH7, MYBPC3, TNNT2, TNNI3, tCAP, MYL2, TPM1, MYH6, MYL3, MYO6, and MYOZ1 were routinely screened, while LAMP2, PRKAG2 and mtDNA were screened in the presence of specific clinical markers

• Patients with Anderson-Fabry disease were excluded.


Results

• Out of the 495 mutated individuals:

– 361 affected (73%)

– 134 healthy carriers (27%)

• The mean age of affected members was significantly higher compared to those of the healthy carriers

34.3 ± 15.2 versus 26.9 ± 15.3 years (p=0.003)


Results• The molecular genetic analysis identified a pathologic

mutation in one of the following disease genes:


MYH7 (137)

MYBPC3 (221)

TNNT2 (29)

TNNI3 (26)

LAMP2 (3)

PRKAG2 (3)

tCAP (10)

MYOZ1 (2)

mtDNA (25)48%

30%

6.4%

5.9% 5.5%2.2%

No.

456

0.7%0.5%

Results

• 39 patients (7%) were found to carry a compound or double heterozygosity.

• Among the patients with double or compound heterozygosity:

– 37 were affected (95%)

– 2 were young healthy carriers (13 and 15 y.o.)


EVENTS IN THE OVERALL GENOTYPED HCM PATIENTSAfter 87±65 months:

79 of 361 (22%) phenotypically affected HCM patients had one of the following events:

12 20 4 43

Results


No.

%

Results


SCD CHF death

HTx ICD shock

ICD shock + HTx

Total number

%

MYH7 5 6 8 2 1 22 16

MYBPC3 11 3 2 7 2 25 11TNNI3 1 1 4 0 1 7 27TNNT2 3 0 0 2 0 5 17

DOUBLE 3 1 5 3 1 13 33LAMP2* 1 0 0 0 0 1 33PRKAG2* 1 0 0 0 0 1 33TCAP 0 0 0 0 0 0 0

MTDNA 2 1 1 2 0 6 31MYOZ1 0 0 0 0 0 0 0

Genes No. %

Double MYBPC3 16 41.1

MYH7+ MYBPC3 11 28.2

MYH7+ mtDNA 6 15.4

MYH7 + double MYBPC3 4 10.2

tCAP + mtDNA 2 5.1

39 patients (7%)

with double or compound heterozygosity

39


Eventsin “healthy mutation carriers”

No. events

Mutated clinically affected 79 in 361 pts (22%)

Healthy carriers 0 in 134 pts (0%)


Conclusions

• The prevalence of double/compound heterozygosity in our series was 7%.

• The rate of complications and malignant evolution was higher in HCM associated with double/compound mutation (higher rate of adverse events in a shorter period of time).


In the clinical practice…

• Male, 42 y.

• Idiopathic DCM (coro -)

• acute heart failure episodes

• ICD implantation

FIRST EXAMPLE: same family, two brothers…

Similar ecg…but different diagnosis

• Male, 46 y.

• HCM

Molecular diagnosisAnalysis of sarcomeric genes for HCM:

MYBPC3 mutation found: Asp228Asn 1Both in the proband and in the younger brother

1 Andersen, Eur J Hum Genet 2004

Family screening:

+ -

- + +

-

An additional known mutation wasfound in mtDNA in the mother and in the three sons

+/- -/+

-/+ +/+ +/+

-/-mtDNA DEFECTS

a. as unique cause of cardiomyopathy

b. as modifier or co-causative of the phenotype

MYH7 ex 22M849C

MYBPC3 ex 18 R597W

GENETIC Analysis

MYH7+MYBPC3 - RELATED FAMILIAL HCM

SECOND EXAMPLE: same family, brother, sister and nephew…

• proband with HCM evoluted in dilated form with LV

dysfunction and CHF, heart transplanted (52 y.)

• mother “with cardiac problems” (HCM?)

• sister with HCM, initial LV dysfunction

• nephew with HCM

FAMILY HISTORY

?

proband

nephew

sister

LV enlargement

LV progressive dysfunction (EF 25%)

Loss of hypertrophy (12 mm)

progressive atrial enlargement

Nephew

EF 50%

Septum 21 mm

Sister

EF 40%

Septum 14 mm

Thank you

high risk of cardiac events in hypertrophic cardiomyopathy

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